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S Kor Spoelstra,1,2 Jojanneke Bruins,2 Leonie Bais,2 Paul Seerden,3 Stynke Castelein,2,4 Henderikus Knegtering2,5 1Addiction Care North Netherlands, Groningen, the Netherlands; 2Lentis Psychiatric Institute, Groningen, the Netherlands; 3GGZ Friesland Psychiatric Institute, Leeuwarden, the Netherlands; 4University of Groningen, Faculty of Behavioural and Social Sciences, Department of Clinical Psychology and Experimental Psychopathology, Groningen, the Netherlands; 5University Medical Center Groningen, University of Groningen, Rob Giel Research Center, Groningen, the NetherlandsCorrespondence: S Kor Spoelstra, Addiction care North Netherlands, Leonard Springerlaan 27, Groningen, 9727 KB, the Netherlands, Tel +31503648900, Fax +31503648999, Email k.spoelstra@vnn.nlPurpose: Paliperidone palmitate is the only available long acting injectable (LAI) antipsychotic with a monthly and three-monthly formulation. LAIs may help battle non-adherence. Studies about the experiences of switching from the monthly (PP1M) to the three-monthly formulation (PP3M) of paliperidone are scarce. Therefore, the aim of this study is to evaluate the perspectives of patients, relatives, and mental health professionals on PP3M compared with PP1M.Material and Methods: This was a multicenter, retrospective, non-interventional one-time questionnaire survey among patients with psychotic disorders who switched from PP1M to PP3M (n = 38), their relatives (n = 13) and mental health professionals (n = 38). General satisfaction and (un)desired effects were measured using the Medication Satisfaction Questionnaire (MSQ) and the Subjects’ Reaction to Antipsychotics (SRA), respectively. Additional questionnaires assessed socio-demographic variables, preference, effectiveness, side-effects, and confidence in PP3M compared to PP1M.Results: Mean number of received PP3M injections was 4.2 (SD 2.5). The three study groups reported a high level of confidence in PP3M. High general satisfaction rates about PP3M among patients (69%) and mental health professionals (95%) were reported. The majority of patients, relatives, and mental health professionals reported similar or in some cases even greater effectiveness and similar or in some cases even less side-effects of PP3M compared to PP1M. Sixty-seven percent of the relatives reported less concerns about non-adherence after switching to PP3M.Conclusion: Most patients, relatives, and mental health professionals prefer PP3M over PP1M. The positive attitudes of all parties may facilitate the more frequent use of PP3M and potentially the clinical outcomes.Keywords: paliperidone palmitate 3-monthly, long-acting injectable antipsychotics, psychotic disorders, mental health professionals, family, perspectives

Background A fundamental challenge for many people with severe mental illness (SMI) is how to deal with cognitive impairments. Cognitive impairments are common in this population and limit daily functioning. Moreover, neural plasticity in people with SMI appears to be reduced, a factor that might hinder newly learned cognitive skills to sustain. The objective of this pilot trial is to investigate the effects of cognitive remediation (CR) on cognitive and daily functioning in people dependent on residential settings. In addition, transcranial direct current stimulation (tDCS) is used to promote neural plasticity. It is expected that the addition of tDCS can enhance learning and will result in longer-lasting improvements in cognitive and daily functioning. Methods This is a pragmatic, triple-blinded, randomized, sham-controlled, pilot trial following a non-concurrent multiple baseline design with the participants serving as their own control. We will compare (1) CR to treatment as usual, (2) active/sham tDCS+CR to treatment as usual, and (3) active tDCS+CR to sham tDCS+CR. Clinical relevance, feasibility, and acceptability of the use of CR and tDCS will be evaluated. We will recruit 26 service users aged 18 years or older, with a SMI and dependent on residential facilities. After a 16-week waiting period (treatment as usual), which will serve as a within-subject control condition, participants will be randomized to 16 weeks of twice weekly CR combined with active (N = 13) or sham tDCS (N = 13). Cognitive, functional, and clinical outcome assessments will be performed at baseline, after the control (waiting) period, directly after treatment, and 6-months post-treatment. Discussion The addition of cognitive interventions to treatment as usual may lead to long-lasting improvements in the cognitive and daily functioning of service users dependent on residential facilities. This pilot trial will evaluate whether CR on its own or in combination with tDCS can be a clinically relevant addition to further enhance recovery. In case the results indicate that cognitive performance can be improved with CR, and whether or not tDCS will lead to additional improvement, this pilot trial will be extended to a large randomized multicenter study. Trial registration Dutch Trial Registry NL7954. Prospectively registered on August 12, 2019.

