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In depression (MDD) treatment there is a clear need for novel treatments, biomarkers and individualized treatment approaches. One of the most promising and most widely investigated biomarkers for antidepressant treatments is the EEG. Most EEG biomarkers however, still lack robustness and reproducibility and suffer significant publication bias as highlighted in a recent meta-analysis (Widge et al., 2018). Therefore, large controlled validation studies are needed with a focus on robustness, replication and clinical relevance. In this presentation resultswill be presented from the largest EEG Biomarker study to date, the international Study to Predict Optimized Treatment in Depression (iSPOT-D), where 1008 MDD patients were randomized to Escitalopram, Sertraline and Venlafaxine. Drug-class specific (Arns et al., 2016) and drug-specific (Arns, Gordon & Boutros, 2015) biomarkers will be highlighted as well as preliminary data from a prospective feasibility trial. Furthermore, data will be presented on repetitive Transcranial Magnetic Stimulation (rTMS) treatment in MDD on EEG and clinical predictors (Krepel et al., 2018; 2019) and a new method called Neuro-Cardiac-Guided TMS (NCG TMS), that exploits network connectivity in the frontal vagal pathway, as a target engagement approach (Iseger et al., 2019). Finally, clinical implications and implementations will be discussed from a 'treatment stratification' perspective, which might be a more realistic goal relative to 'personalized medicine' perspective. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate if biomarkers in QEEG, genetic and neuropsychological measures are suitable for the prediction of antidepressant treatment outcome in depression. Twenty-five patients diagnosed with major depressive disorder were assessed twice, pretreatment and at 8-wk follow-up, on a variety of QEEG and neuropsychological tasks. Additionally, cheek swab samples were collected to assess genetic predictors of treatment outcome. The primary outcome measure was the absolute decrease on the HAM-D rating scale. Regression models were built in order to investigate which markers contribute most to the decrease in absolute HAM-D scores. Patients who had a better clinical outcome were characterized by a decrease in the amplitude of the Auditory Oddball N1 at baseline. The ‘Met/Met’ variant of the COMT gene was the best genetic predictor of treatment outcome. Impaired verbal memory performance was the best cognitive predictor. Raised frontal Theta power was the best EEG predictor of change in HAM-D scores. A tentative integrative model showed that a combination of N1 amplitude at Pz and verbal memory performance accounted for the largest part of the explained variance. These markers may serve as new biomarkers suitable for the prediction of antidepressant treatment outcome. [ABSTRACT FROM AUTHOR]

Inhomogeneous continuous-time Markov chains play an important role in different application areas. In contrast to homogeneous continuous-time Markov chains, where a large number of numerical analysis techniques are available and have been compared, few results about the performance of numerical techniques in the inhomogeneous case are known. This paper presents a new variant of the uniformization technique, the most efficient approach for homogeneous Markov chains. The new uniformization technique allows for the stable computation of strict bounds for the transient distribution of inhomogeneous continuous-time Markov chains, which is not possible with other numerical techniques that provide only an approximation of the distribution and asymptotic bounds. Furthermore, another variant of uniformization is presented that computes an approximation of the transient distribution and is shown to outperform standard differential equation solvers if transition rates change slowly. [ABSTRACT FROM AUTHOR]

Background. Operant conditioning of one's slow cortical potential (SCP) or sensorimotor rhythm (SMR) can be used to control epilepsy or to manipulate external devices, as applied in BCI (Brain-Computer Interface). A commonly accepted view that both SCP and SMR are reflections of central arousal suggests a functional relationship between SCP and SMR networks.Method. The operant conditioning of SCP or SMR was tested with a single electroencephalographic (EEG) channel wireless biofeedback system. A series of trainings taught 19 participants to control SCP or SMR over vertex during 20 neurofeedback sessions. Each session consisted of 96 trials to decrease cortical arousal (SCP positivity/SMR enhancement) and 64 trials to increase cortical arousal (SCP negativity/SMR suppression). In each trial, participants were required to exceed an individual threshold level of the feedback parameter relative to a 500-msec prefeedback baseline and to hold this level for 2 sec (SCP) or 0.5 sec (SMR) to obtain reinforcement.Results. Ten of the 19 participants achieved control over their EEG. In the SCP-trained group, 4 of 9 participants increased the differentiation between their SCP responses on positivity-required versus negativity-required trials. SMR suppression and enhancement was achieved by 3 and 4 of the 10 SMR-trained participants. The SMR-trained responders did not show differentiation in their SMR responses, but did show a differentiation in their SCP responses -- while trained on SMR.Conclusions. The results showed the proposed method was successful to teach control of SCP or SMR. Bidirectional control was very difficult to achieve with the present SMR training procedure. SCP positivity and SMR enhancement were easier to learn. The results suggest that whereas changes in the loop's excitability thresholds by SCP training do not affect the thalamic bursting that underlies the SMR. [ABSTRACT FROM AUTHOR]

