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. 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. 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. 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.

To assess whether concomitant antipsychotic treatment has an influence on the antidepressive effects of repetitive transcranial magnetic stimulation (rTMS). 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. 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. 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.

The prevalence of depressive illness and its devastating personal, social and economic impact are well known. While a considerable number of patients benefit well from pharmacotherapy and psychothe...

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.

Introduction: The effect of concomitant medication on repetitive transcranial magnetic stimulation (rTMS) outcomes in depression remains understudied. Recent analyses show attenuation of rTMS effects by antipsychotic medication and benzodiazepines, but data on the effects of antiepileptic drugs and lithium used as mood stabilizers or augmenting agents are sparse despite clinical relevance. Preclinical electrophysiological studies suggest relevant impact of the medication on treatment, but this might not translate into clinical practice. We aimed to investigate the role of lithium (Li), lamotrigine (LTG) and valproic acid (VPA) by analyzing rTMS treatment outcomes in depressed patients.Methods: 299 patients with uni- and bipolar depression treated with rTMS were selected for analysis in respect to intake of lithium, lamotrigine and valproic acid. The majority (n = 251) were treated with high-frequency (10–20 Hz) rTMS of the lDLPFC for an average of 17 treatment sessions with a figure-of-8 coil with a MagVenture system aiming for 110% resting motor threshold, and smaller groups of patients were being treated with other protocols including intermittent theta-burst stimulation and bilateral prefrontal and medial prefrontal protocols. For group comparisons, we used analysis of variance with the between-subjects factor group or Chi-Square Test of Independence depending on the scales of measurement. For post-hoc tests, we used least significant difference (LSD). For differences in treatment effects between groups, we used an ANOVA with the between-subjects factor group (groups: no mood stabilizer, Li, LTG, VPA, Li + LTG) the within-subjects factor treatment (pre vs. post treatment with rTMS) and also Chi-Square Tests of independence for response and remission.Results: Overall, patients showed an amelioration of symptoms with no significant differences for the main effect of group and for the interaction effect treatment by group. Based on direct comparisons between the single groups taking mood stabilizers against the group taking no mood stabilizers, we see a superior effect of lamotrigine, valproic acid and combination of lithium and lamotrigine for the response and remission rates. Motor threshold was significantly and markedly higher for patients taking valproic acid.Conclusion: Being treated with lithium, lamotrigine and valproic acid had no relevant influence on rTMS treatment outcome. The results suggest there is no reason for clinicians to withhold or withdraw these types of medication from patients who are about to undergo a course of rTMS. Prospective controlled work on the subject is encouraged.