Monitoring Changes in TMS-Evoked EEG and EMG Activity During 1†Hz rTMS of the Healthy Motor Cortex.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique capable of inducing neuroplasticity as measured by changes in peripheral muscle electromyography (EMG) or electroencephalography (EEG) from pre-to-post stimulation. However, temporal courses of neuromodulation during ongoing rTMS are unclear. Monitoring cortical dynamics via TMS-evoked responses using EMG (motor-evoked potentials; MEPs) and EEG (transcranial-evoked potentials; TEPs) during rTMS might provide further essential insights into its mode of action - temporal course of potential modulations. The objective of this study was to first evaluate the validity of online rTMS-EEG and rTMS-EMG analyses, and second to scrutinize the temporal changes of TEPs and MEPs during rTMS. As rTMS is subject to high inter-individual effect variability, we aimed for single-subject analyses of EEG changes during rTMS. Ten healthy human participants were stimulated with 1,000 pulses of 1 Hz rTMS over the motor cortex, while EEG and EMG were recorded continuously. Validity of MEPs and TEPs measured during rTMS was assessed in sensor and source space. Electrophysiological changes during rTMS were evaluated with model fitting approaches on a group- and single-subject level. TEPs and MEPs appearance during rTMS was consistent with past findings of single pulse experiments. Heterogeneous temporal progressions, fluctuations or saturation effects of brain activity were observed during rTMS depending on the TEP component. Overall, global brain activity increased over the course of stimulation. Single-subject analysis revealed inter-individual temporal courses of global brain activity. The present findings are in favor of dose-response considerations and attempts in personalization of rTMS protocols.

Treating depression at home with transcranial direct current stimulation: a feasibility study.

Introduction: Treating major depressive disorder (MDD) with transcranial direct current stimulation (tDCS) devices at home has various logistic advantages compared to tDCS treatment in the clinic. However, preliminary (controlled) studies showed side effects such as skin lesions and difficulties in the implementation of home-based tDCS. Thus, more data are needed regarding the feasibility and possible disadvantages of home-based tDCS. Methods: Ten outpatients (23-69 years) with an acute depressive episode were included for this one-arm feasibility study testing home-based tDCS. All patients self-administered prefrontal tDCS (2 mA, 20 min, anodal left, cathodal right) at home on 30 consecutive working days supported by video consultations. Correct implementation of the home-based treatment was analyzed with tDCS recordings. Feasibility was examined by treatment compliance. For additional analyses of effectiveness, three depression scores were used: Hamilton depression rating scale (HDRS-21), Major Depression Inventory (MDI), and the subscale depression of the Depression-Anxiety-Stress Scale (DASS). Furthermore, usability was measured with the user experience questionnaire (UEQ). Tolerability was analyzed by the number of reported adverse events (AEs). Results: Eight patients did not stick to the protocol. AEs were minimal. Four patients responded to the home treatment according to the MDI. Usability was judged positive by the patients. Conclusions: Regular video consultations or other safety concepts are recommended regardless of the number of video sessions actually conducted. Home-based tDCS seems to be safe and handy in our feasibility study, warranting further investigation.

Deep brain stimulation for treatment resistant obsessive compulsive disorder; an observational study with ten patients under real-life conditions.

Introduction: Obsessive-compulsive disorder (OCD) affects 2-3% of the global population, causing distress in many functioning levels. Standard treatments only lead to a partial recovery, and about 10% of the patients remain treatment-resistant. Deep brain stimulation offers a treatment option for severe, therapy-refractory OCD, with a reported response of about 60%. We report a comprehensive clinical, demographic, and treatment data for patients who were treated with DBS in our institution. Methods: We offered DBS to patients with severe chronic treatment resistant OCD. Severity was defined as marked impairment in functioning and treatment resistance was defined as non-response to adequate trials of medications and psychotherapy. Between 2020 and 2022, 11 patients were implanted bilaterally in the bed nucleus of stria terminalis (BNST). Patients were evaluated with YBOCS, MADRS, GAF, CGI, and WHOQOL-BREF. We performed the ratings at baseline (before surgery), after implantation before the start of the stimulation, after reaching satisfactory stimulation parameters, and at follow-up visits 3, 6, 9, and 12 months after optimized stimulation. Results: One patient has retracted his consent to publish the results of his treatment, thus we are reporting the results of 10 patients (5 males, 5 females, mean age: 37 years). Out of our 10 patients, 6 have shown a clear response indicated by a YBOCS-reduction between 42 and 100 percent at last follow-up. One further patient experienced a subjectively dramatic effect on OCD symptoms, but opted afterwards to stop the stimulation. The other 3 patients showed a slight, non-significant improvement of YBOCS between 8.8 and 21.9%. The overall mean YBOCS decreased from 28.3 at baseline to 13.3 (53% reduction) at the last follow-up. The improvement of the OCD symptoms was also accompanied by an improvement of depressive symptoms, global functioning, and quality of life. Conclusion: Our results suggest that BNST-DBS can be effective for treatment-resistant OCD patients, as indicated by a reduction in symptoms and an overall improvement in functioning. Despite the need for additional research to define the patients' selection criteria, the most appropriate anatomical target, and the most effective stimulation parameters, improved patient access for this therapy should be established.

