Effects of right prefrontal theta-burst transcranial magnetic stimulation or transcranial direct current stimulation on apathy in patients with schizophrenia: A multicenter RCT.

Apathy is a core negative symptom associated with an unfavorable functional outcome. Noninvasive brain stimulation has shown promise in the treatment of schizophrenia but has not been tested specifically for apathy. We conducted a randomized controlled trial of intermittent theta-burst (iTBS) transcranial magnetic stimulation and transcranial direct current stimulation (tDCS) targeted at the right dorsolateral prefrontal cortex (DLPFC) in patients diagnosed with a psychotic disorder suffering from apathy. The study was a multicenter, randomized, placebo-controlled, and rater-blinded trial. Patients (N = 88) were randomized into active iTBS, active tDCS, sham iTBS or sham tDCS treatment, daily for two weeks (excluding weekends). Effects were measured post-treatment and at four week and ten week follow-up. Primary outcome was apathy severity (Apathy Evaluation Scale, clinician-rated). Additional measures included assessment of negative symptoms, depression, anhedonia and quality of life. No significant difference in improvement of apathy or negative symptoms was observed for real versus sham treatment with either iTBS or tDCS, though all groups improved to a small extent. We conclude that two weeks of brain stimulation over the right DLPFC with either iTBS or tDCS is not effective for improving apathy or negative symptoms. Longer and more intensive protocols may yield different results.

Antiviral treatment in schizophrenia: a randomized pilot PET study on the effects of valaciclovir on neuroinflammation.

BACKGROUND: Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. METHODS: We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. RESULTS: Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31-40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. CONCLUSION: We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.

One-Month versus Three-Month Formulation of Paliperidone Palmitate Treatment in Psychotic Disorders: Patients', Relatives', and Mental Health Professionals' Perspectives.

Purpose: 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.

Satisfaction with social connectedness as a predictor for positive and negative symptoms of psychosis: A PHAMOUS study.

PURPOSE: This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder. METHODS: Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS) was used from patients assessed between 2014 and 2019, diagnosed with a psychotic disorder (N = 2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α = 0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated. RESULTS: The mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (ß = -0.47, p < 0.001, 95% CI = -0.70, -025) and two years (ß = -0.59, p < 0.001, 95% CI = -0.88, -0.30), and for negative symptoms after one year (ß = -0.52, p < 0.001, 95% CI = -0.77, -0.27). The prediction of negative symptoms was not significant at two years. CONCLUSION: This research indicates that interventions on SSC might positively impact mental health for people with psychosis. SSC is a small and robust predictor of future levels of positive symptoms. Negative symptoms could be predicted by SSC at one year.

Repetitive transcranial magnetic stimulation (rTMS) for schizophrenia patients treated with clozapine.

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.

The effect of mind-body and aerobic exercise on negative symptoms in schizophrenia: A meta-analysis.

OBJECTIVE: This meta-analysis aims to evaluate the effects of different types of physical exercise (PE) on negative symptoms in schizophrenia patients. Mind-body exercise (MBE), aerobic exercise (AE) and resistance training (RT) will be investigated. METHOD: The Cochrane Library, Medline, Embase and PsycINFO were searched from their inception until April 26, 2018. Randomized controlled trials comparing PE with any control group in patients with schizophrenia were included when negative symptoms had been assessed. This meta-analysis was conducted according to the PRISMA guidelines. The methodological quality of the included studies was assessed with the Cochrane Risk of Bias assessment tool. Moderator, sensitivity, and meta regression analyses were conducted to explore causes of heterogeneity and impact of study quality. RESULTS: We included 22 studies (N = 1249). The overall methodological quality was poor. The meta-analysis (random effects model) showed a medium significant effect in favor of any PE intervention (Hedges' g = 0.434, 95% CI = 0.196-0.671) versus any control condition. MBE and AE respectively showed a medium significant effect (Hedges' g = 0.461) and a small significant effect (Hedges' g = 0.341) versus any control condition. The effect of RT could not be examined. The overall heterogeneity was high (I2 = 76%) and could not be reduced with moderator or sensitivity analyses. CONCLUSION: This meta-analysis demonstrated that PE could be a promising intervention in the treatment of negative symptoms. However, the quality of the included studies was low and heterogeneity was high, which makes it impossible to make a clear recommendation. Therefore, results should be interpreted with care.