Objectives: Biological strategies to improve treatment efficacy in clozapine-treated patients are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) merits consideration as intervention for patients with persistent auditory hallucinations (AH) or negative symptoms (NS) not responding sufficiently to clozapine treatment. Methods: Data from 10 international RCTs of rTMS for patients being treated with clozapine were pooled. Two levels of symptomatic response were defined: improvement of >= 20% and >= 50% on study-specific primary endpoint scales. Changes in the positive and negative syndrome scale (PANSS) from baseline to endpoint assessment were also analysed. Results: Analyses of 131 patients did not reveal a significant difference for >= 20% and >= 50% response thresholds for improvement of AH, negative or total symptoms between active and sham rTMS groups. The number needed to treat (NNT) for an improvement in persistent AH was nine following active rTMS. PANSS scores did not improve significantly from baseline to endpoint between active and sham groups in studies investigating NS and AH. Conclusions: rTMS as a treatment for persistent symptoms in clozapine-treated patients did not show a beneficial effect of active compared to sham treatment. For AH, the size of the NNTs indicates a possible beneficial effect of rTMS.

Visual hallucinations (VH) are difficult to treat because pharmacological interventions are only partially effective and associated with many adverse effects. One of the alternative non-pharmacological treatments for VH is repetitive transcranial magnetic stimulation (rTMS). However, identifying optimal stimulation sites for rTMS is challenging. To determine whether a connectivity-based targeting approach based on resting state (rs) fMRI data can be used to identify regions that may serve as effective rTMS targets. We acquired rs-fMRI scans pre-rTMS and post-rTMS in a single patient with retinitis pigmentosa (near blindness), Parkinson’s disease (PD) and had therapy-resistant VH. Rs-fMRI data were analyzed using fast Eigenvector Centrality Mapping (ECM). A target area was selected based on high ECM values and relative accessibility for rTMS. Subsequently, the patient was stimulated with 1 Hz rTMS during 5 days, followed by 30 Hz theta-burst stimulation during another 5 days. Distributions of surrogate and bootstrap data were used to statistically evaluate the effect of rTMS. The bilateral supplementary motor areas (SMA) were selected as rTMS target areas. When pre-rTMS were compared to post-rTMS, different ECM values were found in the SMA, precuneus, occipital pole and hippocampus. Clinical evaluation and follow-up showed that the intensity and frequency of the VH were decreased after rTMS. Our connectivity-based targeting approach applied to rs-fMRI data seems to be successful in identifying an optimal target area for rTMS on a single subject basis. Our results show changes in the connectivity pattern, both in the target area and associated hubs involved in VH pathogenesis.