Effectiveness of Repetitive Transcranial Magnetic Stimulation in the Treatment of Depression in the Elderly: A Retrospective Natural Analysis.

INTRODUCTION: Depression in the elderly is an understudied condition. Psychopharmacological and psychotherapeutic approaches suffer from specific difficulties with this patient group. Brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a therapeutic alternative. rTMS remains understudied in this age group when compared with younger patients. METHODS: A cohort of 505 patients with depression was analyzed in retrospect concerning their response to rTMS treatment. A total of 15.5% were 60 years old or older, defined as the elderly group of depressed patients. The majority of these were treated with high-frequency protocols over the left dorsolateral prefrontal cortex (DLPFC). For group comparisons, we used Student t-tests or chi-square-tests, depending on the scales of measurement. As measures for effect size, we used Cohen's d for the relative and absolute change in the HDRS total score. RESULTS: Groups did not differ significantly with respect to baseline depression severity or treatment parameters. In the group of elderly patients, a higher number of females were present. Groups did not differ significantly with respect to treatment efficacy, as indicated by the absolute and relative changes in the HDRS-21 sum score. Elderly patients tended to take higher numbers of mood stabilizers. Elderly patients showed a significantly superior reduction for the item "appetite" and a superior reduction tending towards significance for the item "work and interests". CONCLUSIONS: Antidepressant rTMS treatment showed comparable efficacy for patients above 60 years to that in younger patients. Differences between the age groups concerning amelioration of distinct HDRS single items deserve further investigation.

Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

Activate & fire: a feasibility study in combining acoustic stimulation and continuous theta burst stimulation in chronic tinnitus.

BACKGROUND: Low frequency repetitive transcranial magnetic stimulation (rTMS) is commonly used to inhibit pathological hyperactivity of the auditory cortex in tinnitus. Novel and supposedly superior and faster inhibitory protocols such as continuous theta burst stimulation (cTBS) were examined as well, but so far there is not sufficient evidence for a treatment application in chronic tinnitus. rTMS effects in general are dependent on the brain state immediate before stimulation. This feasibility study was designed based on the concept to shift the pathological intrinsic brain state of tinnitus patients via acoustic stimulation ("activate") and induce inhibitory effects via cTBS ("fire"). METHODS: Seven tinnitus patients with response in residual inhibition received 10 consecutive daily sessions of a combinatory treatment comprised of 3-minute acoustic stimulation with white noise followed by 600 pulses of cTBS over the left temporo-parietal cortex (activate & fire). A control group of 5 patients was treated parallel to the activate & fire data collection with 10 sessions á 3000 pulses of 1 Hz rTMS over the left temporo-parietal cortex. RESULTS: The activate & fire protocol was well tolerated except in one patient with tinnitus loudness increase. This patient was excluded from analyses. No statistical superiority of the activate & fire treatment approach in alleviating tinnitus-related symptoms was evident. Power calculations showed an effect size of 0.706 and a needed sample size of 66 for statistical significant group differences. On a descriptive level the activate & fire group demonstrated a stronger decrease in tinnitus-related symptoms. CONCLUSION: The present feasibility study showed that combining acoustic stimulation with magnetic brain stimulation may be well-tolerable in the majority of patients and represents a promising treatment approach for tinnitus by hypothetically alter the intrinsic state prior to brain stimulation.

