Anna Walter

BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis.

BACKGROUND Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and synaptic plasticity in the central nervous system, especially in the hippocampus, and has been implicated in the pathophysiology of several neuropsychiatric disorders. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a functionally relevant single nucleotide polymorphism affecting the secretion of BDNF and is implicated in differences in hippocampal volumes. METHODS This is a systematic meta-analytical review of findings from imaging genetic studies on the impact of the rs6265 SNP on hippocampal volumes in neuropsychiatric patients with major depressive disorder, anxiety, bipolar disorder or schizophrenia. RESULTS The overall sample size of 18 independent clinical cohorts comprised 1695 patients. Our results indicated no significant association of left (Hedges g=0.08, p=0.12), right (g=0.07, p=0.22) or bilateral (g=0.07, p=0.16) hippocampal volumes with BDNF rs6265 in neuropsychiatric patients. There was no evidence for a publication bias or any demographic, clinical, or methodological moderating effects. Both Val/Val homozygotes (g=0.32, p=0.004) and Met-carriers (g=0.20, p=0.004) from the patient sample had significantly smaller hippocampal volumes than the healthy control sample with the same allele. The magnitude of these effects did not differ between the two genotypes. CONCLUSION This meta-analysis suggests that there is no association between this BDNF polymorphism and hippocampal volumes. For each BDNF genotype, the hippocampal volumes were significantly lower in neuropsychiatric patients than in healthy controls.

Effects of Cannabis on Impulsivity: A Systematic Review of Neuroimaging Findings

We conducted a systematic review to assess the evidence for specific effects of cannabis on impulsivity, disinhibition and motor control. The review had a specific focus on neuroimaging findings associated with acute and chronic use of the drug and covers literature published up until May 2012. Seventeen studies were identified, of which 13 met the inclusion criteria; three studies investigated acute effects of cannabis (1 fMRI, 2 PET), while six studies investigated non-acute functional effects (4 fMRI, 2 PET), and four studies investigated structural alterations. Functional imaging studies of impulsivity studies suggest that prefrontal blood flow is lower in chronic cannabis users than in controls. Studies of acute administration of THC or marijuana report increased brain metabolism in several brain regions during impulsivity tasks. Structural imaging studies of cannabis users found differences in reduced prefrontal volumes and white matter integrity that might mediate the abnormal impulsivity and mood observed in marijuana users. To address the question whether impulsivity as a trait precedes cannabis consumption or whether cannabis aggravates impulsivity and discontinuation of usage more longitudinal study designs are warranted.

Hippocampal volume in subjects at high risk of psychosis: A longitudinal MRI study

INTRODUCTION The hippocampal formation has been studied extensively in schizophrenic psychoses and alterations in hippocampal anatomy have been consistently reported. Chronic schizophrenia seems to be associated with bilateral hippocampal volume (HV) reduction, while in patients with an at-risk mental state (ARMS) there are contradictory results. This is the first region of interest (ROI) based follow-up MRI study of hippocampal volume comparing ARMS individuals with and without transition to psychosis. The aim was to investigate the timing of HV changes in ARMS in the early phase of psychosis. METHODS Magnetic resonance imaging data from 18 antipsychotic-naïve individuals with an ARMS were collected within the FePsy-clinic for early detection of psychoses. During follow-up 8 subjects transitioned to psychosis (ARMS-T) and 10 did not (ARMS-NT). Subjects were re-scanned after the onset of psychosis or at the end of the follow-up if they did not develop psychosis. RESULTS Across both groups there was a significant decrease in HV over time (p<0.05). There was no significant difference in progression between ARMS-T and ARMS-NT. Antipsychotic medication at follow up was associated with increased HV (p<0.05). CONCLUSIONS We found a decrease of HV over time in subjects with an ARMS, independently of clinical outcome. We may speculate that the decrease of HV over time might reflect brain degeneration processes.

Modulation of motivational salience processing during the early stages of psychosis