Effects of bilateral prefrontal rTMS on brain activation during social-emotional evaluation in schizophrenia: A double-blind, randomized, exploratory study.

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 rTMS may normalize an increased brain response to ambiguous emotional stimuli, but future studies should confirm these findings.

The development and evaluation of a computerized decision aid for the treatment of psychotic disorders.

BACKGROUND: Routinely monitoring of symptoms and medical needs can improve the diagnostics and treatment of medical problems, including psychiatric. However, several studies show that few clinicians use Routine Outcome Monitoring (ROM) in their daily work. We describe the development and first evaluation of a ROM based computerized clinical decision aid, Treatment-E-Assist (TREAT) for the treatment of psychotic disorders. The goal is to generate personalized treatment recommendations, based on international guidelines combined with outcomes of mental and physical health acquired through ROM. We present a pilot study aimed to assess the feasibility of this computerized clinical decision aid in daily clinical practice by evaluating clinicians' experiences with the system. METHODS: Clinical decision algorithms were developed based on international schizophrenia treatment guidelines and the input of multidisciplinary expert panels from multiple psychiatric institutes. Yearly obtained diagnostic (ROM) information of patients was presented to treating clinicians combined with treatment suggestions generated by the algorithms of TREAT. In this pilot study 6 clinicians and 16 patients of Lentis Psychiatric Institute used the application. Clinicians were interviewed and asked to fill out self-report questionnaires evaluating their opinions about ROM and the effectiveness of TREAT. RESULTS: Six clinicians and 16 patients with psychotic disorders participated in the pilot study. The clinicians were psychiatrists, physicians and nurse-practitioners which all worked at least 8 years in mental health care of which at least 3 years treating patients with psychotic illnesses. All Clinicians found TREAT easy to use and would like to continue using the application. They reported that TREAT offered support in using diagnostic ROM information when drafting the treatment plans, by creating more awareness of current treatment options. CONCLUSION: This article presents a pilot study on the implementation of a computerized clinical decision aid linking routine outcome monitoring to clinical guidelines in order to generate personalized treatment advice. TREAT was found to be feasible for daily clinical practice and effective based on this first evaluation by clinicians. However, adjustments have to be made to the system and algorithms of the application. The ultimate goal is to provide appropriate evidence based care for patients with severe mental illnesses.

Towards a comprehensive routine outcome monitoring program for people with psychotic disorders: The Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS).

BACKGROUND: Patients with psychotic disorders are at risk of developing mental health and social problems, and physical disorders. To monitor and treat these problems when indicated, an annual routine outcome monitoring program, Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS), was developed. This paper presents the background and content of PHAMOUS, implementation of PHAMOUS, characteristics of the patients screened in 2015, and the outcome of patients with three annual screenings between 2011 and 2015. METHODS: PHAMOUS was implemented in four mental health institutions in the Northern Netherlands in 2006. During the PHAMOUS screening, patients are assessed on socio-demographics, psychiatric symptoms, medication, physical parameters, lifestyle, (psycho)social functioning and quality of life, using internationally validated instruments. RESULTS: In 2015, 1955 patients with psychotic disorders were enrolled in the PHAMOUS screening. The majority (72%) was receiving mental healthcare for ten years or longer. A small group was hospitalized (10%) in the past year. Half of the patients were in symptomatic remission. Less than 10% had a paid job. More than half of the patients fulfilled the criteria for metabolic syndrome (54%). The subsample with three annual screenings from 2011 to 2015 (N = 1230) was stable, except the increasing prevalence of high glucose levels and satisfaction with social relationships (Cochran's Q = 16.33, p = .001 resp. Q = 14.79, p = .001). CONCLUSION: The annual PHAMOUS screening enables to follow the mental, physical and social health problems of patients, which offers a good basis for shared-decision making with regard to updating the annual treatment plan, next to a wealth of data for scientific research.

Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: Meta-analysis of controlled trials.