Introduction: Efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) targeting the temporo-parietal junction (TPJ) for the treatment of auditory verbal hallucinations (AVH) remains under debate. We assessed the influence of a 1 Hz rTMS treatment on neural networks involved in a cognitive mechanism proposed to subserve AVH.Methods: Patients with schizophrenia (N = 24) experiencing medication-resistant AVH completed a 10-day 1 Hz rTMS treatment. Participants were randomized to active stimulation of the left or bilateral TPJ, or sham stimulation. The effects of rTMS on neural networks were investigated with an inner speech task during fMRI. Changes within and between neural networks were analyzed using Independent Component Analysis.Results: rTMS of the left and bilateral TPJ areas resulted in a weaker network contribution of the left supramarginal gyro to the bilateral fronto-temporal network. Left-sided rTMS resulted in stronger network contributions of the right superior temporal gyrus to the auditory-sensorimotor network, right inferior gyrus to the left fronto-parietal network, and left middle frontal gyrus to the default mode network. Bilateral rTMS was associated with a predominant inhibitory effect on network contribution. Sham stimulation showed different patterns of change compared to active rTMS.Conclusion: rTMS of the left temporo-parietal region decreased the contribution of the left supramarginal gyros to the bilateral fronto-temporal network, which may reduce the likelihood of speech intrusions. On the other hand, left rTMS appeared to increase the contribution of functionally connected regions involved in perception, cognitive control and self-referential processing. These findings hint to potential neural mechanisms underlying rTMS for hallucinations but need corroboration in larger samples.

Purpose Glutamatergic models of psychosis propose that dysfunction of N -methyl- d -aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate + glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy ( 1 H MRS) to calculate their association with AVH. Methods Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8 mm 3 voxel placed in the left lateral prefrontal region, belonging to both the cingulum and forceps minor. Patients with lifetime AVH (AVH group; n = 45) and patients without lifetime AVH were compared (NoAVH group; n = 22) to control participants. Results Levels of Glx were significantly different between the groups (F(2,94) = 5.27, p = 0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group ( p = 0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH ( p = 0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale). Conclusion The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

Insight is impaired in most patients with psychosis and has been associated with poorer prognosis. The exact neural basis of impaired insight is still unknown, but it may involve disrupted prefrontal neural connectivity. Numerous studies have indeed found white matter (WM) abnormalities in psychosis. The association between prefrontal WM abnormalities and insight has not been studied yet by means of proton magnetic resonance spectroscopy (H-1-MRS). H-1-MRS can be used to measure N-acetylaspartate (NAA), which is considered to be a marker of neuronal integrity. We measured insight with the Birchwood Insight Scale (BIS) as well as item G12 of the Positive and Negative Syndrome Scale (PANSS) in 88 patients with psychosis. Prefrontal WM concentrations of NAA and ratios of NAA to creatine (Cr) were assessed with H-1-MRS. Nonparametric partial correlational analyses were conducted between NAA concentrations and insight controlling for illness duration, standardized antipsychotic dose, symptom scores, voxel grey matter content and voxel cerebrospinal fluid content. We found a significant correlation between reduced NAA/Cr ratios and poorer insight as measured with the BIS, which remained significant after additional correction for full width at half maximum, signal/noise and age. This is the first study reporting a relationship between lower prefrontal concentrations of a marker of neuronal integrity and impaired insight, providing further evidence that prefrontal pathology may play an important role in impaired insight in psychosis. This may be explained by the involvement of the prefrontal cortex in several executive and metacognitive functions, such as cognitive flexibility and perspective taking. (C) 2016 Elsevier B.V. All rights reserved.

Background: Prefrontal repetitive Transcranial Magnetic Stimulation (rTMS) may improve negative symptoms in patients with schizophrenia, but few studies have investigated the underlying neural mechanism.Objective: This study aims to investigate changes in the levels of glutamate and glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate (NAA) in the left dorsolateral prefrontal cortex of patients with schizophrenia treated with active bilateral prefrontal rTMS as compared to sham-rTMS, as measured with H-1-Magnetic Resonance Spectroscopy (H-1-MRS).Methods: Patients were randomized to a 3-week course of active or sham high-frequency rTMS. Pretreatment and post-treatment 1H-MRS data were available for 24 patients with schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale >= 15). Absolute metabolite concentrations were calculated using LCModel with the water peak as reference. To explore the association between treatment condition and changes in concentration of Glx and NAA, we applied a linear regression model.Results: We observed an increase of Glx concentration in the active treatment group and a decrease of Glx concentration in the group receiving sham treatment. The association between changes in Glx concentration and treatment condition was significant. No significant associations between changes in NAA and treatment condition were found.Conclusions: Noninvasive neurostimulation with high-frequency bilateral prefrontal rTMS may influence Glx concentration in the prefrontal cortex of patients with schizophrenia. Larger studies are needed to confirm these findings and further elucidate the underlying neural working mechanism of rTMS. (C) 2016 Elsevier Inc. All rights reserved.