BACKGROUND Deficits in motivational salience processing have been related to psychotic symptoms and disturbances in dopaminergic neurotransmission. We aimed at exploring changes in salience processing and brain activity during different stages of psychosis and antipsychotic medication effect. METHODS We used fMRI during the Salience Attribution Task to investigate hemodynamic differences between 19 healthy controls (HCs), 34 at-risk mental state (ARMS) individuals and 29 individuals with first-episode psychosis (FEP), including a subgroup of 17 FEP without antipsychotic medication (FEP-UM) and 12 FEP with antipsychotic medication (FEP-M). Motivational salience processing was operationalized by brain activity in response to high-probability rewarding cues (adaptive salience) and in response to low-probability rewarding cues (aberrant salience). RESULTS Behaviorally, adaptive salience response was not accelerated in FEP, although they correctly distinguished between trials with low and high reward probability. In comparison to HC, ARMS exhibited a lower hemodynamic response during adaptive salience in the right inferior parietal lobule and FEP-UM in the left dorsal cingulate gyrus. The FEP-M group exhibited a lower adaptive salience response than HC in the right insula and than ARMS in the anterior cingulate gyrus. In unmedicated individuals, the severity of hallucinations and delusions correlated negatively with the insular- and anterior cingulate hemodynamic response during adaptive salience. We found no differences in aberrant salience processing associated with behavior or medication. CONCLUSION The changes in adaptive motivational salience processing during psychosis development reveal neurofunctional abnormalities in the somatosensory and premotor cortex. Antipsychotic medication seems to modify hemodynamic responses in the anterior cingulate and insula.

The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: A joint meta-analysis of published and new data

BACKGROUND The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functionally relevant single nucleotide polymorphism (SNP). The gene itself, as well as the SNP rs6265, have been implicated in hippocampal learning and memory. However, imaging genetic studies have produced controversial results about the impact of this SNP on hippocampal volumes in healthy subjects. METHODS We examined the association between the rs6265 polymorphism and hippocampal volume in 643 healthy young subjects using automatic segmentation and subsequently included these data in a meta-analysis based on published studies with 5298 healthy subjects in total. RESULTS We found no significant association between SNP rs6265 and hippocampal volumes in our sample (g=0.05, p=0.58). The meta-analysis revealed a small, albeit significant difference in hippocampal volumes between genotype groups, such that Met-carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (g=0.09, p=0.04), an association that was only evident when manual (g=0.22, p=0.01) but not automatic tracing approaches (g=0.04, p=0.38) were used. Studies using manual tracing showed evidence for publication bias and a significant decrease in effect size over the years with increasing sample sizes. CONCLUSIONS This study does not support the association between SNP rs6265 and hippocampal volume in healthy individuals. The weakly significant effect observed in the meta-analysis is mainly driven by studies with small sample sizes. In contrast, our original data and the meta-analysis of automatically segmented hippocampal volumes, which was based on studies with large samples sizes, revealed no significant genotype effect. Thus, meta-analyses of the association between rs6265 and hippocampal volumes should consider possible biases related to measuring technique and sample size.

Duration of untreated psychosis and cognitive functioning.

BACKGROUND Studies examining the influence of duration of untreated psychosis (DUP) or duration of untreated illness (DUI) on cognition vary with regard to results and methods. This study is the first in this field to include an at risk mental state with later transition to psychosis (ARMS-T) sample and to analyse how the DUI relates to their cognitive functioning. Because methodological operationalization of cognitive functioning in previous studies is highly heterogeneous, we aimed to compare different approaches. METHOD 60 first episode psychosis (FEP) patients and 24 ARMS-T patients were examined. Associations between DUP, DUI and neurocognitive performance were tested by three different operationalizations of cognition: as the raw outcome measure of different neuropsychological tests, as outcome scores which were normed on a sample of 75 healthy participants, and as the deterioration index (DI). RESULTS There were no significant correlations between DUP or DUI and outcome of neuropsychological tests in both normed and raw scores. When adjusted for covariates, DUP and DUI also did not significantly predict any cognitive performance. There was no significant relationship between DUP or DUI and the DI index. However, longer DUP and DUI were significantly associated with stronger negative symptoms. CONCLUSIONS This study could not confirm an association between duration of untreated psychosis or duration of untreated illness and neurocognitive performance in the ARMS-T and FEP samples. This could be because schizophrenic psychoses are neurodevelopmental disorders in which most cognitive deficits exist long before the onset of psychiatric symptoms.

Cannabis use and brain structural alterations of the cingulate cortex in early psychosis

As cannabis use is more frequent in patients with psychosis than in the general population and is known to be a risk factor for psychosis, the question arises whether cannabis contributes to recently detected brain volume reductions in schizophrenic psychoses. This study is the first to investigate how cannabis use is related to the cingulum volume, a brain region involved in the pathogenesis of schizophrenia, in a sample of both at-risk mental state (ARMS) and first episode psychosis (FEP) subjects. A cross-sectional magnetic resonance imaging (MRI) study of manually traced cingulum in 23 FEP and 37 ARMS subjects was performed. Cannabis use was assessed with the Basel Interview for Psychosis. By using repeated measures analyses of covariance, we investigated whether current cannabis use is associated with the cingulum volume, correcting for age, gender, alcohol consumption, whole brain volume and antipsychotic medication. There was a significant three-way interaction between region (anterior/posterior cingulum), hemisphere (left/right cingulum) and cannabis use (yes/no). Post-hoc analyses revealed that this was due to a significant negative effect of cannabis use on the volume of the posterior cingulum which was independent of the hemisphere and diagnostic group and all other covariates we controlled for. In the anterior cingulum, we found a significant negative effect only for the left hemisphere, which was again independent of the diagnostic group. Overall, we found negative associations of current cannabis use with grey matter volume of the cingulate cortex, a region rich in cannabinoid CB1 receptors. As this finding has not been consistently found in healthy controls, it might suggest that both ARMS and FEP subjects are particularly sensitive to exogenous activation of these receptors.