BACKGROUND: Negative symptoms in schizophrenia concern a clinically relevant reduction of goal-directed behavior that strongly and negatively impacts daily functioning. Existing treatments are of marginal effect and novel approaches are needed. Noninvasive neurostimulation by means of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are novel approaches that may hold promise. OBJECTIVES: To provide a quantitative integration of the published evidence regarding effects of rTMS and tDCS over the frontal cortex on negative symptoms, including an analysis of effects of sham stimulation. METHODS: Meta-analysis was applied, using a random effects model, to calculate mean weighted effect sizes (Cohen's d). Heterogeneity was assessed by using Cochrans Q and I2 tests. RESULTS: For rTMS treatment, the mean weighted effect size compared to sham stimulation was 0.64 (0.32-0.96; k = 22, total N = 827). Studies with younger participants showed stronger effects as compared to studies with older participants. For tDCS studies a mean weighted effect size of 0.50 (-0.07 to 1.07; k = 5, total N = 134) was found. For all frontal noninvasive neurostimulation studies together (i.e., TMS and tDCS studies combined) active stimulation was superior to sham, the mean weighted effect size was 0.61 (24 studies, 27 comparisons, 95% confidence interval 0.33-0.89; total N = 961). Sham rTMS (baseline - posttreatment comparison) showed a significant improvement of negative symptoms, d = 0.31 (0.09-0.52; k = 16, total N = 333). Whereas previous meta-analyses were underpowered, our meta-analysis had a power of 0.87 to detect a small effect. CONCLUSIONS: The available evidence indicates that noninvasive prefrontal neurostimulation can improve negative symptoms. This finding suggests a causal role for the lateral frontal cortex in self-initiated goal-directed behavior. The evidence is stronger for rTMS than for tDCS, although this may be due to the small number of studies as yet with tDCS. More research is needed to establish moderator variables that may affect response to neurostimulation and to optimize treatment parameters in order to achieve stable and durable (and thus clinically relevant) effects.

Natural Medicines for Psychotic Disorders: A Systematic Review.

Patients with psychotic disorders regularly use natural medicines, although it is unclear whether these are effective and safe. The aim of this study was to provide an overview of evidence for improved outcomes by natural medicines. A systematic literature search was performed through Medline, PsycINFO, CINAHL, and Cochrane until May 2015. In 110 randomized controlled trials, evidence was found for glycine, sarcosine, N-acetylcysteine, some Chinese and ayurvedic herbs, ginkgo biloba, estradiol, and vitamin B6 to improve psychotic symptoms when added to antipsychotics. Ginkgo biloba and vitamin B6 seemed to reduce tardive dyskinesia and akathisia. Results on other compounds were negative or inconclusive. All natural agents, except reserpine, were well tolerated. Most study samples were small, study periods were generally short, and most results need replication. However, there is some evidence for beneficial effects of certain natural medicines.

Effects of aripiprazole versus risperidone on brain activation during planning and social-emotional evaluation in schizophrenia: A single-blind randomized exploratory study.

Impaired function of prefrontal brain networks may be the source of both negative symptoms and neurocognitive problems in psychotic disorders. Whereas most antipsychotics may decrease prefrontal activation, the partial dopamine D2-receptor agonist aripiprazole is hypothesized to improve prefrontal function. This study investigated whether patients with a psychotic disorder would show stronger activation of prefrontal areas and associated regions after treatment with aripiprazole compared to risperidone treatment. In this exploratory pharmacological neuroimaging study, 24 patients were randomly assigned to either aripiprazole or risperidone. At baseline and after nine weeks treatment they underwent an interview and MRI session. Here we report on brain activation (measured with arterial spin labeling) during performance of two tasks, the Tower of London and the Wall of Faces. Aripiprazole treatment decreased activation of the middle frontal, superior frontal and occipital gyrus (ToL) and medial temporal and inferior frontal gyrus, putamen and cuneus (WoF), while activation increased after risperidone. Activation increased in the ventral anterior cingulate and posterior insula (ToL), and superior frontal, superior temporal and precentral gyrus (WoF) after aripiprazole treatment and decreased after risperidone. Both treatment groups had increased ventral insula activation (ToL) and middle temporal gyrus (WoF), and decreased occipital cortex, precuneus and caudate head activation (ToL) activation. In conclusion, patients treated with aripiprazole may need less frontal resources for planning performance and may show increased frontotemporal and frontostriatal reactivity to emotional stimuli. More research is needed to corroborate and extend these preliminary findings.

Neural basis of self-initiative in relation to apathy in a student sample.