One way or another: Treatment effects of 1 Hz rTMS using different current directions in a small sample of tinnitus patients.

INTRODUCTION: So far studies on the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for tinnitus are inconclusive. Two large scale placebo-controlled randomized clinical trials (RCT) examined the efficacy of low frequency temporal cortex rTMS and report different findings. As the used TMS devices differ in their used primary current direction by default, this technical parameter was speculated as a potential reason for the observed incongruences in tinnitus-related outcomes. The aim of the present pilot study was to investigate the treatment effect of 1 Hz rTMS using two different current flows. MATERIALS AND METHODS: Nine tinnitus patients were treated in two different groups each comprised of 10 treatment sessions á 3000 biphasic pulses of 1 Hz rTMS applied over the left temporo-parietal cortex using either an anterior-posterior to posterior-anterior (AP-PA) or posterior-anterior to anterior-posterior (PA-AP) induced current flow. RESULTS: 1 Hz rTMS with a primary posterior-anterior to anterior-posterior (PA-AP) current flow caused a superior reduction in tinnitus-related symptoms, particularly tinnitus unpleasantness, loudness and tinnitus-related distress. CONCLUSIONS: The present pilot study demonstrated that the technical TMS parameter current direction might be essential for the efficacy of rTMS as a treatment for tinnitus. Systematic investigations of technical TMS parameters like current direction in larger samples of tinnitus patients are highly needed.

Effectiveness of Repetitive Transcranial Magnetic Stimulation in the Treatment of Bipolar Disorder in Comparison to the Treatment of Unipolar Depression in a Naturalistic Setting.

Repetitive transcranial magnetic stimulation (rTMS) is effective in the treatment of depression. However, for the subset of patients with bipolar disorder, less data is available and overall strength of evidence is weaker than for its use in unipolar depression. A cohort of 505 patients (of which 46 had a diagnosis of bipolar disorder) with depression who were treated with rTMS were analyzed retrospectively with regards to their response to several weeks of treatment. Hamilton Depression Rating Scale (HDRS) was assessed as main outcome. Unipolar and bipolar patients with depression did not differ significantly in baseline demographic variables or severity of depression. Both groups did not differ significantly in their response to treatment as indicated by absolute and relative changes in the HDRS and response and remission rates. On HDRS subitem-analysis, bipolar patients showed superior amelioration of the symptom "paranoid symptoms" in a statistically significant manner. In conclusion, depressed patients with a diagnosis of bipolar disorder benefit from rTMS in a similar fashion as patients with unipolar depression in a naturalistic setting. rTMS might be more effective in reducing paranoia in bipolar than in unipolar patients.

Personalization of Repetitive Transcranial Magnetic Stimulation for the Treatment of Chronic Subjective Tinnitus.

BACKGROUND: Personalization of repetitive transcranial magnetic stimulation (rTMS) for tinnitus might be capable to overcome the heterogeneity of treatment responses. The assessment of loudness changes after short rTMS protocols in test sessions has been proposed as a strategy to identify the best protocol for the daily treatment application. However, the therapeutic advantages of this approach are currently not clear. The present study was designed to further investigate the feasibility and clinical efficacy of personalized rTMS as compared to a standardized rTMS protocol used for tinnitus. METHODS: RTMS personalization was conducted via test sessions and reliable, sham-superior responses respectively short-term reductions in tinnitus loudness following active rTMS protocols (1, 10, 20 Hz, each 200 pulses) applied over the left and right temporal cortex. Twenty pulses at a frequency of 0.1 Hz served as a control condition (sham). In case of a response, patients were randomly allocated to ten treatment sessions of either personalized rTMS (2000 pulses with the site and frequency producing the most pronounced loudness reduction during test sessions) or standard rTMS (1 Hz, 2000 pulses left temporal cortex). Those participants who did not show a response during the test sessions received the standard protocol as well. RESULTS: The study was terminated prematurely after 22 patients (instead of 50 planned) as the number of test session responders was much lower than expected (27% instead of 50%). Statistical evaluation of changes in metric tinnitus variables and treatment responses indicated only numerical, but not statistical superiority for personalized rTMS compared to standard treatment. CONCLUSIONS: The current stage of investigation does not allow for a clear conclusion about the therapeutic advantages of personalized rTMS for tinnitus based on test session responses. The feasibility of this approach is primarily limited by the low test session response rate.

Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression.

INTRODUCTION: 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. METHODS: 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. FINDINGS: 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.

Heading for Personalized rTMS in Tinnitus: Reliability of Individualized Stimulation Protocols in Behavioral and Electrophysiological Responses.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool potentially modulating pathological brain activity. Its clinical effectiveness is hampered by varying results and characterized by inter-individual variability in treatment responses. RTMS individualization might constitute a useful strategy to overcome this variability. A precondition for this approach would be that repeatedly applied protocols result in reliable effects. The condition tinnitus provides the advantage of immediate behavioral consequences (tinnitus loudness changes) after interventions and thus offers an excellent model to exemplify TMS personalization. OBJECTIVE: The aim was to investigate the test-retest reliability of short rTMS stimulations in modifying tinnitus loudness and oscillatory brain activity as well as to examine the feasibility of rTMS individualization in tinnitus. METHODS: Three short verum (1, 10, 20 Hz; 200 pulses) and one sham (0.1 Hz; 20 pulses) rTMS protocol were administered on two different days in 22 tinnitus patients. Before and after each protocol, oscillatory brain activity was recorded with electroencephalography (EEG), together with behavioral tinnitus loudness ratings. RTMS individualization was executed on the basis of behavioral and electrophysiological responses. Stimulation responders were identified via consistent sham-superior increases in tinnitus loudness (behavioral responders) and alpha power increases or gamma power decreases (alpha responders/gamma responders) in accordance with the prevalent neurophysiological models for tinnitus. RESULTS: It was feasible to identify individualized rTMS protocols featuring reliable tinnitus loudness changes (55% behavioral responder), alpha increases (91% alpha responder) and gamma decreases (100% gamma responder), respectively. Alpha responses primary occurred over parieto-occipital areas, whereas gamma responses mainly appeared over frontal regions. On the contrary, test-retest correlation analyses per protocol at a group level were not significant neither for behavioral nor for electrophysiological effects. No associations between behavioral and EEG responses were found. CONCLUSION: RTMS individualization via behavioral and electrophysiological data in tinnitus can be considered as a feasible approach to overcome low reliability at the group level. The present results open the discussion favoring personalization utilizing neurophysiological markers rather than behavioral responses. These insights are not only useful for the rTMS treatment of tinnitus but also for neuromodulation interventions in other pathologies, as our results suggest that the individualization of stimulation protocols is feasible despite absent group-level reliability.

A direct comparison of neuronavigated and non-neuronavigated intermittent theta burst stimulation in the treatment of depression.

OBJECTIVE: To investigate whether a four-week course of neuronavigated intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is superior to the non-neuronavigated F3-EEG method of positioning. METHODS: We conducted a single-center, two-arm, randomized and double-blinded study (clinicaltrials.gov NCT03953521). 37 inpatients with an at least moderate depressive episode were randomized to receive either neuronavigated or 10-20-EEG-system based F3 guided iTBS. Both groups received twenty week daily sessions of iTBS while continuing to receive standard-of-care treatment by their ward physicians. For navigated iTBS, we used magnetic resonance imaging to target the border between the anterior and middle third of the middle frontal gyrus considered to represent the left dorsolateral prefrontal cortex (lDLPFC). Differences in the treatment arms were blinded by completely mimicking the procedures of the respective other treatment group. Rating physicians were not involved in the treatment procedure. Primary outcome was defined as the change of the 21-item version of the Hamilton Depression Score (HAMD) from baseline to end of treatment at week 4. Secondary outcomes included HAMD score during the treatment, Patient Health Questionnaire-9, WHO Quality of Life-BREF and Clinical Global Impression. For primary outcome, we used a planned group comparison for the absolute change in the HAMD. For secondary outcome measures we calculated analyses of variance (ANOVAs) with the within-subjects factor time (primary: baseline vs. week 4; secondary: all visits) and the between-subjects factor group (navigated vs. F3 guided group). We also did planned contrasts between both groups for all variables and all treatment and follow-up visits with the aim not to oversee any group differences. For group contrasts we used Student T-tests for metric and chi-square tests for categorial variables. Significance threshold was set to 5% uncorrected for multiple comparisons. RESULTS: Enrolment of 80 patients with interim analysis was planned. Interim analysis was performed after 37 patients (intention to treat). 6 patients dropped out, leaving 31 for analysis. With respect to primary outcome criteria, absolute change in the HAMD did not differ significantly between groups. In accordance, relative change and number of responders and remitters were not significantly different. Overall number of responders was 53% and of remitters was 60%. On a descriptive level, the results favor the clinical effects of the F3 group for the absolute and relative change in the HAMD and the number of responders. Number of remitters were exactly the same for both groups. Therefore, we decided to stop the trial due to the added burden of magnetic resonance imaging and neuronavigated treatment in relation to the effect. Secondary outcomes did also not differ significantly between groups. Patients did not differ in their baseline characteristics nor with respect to intake of medication during the trial period and all had access to the same therapeutic interventions. CONCLUSION: We noticed a high antidepressive effect of add-on iTBS treatment to standard inpatient treatment but failed to demonstrate a clinical superiority of neuronavigated localization. The non-navigated, F3 guided iTBS treatment used as a control group may be sophisticated enough to dilute potential added benefits, and the difference between the localization approaches is either negligible or too small to justify the additional efforts of navigation. The effects of concomitant treatment may mask effects, but our patient population reflects clinical reality in an inpatient setting. Further prospective studies are warranted to compare neuronavigated with surface-based approaches.