Evidence for an agitated–aggressive syndrome predating the onset of psychosis

BACKGROUND Aggression and suicidality prior to the initiation of treatment are frequent phenomena in psychosis patients. Increased scores in the Brief Psychiatric Rating Scale Excited Component (BPRS-EC) have been shown to predict involuntary treatment, aggression, and suicide in first-episode psychosis (FEP) patients. However, it is unclear if an agitated-aggressive syndrome as measured with the BPRS-EC is already present in at-risk mental state (ARMS). METHODS BPRS-EC scores from 43 ARMS patients, 50 FEP patients, and 25 healthy controls (HC) were analyzed. Multivariate analyses were performed to review if group differences were mediated by potential confounders. In addition, the association of BPRS-EC scores with clinical variables was examined. RESULTS BPRS-EC scores were significantly different across diagnostic groups (H(2)=22.1; p<.001), and post-hoc analyses showed significantly higher BPRS-EC scores for ARMS (p=.001) and for FEP patients (p<.001) compared to HC. Differences remained significant after controlling for gender, years of education, and intelligence. No significant differences emerged between ARMS and FEP patients. BPRS-EC was significantly correlated with lower intelligence (r=-.27; p=.008), reduced level of functioning (r=-.44; p<.001), and with smoking behavior (r=.22; p=.019). CONCLUSIONS ARMS and FEP patients in our sample had significantly higher BPRS-EC scores compared to HC. This may constitute a correlate of an agitated-aggressive syndrome and an increased risk for aggression and suicidality.

Pituitary gland volume in at-risk mental state for psychosis: a longitudinal MRI analysis.

INTRODUCTION Pituitary enlargement has been reported in individuals with schizophrenic psychosis or an at-risk mental state for psychosis (ARMS). In a previous study, our group could show pituitary volume increase in first episode and ARMS patients with later transition to psychosis (ARMS-T). However, there are no longitudinal studies on this issue so far. We therefore examined longitudinally whether transition to psychosis would be accompanied by a further increase of pituitary volume in antipsychotic-naïve ARMS patients. METHODS Magnetic resonance imaging (MRI) data were acquired from 23 antipsychotic-naïve individuals with an ARMS. Ten subjects developed psychosis (ARMS-T) and 13 did not (ARMS-NT). ARMS-T were re-scanned after the onset of psychosis, and ARMS-NT were re-scanned at the end of the study period. RESULTS There was no significant difference of the pituitary volume between ARMS-T and ARMS-NT in our sample, and there were no significant pituitary volume changes over time. Discussion Longitudinally, we could not detect any further volumetric changes in the pituitary volume with transition to psychosis. CONCLUSIONS This, together with the result of our previous study, could indicate that the perceived level of stress in ARMS patients is constantly high from very early onward.

Alterations in the hippocampus and thalamus in individuals at high risk for psychosis

Reduction in hippocampal volume is a hallmark of schizophrenia and already present in the clinical high-risk state. Nevertheless, other subcortical structures, such as the thalamus, amygdala and pallidum can differentiate schizophrenia patients from controls. We studied the role of hippocampal and subcortical structures in clinical high-risk individuals from two cohorts. High-resolution T1-weighted structural MRI brain scans of a total of 91 clinical high-risk individuals and 64 healthy controls were collected in two centers. The bilateral volume of the hippocampus, the thalamus, the caudate, the putamen, the pallidum, the amygdala, and the accumbens were automatically segmented using FSL-FIRST. A linear mixed-effects model and a prospective meta-analysis were applied to assess group-related volumetric differences. We report reduced hippocampal and thalamic volumes in clinical high-risk individuals compared to healthy controls. No volumetric alterations were detected for the caudate, the putamen, the pallidum, the amygdala, or the accumbens. Moreover, we found comparable medium effect sizes for group-related comparison of the thalamus in the two analytical methods. These findings underline the relevance of specific alterations in the hippocampal and subcortical volumes in the high-risk state. Further analyses may allow hippocampal and thalamic volumes to be used as biomarkers to predict psychosis.