Human behaviour can be externally driven, e.g. catching a falling glass, or self-initiated and goal-directed, e.g. drinking a cup of coffee when one deems it is time for a break. Apathy refers to a reduction of self-initiated goal-directed or motivated behaviour, frequently present in neurological and psychiatric disorders. The amount of undertaken goal-directed behaviour varies considerably in clinical as well as healthy populations. In the present study, we investigated behavioural and neural correlates of self-initiated action in a student sample (N = 39) with minimal to high levels of apathy. We replicated activation of fronto-parieto-striatal regions during self-initiation. The neural correlates of self-initiated action did not explain varying levels of apathy in our sample, neither when mass-univariate analysis was used, nor when multivariate patterns of brain activation were considered. Other hypotheses, e.g. regarding a putative role of deficits in reward anticipation, effort expenditure or executive difficulties, deserve investigation in future studies.

Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia: A 1H MRS study.

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 (1H 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 8mm3 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.

Effects of low frequency rTMS treatment on brain networks for inner speech in patients with schizophrenia and auditory verbal hallucinations.

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 1Hz 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 1Hz 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 gyrus 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 gyrus 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.

Treatment of negative symptoms: Where do we stand, and where do we go?

Negative symptoms, e.g. social withdrawal, reduced initiative, anhedonia and affective flattening, are notoriously difficult to treat. In this review, we take stock of recent research into treatment of negative symptoms by summarizing psychosocial as well as pharmacological and other biological treatment strategies. Major psychosocial approaches concern social skills training, cognitive behavior therapy for psychosis, cognitive remediation and family intervention. Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms. With regard to pharmacological interventions, antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms. Recent studies have investigated glutamatergic compounds, e.g. glycine receptor inhibitors and drugs that target the NMDA receptor or metabotropic glutamate 2/3 (mGlu2/3) receptor, but no consistent evidence of improvement of negative symptoms was found. Finally, some small studies have suggested improvement of negative symptoms after non-invasive electromagnetic neurostimulation, but this has only been partly replicated and it is still unclear whether these are robust improvements. We address methodological issues, in particular the heterogeneity of negative symptoms and treatment response, and suggest avenues for future research. There is a need for more detailed studies that focus on different dimensions of negative symptoms.

Association between prefrontal N-acetylaspartate and insight in psychotic disorders.

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 (1H-MRS). 1H-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 1H-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.

Effect of Bilateral Prefrontal rTMS on Left Prefrontal NAA and Glx Levels in Schizophrenia Patients with Predominant Negative Symptoms: An Exploratory Study.

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 1H-Magnetic Resonance Spectroscopy (1H-MRS). METHODS: Patients were randomized to a 3-week course of active or sham high-frequency rTMS. Pre-treatment 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.

Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders.

Apathy can be described as a loss of goal-directed purposeful behavior and is common in a variety of neurological and psychiatric disorders. Although previous studies investigated associations between abnormal brain functioning and apathy, it is unclear whether the neural basis of apathy is similar across different pathological conditions. The purpose of this systematic review was to provide an extensive overview of the neuroimaging literature on apathy including studies of various patient populations, and evaluate whether the current state of affairs suggest disorder specific or shared neural correlates of apathy. Results suggest that abnormalities within fronto-striatal circuits are most consistently associated with apathy across the different pathological conditions. Of note, abnormalities within the inferior parietal cortex were also linked to apathy, a region previously not included in neuroanatomical models of apathy. The variance in brain regions implicated in apathy may suggest that different routes towards apathy are possible. Future research should investigate possible alterations in different processes underlying goal-directed behavior, ranging from intention and goal-selection to action planning and execution.

Personality and coping in first episode psychosis linked to mental health care use.

A body of literature focuses on associations of neuroticism, extraversion, passive coping and active coping with the course of psychotic illness. Less is known about other personality and coping variables - and underlying causal mechanisms between variables remain unclear. We explored causal effects from personality, coping and symptoms on mental health care consumption over two years in 208 first episode patients. Causal inference search algorithms lead to formation of a hypothetical causal model based on presumptions on (non-)mutuality between variables and consistent with data. Structural equation modelling estimated effect sizes conditionally on the causal model. Our observed model implies that none of the coping or personality variables have any effect on the number of days of hospitalisation, whereas general psychopathology symptoms do have a direct positive effect. For ambulatory care it is proposed that openness to experience, depressive symptoms and age have direct positive effects. Reassuring thoughts as a coping strategy seems to have a direct negative effect on the use of ambulatory care and mediates indirect effects of other personality and coping variables on ambulatory care. Furthermore, while previously established relations between personality and symptoms are confirmed by our model, it challenges traditional ideas about causation between personality and symptoms.