This exploratory study reports on the effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on (prefrontal) brain activity changes during ambiguous emotional evaluation in patients with schizophrenia. Before and after randomly assigned treatment with active and sham rTMS, patients performed the Wall of Faces task during fMRI scanning. fMRI analysis showed that rTMS treatment resulted in reduced activation of striato-fronto-parietal brain areas, while activation increased compared to baseline after sham. Thus, prefrontal rIMS may normalize an increased brain response to ambiguous emotional stimuli, but future studies should confirm these findings. (C) 2018 Elsevier B.V. All rights reserved.

Background Cognitive deficits are commonly observed in people diagnosed with schizophrenia and have been found to be more predictive of future daily and community functioning than the severity of clinical symptoms (e.g., hallucinations and delusions). Cognitive remediation (CR) is a psychological treatment developed to improve cognitive functioning and thereby daily functioning. Despite the effectivity of CR programs, reduced neuroplasticity in brain networks underlying the cognitive tasks may impede the effectiveness of these treatment programs. Increasing the neuroplasticity in these networks by the use of non-invasive brain stimulation (NIBS) like transcranial direct current stimulation or transcranial magnetic stimulation might boost the effect of CR. In a systematic review, we will address the question whether the combination of non-invasive brain stimulation and cognitive remediation may be a promising treatment strategy. We will apply a transdiagnostic perspective in order to determine the potential benefit of combining CR and NIBS in general, and not specific to a diagnostic category. Methods A systematic review of literature was conducted by searching PsycINFO, Pubmed, Web of Science, and Medline databases for combined treatments of CR and NIBS. Included studies were assessed for cognitive, clinical and functional outcomes. Results 64 studies were identified, with 40 studies including clinical populations (e.g., schizophrenia, Alzheimer’s disease, HIV, MS). The cognitive outcomes showed mixed results. Most effects were found on complex attention and executive functioning. In these domains about 38% of the studies found an added positive treatment effect for combining interventions, in comparison to single interventions (i.e. CR, NIBS, or CR+sham-stimulation). Functional outcome measures were included in ten of the 40 studies with clinical populations. Eight studies found a positive trend towards greater improvements in daily functioning when CR and NIBS were combined. Discussion So far, findings indicate promising effects of combining CR and NIBS on cognitive functioning and daily functioning in healthy and various clinical populations. There is a lot of variety between studies (e.g., duration of treatment, number of total sessions, number of weekly sessions, cognitive domains targeted) which may explain the mixed results. Especially, the design of the CR varied widely. Strategy-use and targeting meta-cognition, which were identified as effective elements of CR as a stand-alone treatment were not included in many combined CR+NIBS designs. Future studies have to elucidate whether the combining CR (including strategy-use and meta-cognition) and NIBS has an additive effect on cognitive and/or daily functioning compared to non-combined treatment. Moreover, future studies should evaluate whether beneficial effects from the experimental studies translate into long-term improvement in activities of daily life.

