Towards Using Microstate-Neurofeedback for the Treatment of Psychotic Symptoms in Schizophrenia. A Feasibility Study in Healthy Participants

Spontaneous EEG signal can be parsed into sub-second periods of stable functional states (microstates) that assumingly correspond to brief large scale synchronization events. In schizophrenia, a specific class of microstate (class "D") has been found to be shorter than in healthy controls and to be correlated with positive symptoms. To explore potential new treatment options in schizophrenia, we tested in healthy controls if neurofeedback training to self-regulate microstate D presence is feasible and what learning patterns are observed. Twenty subjects underwent EEG-neurofeedback training to up-regulate microstate D presence. The protocol included 20 training sessions, consisting of baseline trials (resting state), regulation trials with auditory feedback contingent on microstate D presence, and a transfer trial. Response to neurofeedback was assessed with mixed effects modelling. All participants increased the percentage of time spent producing microstate D in at least one of the three conditions (p < 0.05). Significant between-subjects across-sessions results showed an increase of 0.42 % of time spent producing microstate D in baseline (reflecting a sustained change in the resting state), 1.93 % of increase during regulation and 1.83 % during transfer. Within-session analysis (performed in baseline and regulation trials only) showed a significant 1.65 % increase in baseline and 0.53 % increase in regulation. These values are in a range that is expected to have an impact upon psychotic experiences. Additionally, we found a negative correlation between alpha power and microstate D contribution during neurofeedback training. Given that microstate D has been related to attentional processes, this result provides further evidence that the training was to some degree specific for the attentional network. We conclude that microstate-neurofeedback training proved feasible in healthy subjects. The implementation of the same protocol in schizophrenia patients may promote skills useful to reduce positive symptoms by means of EEG-neurofeedback.

Keep at bay! - Abnormal personal space regulation as marker of paranoia in schizophrenia.

BACKGROUND During threat, interpersonal distance is deliberately increased. Personal space regulation is related to amygdala function and altered in schizophrenia, but it remains unknown whether it is particularly associated with paranoid threat. METHODS We compared performance in two tests on personal space between 64 patients with schizophrenia spectrum disorders and 24 matched controls. Patients were stratified in those with paranoid threat, neutral affect or paranoid experience of power. In the stop-distance paradigm, participants indicated the minimum tolerable interpersonal distance. In the fixed-distance paradigm, they indicated the level of comfort at fixed interpersonal distances. RESULTS Paranoid threat increased interpersonal distance two-fold in the stop-distance paradigm, and reduced comfort ratings in the fixed-distance paradigm. In contrast, patients experiencing paranoid power had high comfort ratings at any distance. Patients with neutral affect did not differ from controls in the stop-distance paradigm. Differences between groups remained when controlling for gender and positive symptom severity. Among schizophrenia patients, the stop-distance paradigm detected paranoid threat with 93% sensitivity and 83% specificity. CONCLUSIONS Personal space regulation is not generally altered in schizophrenia. However, state paranoid experience has distinct contributions to personal space regulation. Subjects experiencing current paranoid threat share increased safety-seeking behavior.

Nonverbal synchrony in social interactions of patients with schizophrenia indicates socio-communicative deficits

Background Disordered interpersonal communication can be a serious problem in schizophrenia. Recent advances in computer-based measures allow reliable and objective quantification of nonverbal behavior. Research using these novel measures has shown that objective amounts of body and head movement in patients with schizophrenia during social interactions are closely related to the symptom profiles of these patients. In addition to and above mere amounts of movement, the degree of synchrony, or imitation, between patients and normal interactants may be indicative of core deficits underlying various problems in domains related to interpersonal communication, such as symptoms, social competence, and social functioning. Methods Nonverbal synchrony was assessed objectively using Motion Energy Analysis (MEA) in 378 brief, videotaped role-play scenes involving 27 stabilized outpatients diagnosed with paranoid-type schizophrenia. Results Low nonverbal synchrony was indicative of symptoms, low social competence, impaired social functioning, and low self-evaluation of competence. These relationships remained largely significant when correcting for the amounts of patients‘ movement. When patients showed reduced imitation of their interactants’ movements, negative symptoms were likely to be prominent. Conversely, positive symptoms were more prominent in patients when their interaction partners’ imitation of their movements was reduced. Conclusions Nonverbal synchrony can be an objective and sensitive indicator of the severity of patients’ problems. Furthermore, quantitative analysis of nonverbal synchrony may provide novel insights into specific relationships between symptoms, cognition, and core communicative problems in schizophrenia.

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis.

Importance In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published. Objective To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis. Data Sources MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014. Study Selection At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo. Data Extraction and Synthesis At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting. Main Outcomes and Measures The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events. Results Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs. Conclusions and Relevance Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.