Background. This study reports on a new method for gold performance enhancement employing personalized real-life neurofeedback during golf putting.Method. Participants (n=6) received an assessment and three real-life neurofeedback training sessions. In the assessment, a personal event-locked electroenecphalographic (EEG) profile at FPz was determined for successful versus unsuccessful putts. Target frequency bands and amplitudes marking optimal prefrontal brain state were derived from the profile by two raters. The training sessions consisted of four series 80 putts in an ABAB design. The feedback in the second and fourth series was administered in the form a continuous NoGo tone, whereas in the first and third series no feedback was provided. This tone was terminated only when the participants EEG met the assessment-defined criteria. In the feedback series, particpants were instructed to perform the putt only after the NoGo tone had ceased.Results. From the personalized event-locked EEG profiles, individual training protocols were established. The interrater reliability was 91%. The overall percentage of successful putts was significantly larger in the second and fourth series (feedback) of training compared to the first and third series (no feedback). Furthermore, most participants improved their performance with feedback on their personalized EEG profile, with 25% on average.Conclusions. This study demonstrates that the 'zone' or the optimal mental state for golf putting shows clear recognizable personalized patterns. The learning effects suggest that this real-life approach to neurofeedback improves learning speed, probably by tapping into learning associated with contextual conditioning rather than operant conditioning, indicating perspectives for clinical applications. [ABSTRACT FROM AUTHOR]

Question The efficacy of rTMS in the treatment of major depressive disorder (MDD) has been well established in recent years in multi-center RCT’s as well as meta-analyses. Most studies to date have employed the ‘5-cm’ rule for targeting stimulation of the Dorsolateral Prefrontal Cortex (DLPFC). New variations and improvements of this targeting technique include a ‘6-cm’ rule, the Beam-F3 method, and neuronavigated rTMS. Furthermore, it has been proposed that the efficacy of rTMS in MDD is more related to stimulating the area that is functionally connected to the subgenual anterior cingulate cortex (sgACC) rather then to specific cortical areas (Fox et al., 2012). Therefore, we set-out to develop and test a new method that employs knowledge about the functional role of the sgACC to establish in real time if the right cortical area is targeted. Method Several studies have shown that areas in the ventromedial prefrontal cortex (VMPFC; including the subgenual and rostral ACC) are involved in processing of emotional information as well as the regulation of heart rate in response to emotional stimuli. Therefore, based on the notion that rTMS aims to transsynaptically stimulate the sgACC, we used electrocardiogram (ECG) R-peak triggered single pulse TMS to various frontal locations to establish the location that most consistently resulted in a lengthening of the R-R latency (reflective of a heart rate deceleration). This method of Neuro-Cardiac-Guided TMS or NCG TMS thus could be the equivalent of what the Motor Threshold is for the motor system, but then for the DLPFC with heart rate as an output. Results First preliminary results using a burst of 10 Hz TMS stimulation demonstrated that in a subject with a relatively large head circumference, no response was found at the ‘5 cm’ site (corresponding to FC4 in this subject), whereas the F4 location did result in a consistent heart rate deceleration. More data are currently being collected using a single pulse R-peak triggered approach and data will be presented. Conclusions In the treatment of MDD, Neuro-Cardiac-Guided TMS has the potential to become the equivalent of the ‘motor threshold’ for the DLPFC, and thereby would be a cost-effective and easy to use method for localizing the right stimulation target in the treatment of MDD, and also serve as a real-time control of adequate coil contact in patients undergoing rTMS treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. Methods: The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the −1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. Results: There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. Conclusions: COMT Val108/158Met and DBH −1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. Significance: We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date. [Copyright &y& Elsevier]

Background: MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity.Methods: Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants.Results: Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity.Limitations: Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs).Conclusions: Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline. [ABSTRACT FROM AUTHOR]

Background:To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients.Methods:A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees.Results:In total, 176 MPM patients (mean age: 63.5 years±10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (390 mg dl−1) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (627 mg dl−1) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl−1) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS).Conclusions:Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy. [ABSTRACT FROM AUTHOR]

Abstract: The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N =15) and post-traumatic stress disorder (PTSD) (N =14) relative to healthy controls (N =15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups. [ABSTRACT FROM AUTHOR]

To overcome the limitations of the syndrome-based diagnostic routine in neuropsychiatric disorder and to provide biomarker-informed decisions for treatment, recently the Research Domain Criteria have been initialized [1] . They include separate criteria for autonomous and arousal systems. Based on findings of altered wakefulness-regulation and autonomous function in major depressive disorder (MDD), the goal of this study therefore was to investigate the predictive value for treatment outcome of central nervous system (CNS) and autonomous nervous system (ANS) arousal and their interaction in a large cohort of patients from the iSPOT-D trial that received either a selective-serotonin reuptake-inhibitor (SSRI) or a serotonin-norepinephrine-reuptake-inhibitor (SNRI). Methods CNS and ANS-arousal (defined by electroencephalogram vigilance and heart rate) and their change over time were assessed during rest. Differences of treatment outcome as defined by the decline of Hamilton Rating Scale for Depression-(HRSD) from baseline to week 8 after treatment initiation for the whole sample and for SSRI and SNRI groups separately were analysed using a binary logistic regression model and repeated measure analysis of variance (ANOVA). Results Responders and remitters were characterized by a steeper decline of CNS-arousal. Subgroup analysis showed that this effect was only present for the SSRI arm whereas SNRI responders showed a more pronounced increase of ANS-arousal. Further, SSRI responders showed a correlation between ANS and CNS measures, SSRI non-responders and the whole SNRI subgroup did not. Conclusions CNS and ANS-arousal during rest predict positive treatment outcome to antidepressant medication. The differences of CNS and ANS-profiles for SSRI or SNRI prediction are interpreted as neurophysiological traits that indicate responsiveness to different drug-classes rather than disorder specific aspects. [ABSTRACT FROM AUTHOR]