Objective: Negative symptoms can be grouped into two factors, expressive deficits and social-emotional withdrawal. We aimed to examine the neural correlates of the two negative symptom factors during a social cognition task, which measures emotional ambiguity in a social context by presenting an array of faces with varying degrees of consistency in emotional expressions. Methods: Patients with schizophrenia (N=38) and healthy controls (N=20) performed a social cognition task during fMRI that probed both affect and ambiguity. Differences in brain activation between the healthy controls and patients were non-parametrically tested. Subsequently, the expressive deficits and social-emotional withdrawal factors were regressed against task-related brain activation. Results: Severity of expressive deficits was negatively correlated with activation of the ventromedial prefrontal cortex when comparing ambiguous emotional decisions to ambiguous gender decisions. During emotional ambiguity, severity of expressive deficits was negatively correlated with activation in thalamic, prefrontal, precentral, parietal and temporal brain areas. No associations between social-emotional withdrawal and brain activation were observed. Conclusion: Hypoactivation of the fronto-thalamic circuitry during ambiguous social appraisal may imply a reduced action readiness in social situations, underlying expressive deficits but not social-emotional withdrawal. The findings provide further evidence for different neurobiological bases of the two factors of negative symptoms.

Glutamatergic models of psychosis propose that dysfunction of N-methyl-d-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate+glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy (Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8mmLevels of Glx were significantly different between the groups (F(2,94)=5.27, p=0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group (p=0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH (p=0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale).The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

Background.Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects.Method.A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used.Results.A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p = 0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group.Conclusions.Bilateral 10 Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.

H-Magnetic Resonance Spectroscopy (1H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A 1H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate.

Background Prefrontal cortical dysfunction is frequently reported in schizophrenia and is thought to underlie negative symptoms of schizophrenia. Repetitive Transcranial Magnetic Stimulation (rTMS) can modulate neuronal activity and has been shown to improve negative symptoms in patients with schizophrenia, but the underlying neural mechanism is unknown. Objective To examine whether 3 weeks of 10 Hz rTMS treatment of the bilateral dorsolateral prefrontal cortex (DLPFC) would improve frontal brain activation in patients with negative symptoms of schizophrenia, as measured by functional magnetic resonance imaging (fMRI) during the Tower of London (ToL) task. Methods 24 patients with the diagnosis of schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale ≥ 15) participated. Patients were randomized to a 3-week (15 day) course of active or sham rTMS. All patients performed the ToL task during fMRI scanning both pre-treatment and post-treatment. Differences in brain activation between the two groups were compared non-parametrically. Results After rTMS treatment, brain activity in the active group increased in the right DLPFC and the right medial frontal gyrus as compared to the sham group. In addition, the groups significantly differed with regard to activation change in the left posterior cingulate, with decreased activation in the active and increased activation in the sham group. Conclusions Treatment with rTMS over the DLPFC may have the potential for increasing task-related activation in frontal areas in patients with schizophrenia. Effects of different rTMS parameters and fMRI tasks targeting relevant brain circuitry deserve further investigation. Trial registration Nederlands Trial Register, registration number: NTR1261

Patients with schizophrenia often suffer from apathy: a quantitative reduction of voluntary, goal-directed behaviors that impairs daily functioning. We hypothesized that schizophrenia patients with high levels of apathy would show decreased activation in brain regions involved in planning and goal-directed behavior.Patients with schizophrenia or psychotic spectrum disorder (n = 47) and healthy controls (n = 20) performed the Tower of London (ToL) task during fMRI scanning using arterial spin labeling. To investigate the relationship between apathy and planning in patients, a proxy measure of apathy based on the Positive and Negative syndrome Scale was regressed against the task-related brain activation. Brain activation was also compared between patients and healthy controls.Higher levels of apathy were associated with less task-related activation within the inferior parietal lobule precuneus and thalamus. Compared to controls, patients showed lower activation in lateral prefrontal regions, parietal and motor areas, and a higher activation of medial frontal areas.Apathy was related to abnormal activation in thalamus and parietal regions during the ToL task. This supports the hypothesis that impaired function of brain regions involved in planning and goal-directed behavior may underlie apathy in schizophrenia. Moreover, impaired lateral prefrontal activation in schizophrenia patients compared to controls is consistent with the hypofrontality model of schizophrenia. In contrast, stronger medial frontal activation in patients may be related to increased effort to perform a task with conflicting task solutions. (C) 2014 Elsevier B.V. All rights reserved.