Attenuation of antidepressive effects of transcranial magnetic stimulation in patients whose medication includes drugs for psychosis.

OBJECTIVE: To assess whether concomitant antipsychotic treatment has an influence on the antidepressive effects of repetitive transcranial magnetic stimulation (rTMS). METHODS: We analyzed severity of depression before and after treatment with rTMS in a sample of 299 depressed in- and outpatients in retrospect in relation to treatment with drugs for psychosis. The sample consisted of real-life patients in a tertiary hospital. We ran group contrasts between the group taking and the group not taking drugs for psychosis, testing for differences in Hamilton Depression Rating Scale (HDRS). Effect sizes for HDRS group contrasts were reported as Cohen's d and number needed to treat (NNT) calculated from d. To control for group differences we repeated the Student t-tests for the change in the HDRS using analysis of covariance including confounding variables. RESULTS: Depressed patients taking drugs for psychosis showed significantly less amelioration of depressive symptoms after rTMS treatment as measured by absolute and relative change in HDRS with small effect size or NNT of 4.5 to 8.4, respectively. Controlling significant group contrasts revealed that the effect of taking drugs for psychosis does not depend on age, number of applied TMS pulses, type or severity of depression at baseline, comorbidities or differences in the intake of additional medication. CONCLUSION: Drugs for psychosis attenuate antidepressive effects of rTMS independently of confounding factors. The effect is statistically significant and of potentially great clinical importance. The exact mechanism remains to be elucidated and further studies are warranted.

Transcranial magnetic stimulation in the treatment of depression during pregnancy: a review.

The aim of this study is to elucidate the role of repetitive transcranial magnetic stimulation (rTMS) for treating depression during pregnancy. The treatment of depression in pregnant women poses a number of therapeutic challenges. Psychotherapy can be beneficial but is associated with limited availability and possibly an onset of effect which may be too long to be acceptable. Pharmacotherapy is limited by concerns of fetotoxicity, both real and possibly exaggerated in the view of patients and caregivers alike. While efficacy and safety of rTMS are well established for the treatment of depression, the available data for use in pregnancy is still sparse. We reviewed the available literature on the topic on PubMed. In addition to a number of case reports, three studies concerning the treatment of depressed pregnant women with rTMS are available. According to the data, rTMS seems to be safe for both the pregnant woman and her unborn offspring. No obstetric complications or adverse postnatal effects on development have been reported. rTMS alleviated depressive symptoms better than sham treatment in one study. rTMS seems to be safe and effective in treating depression in pregnant women. Further studies with larger numbers of participants are warranted to further clarify the significance of rTMS for the treatment of depression in pregnancy.

Anti-Suicidal Efficacy of Repetitive Transcranial Magnetic Stimulation in Depressive Patients: A Retrospective Analysis of a Large Sample.