BACKGROUND: Repetitive transcranial magnetic stimulation of the left temporo-parietal junction area has been studied as a treatment option for auditory verbal hallucinations. Although the right temporo-parietal junction area has also shown involvement in the genesis of auditory verbal hallucinations, no studies have used bilateral stimulation. Moreover, little is known about durability effects. We studied the short and long term effects of 1 Hz treatment of the left temporo-parietal junction area in schizophrenia patients with persistent auditory verbal hallucinations, compared to sham stimulation, and added an extra treatment arm of bilateral TPJ area stimulation. METHODS: In this randomized controlled trial, 51 patients diagnosed with schizophrenia and persistent auditory verbal hallucinations were randomly allocated to treatment of the left or bilateral temporo-parietal junction area or sham treatment. Patients were treated for six days, twice daily for 20 minutes. Short term efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucinations Rating Scale (AHRS), and the Positive and Negative Affect Scale (PANAS). We included follow-up measures with the AHRS and PANAS at four weeks and three months. RESULTS: The interaction between time and treatment for Hallucination item P3 of the PANSS showed a trend for significance, caused by a small reduction of scores in the left group. Although self-reported hallucination scores, as measured with the AHRS and PANAS, decreased significantly during the trial period, there were no differences between the three treatment groups. CONCLUSION: We did not find convincing evidence for the efficacy of left-sided rTMS, compared to sham rTMS. Moreover, bilateral rTMS was not superior over left rTMS or sham in improving AVH. Optimizing treatment parameters may result in stronger evidence for the efficacy of rTMS treatment of AVH. Moreover, future research should consider investigating factors predicting individual response. TRIAL REGISTRATION: Dutch Trial Register NTR1813.

In verbal communication, not only the meaning of the words convey information, but also the tone of voice (prosody) conveys crucial information about the emotional state and intentions of others. In various studies right frontal and right temporal regions have been found to play a role in emotional prosody perception. Here, we used triple-pulse repetitive transcranial magnetic stimulation (rTMS) to shed light on the precise time course of involvement of the right anterior superior temporal gyrus and the right fronto-parietal operculum. We hypothesized that information would be processed in the right anterior superior temporal gyrus before being processed in the right fronto-parietal operculum. Right-handed healthy subjects performed an emotional prosody task. During listening to each sentence a triplet of TMS pulses was applied to one of the regions at one of six time points (400-1900 ms). Results showed a significant main effect of Time for right anterior superior temporal gyrus and right fronto-parietal operculum. The largest interference was observed half-way through the sentence. This effect was stronger for withdrawal emotions than for the approach emotion. A further experiment with the inclusion of an active control condition, TMS over the EEG site POz (midline parietal-occipital junction), revealed stronger effects at the fronto-parietal operculum and anterior superior temporal gyrus relative to the active control condition. No evidence was found for sequential processing of emotional prosodic information from right anterior superior temporal gyrus to the right fronto-parietal operculum, but the results revealed more parallel processing. Our results suggest that both right fronto-parietal operculum and right anterior superior temporal gyrus are critical for emotional prosody perception at a relatively late time period after sentence onset. This may reflect that emotional cues can still be ambiguous at the beginning of sentences, but become more apparent half-way through the sentence.

prefrontal and parietal cortex, and the caudate nucleus in schizophrenia. We predicted that brain activity would positively correlate with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia. Methods: Twenty-five healthy adults and 17 people with schizophrenia or schizoaffective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by ELISA. Results: We found a positive correlation between circulating plasma BDNF levels and brain activity in the right parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant difference. Discussion: This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning suggesting that plasma BDNF levels may reflect brain activity in healthy humans. The lack of relationship between plasma BDNF and task related brain activity in patients demonstrates that circulating blood BDNF is not related to frontal-parietal-striatal activity during learning in schizophrenia.