Background: Suicide is a major public health problem. About 90% of suicide victims have one or more major psychiatric disorder, with a reported 20-fold increased risk for suicide in patients with affective disorders in comparison with healthy subjects. Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective alternative or adjunctive treatment option for patients with depressive disorders, but little is known about its effects on suicide risk. Objective: For the assessment of the effectiveness of rTMS on suicidal ideation and behaviors, we performed a retrospective analysis of a large sample of patients with depressive disorders, who were treated with rTMS. Methods: We analyzed the records of 711 TMS in- and out-patients with depressive affective disorders in a tertiary referral hospital between 2002 and 2017. Out of these patients we were able to collect Hamilton depression rating scale (HAMD) data of 332 patients (180 females, 152 males; age range 20 to 79 years; mean age 47.3 ± 12.3) for which we analyzed the change of suicidal ideation by using item 3 (suicidality) of HAMD. Results: Out of all 711 patients treated with rTMS for their depression, one patient (0.1%) committed suicide during the TMS treatment. In the statistical analysis of the subsample with 332 patients there was an overall amelioration of depressive symptoms accompanied by a significant decrease in the suicidality item with a medium effect size. Decrease in suicidality was not inferior to changes in other items as indicated by effect sizes. Forty-seven percent of patients showed an amelioration in suicidality, 41.3% of patients did not show a change in their suicidality's scores, and 11.7% of patients showed an increase in suicidality's scores from baseline to final rating. Correlation of item 3 (suicidality) and item 7 (drive) demonstrated a significant positive association, revealing improved drive with a parallel decreased suicidality. Conclusion: Based on the proposed data, there is no evidence that rTMS increases the risk for suicide during the course of the treatment. Conversely, rTMS tends to reduce suicidal ideation. Our findings call for further rTMS controlled studies using large sample sizes and specific suicidality assessment measures to obtain more conclusive results.

Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1.

The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2-/-) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol. When challenged with a HFD, wild type and SNTA/B2-/- mice have similar weight gain, adiposity, serum and liver triglycerides. Hepatic ABCA1, serum insulin and insulin sensitivity are normal while glucose tolerance is impaired. Liver cholesterol is reduced, and expression of SREBP2 and HMG-CoA-R is increased in the knockout mice. Scavenger receptor-BI (SR-BI) protein is strongly diminished in the liver of SNTA/B2-/- mice while SR-BI binding protein NHERF1 is not changed and PDZK1 is even induced. Knock-down of SNTA, SNTB2 or both has no effect on hepatocyte SR-BI and PDZK1 proteins. Further, SR-BI levels are not reduced in brown adipose tissue of SNTA/B2-/- mice excluding that syntrophins directly stabilize SR-BI. SR-BI stability is regulated by MAPK and phosphorylated ERK2 is induced in the liver of the knock-out mice. Blockage of ERK activity upregulates hepatocyte SR-BI showing that increased MAPK activity contributes to low SR-BI. Sphingomyelin which is well described to regulate cholesterol metabolism is reduced in the liver and serum of the knock-out mice while the size of serum lipoproteins is not affected. Current data exclude a major function of these syntrophins in ABCA1 activity and insulin release but suggest a role in regulating glucose uptake, ERK and SR-BI levels, and sphingomyelin metabolism in obesity.

Lipidomic analysis of the liver from high-fat diet induced obese mice identifies changes in multiple lipid classes.

Fatty liver is closely associated with obesity and sensitizes the liver to further insults. The aims of the current study are (1) to identify lipid species changed in rodent fatty liver, (2) to analyze for possible associations of these lipids with triglycerides, cholesterol or CXCL8 which is elevated in the steatotic liver and (3) to find out whether systemic levels of these lipids are concordantly altered. Lipidomic analysis has confirmed an already reported reduction of phosphatidylcholine in the steatotic liver. Phosphatidylserine is lower and phosphatidylethanolamine tends to be diminished. Sphingomyelin levels are normal while monounsaturated ceramides and hexosylceramides are reduced. Sixteen of the 20 fatty acid species measured in the total lipid fraction are elevated while α-linolenic acid is diminished. Of note, medium chain saturated fatty acids are markedly decreased. Plasmalogen 18:0 and 18:1 species are strongly increased in the steatotic liver. None of the markedly changed individual lipid species strongly correlates with hepatic CXCL8 mRNA, triglycerides or cholesterol. About 60% of the lipids altered in fatty liver are congruently altered in serum. These data show that there are multiple changes in lipid composition in fatty liver and part of the lipids may be monitored by serum analysis.