The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function.

CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)-to better understand how they might induce risk. We recently reported effects on functional VF-related (for ZNF804A-rs1344706) and structural (for both) connectivity. We genotyped and fMRI-scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C-rs1006737, and its interaction with ZNF804A-rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions-PPI). Using public data, we reported effects of CACNA1C-rs1006737 and diagnosis on brain expression. The CACNA1C-rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto-temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up-regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole-brain, voxel-wise, and familywise-error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis-which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.

Schizophrenia moderates the relationship between white matter integrity and cognition.

Cognitive impairment is a primary feature of schizophrenia, with alterations in several cognitive domains appearing in the pre-morbid phase of the disorder. White matter microstructure is also affected in schizophrenia and considered to be related to cognition, but the relationship of the two is unclear. As interaction between cognition and white matter structure involves the interplay of several brain structures and cognitive abilities, investigative methods which can examine the interaction of multiple variables are preferred. A multiple-groups structural equation model (SEM) was used to assess the relationship between diffusion tension imaging data (fractional anisotropy of selected white matter tracts) and cognitive abilities of 196 subjects - 135 healthy subjects and 61 patients with schizophrenia. It was found that multiple-indicators, multiple-causes model best fitted the data analysed. Schizophrenia moderated the relation of white matter function on cognition with a large effect size. This paper extends previous work on modelling intelligence within a SEM framework by incorporating neurological elements into the model, and shows that white matter microstructure in patients with schizophrenia interacts with cognitive abilities.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.

Predictive validity of the Short-Term Assessment of Risk and Treatability (START) for multiple adverse outcomes: The effect of diagnosis.

The Short-Term Assessment of Risk and Treatability (START) assists risk assessment for seven risk outcomes based on scoring of risk and protective factors and assignment of clinically-informed risk levels. Its predictive validity for violence and self-harm has been established in males with schizophrenia, but accuracy across pathologically diverse samples is unknown. Routine START assessments and 3-month risk outcome data of N = 527 adult, inpatients in a UK secure mental health facility were collected. The sample was divided into diagnostic groups; predictive validity was established using receiver operating characteristics regression (rocreg) analysis in which potential covariates were controlled. In most single-diagnosis groups START risk factors ('vulnerabilities'), protective factors ('strengths'), and clinically-informed estimates predicted multiple risk outcomes with effect sizes similar to previous research. Self-harm was not predicted among patients with an organic diagnosis. The START risk estimates predicted physical aggression in all diagnostic groups, and verbal aggression, self-harm and self-neglect in most diagnostic groups. The START can assist assessment of aggressive, self-harm, and self-neglect across a range of diagnostic groups. Further research with larger sample sizes of those with multiple diagnoses is required.

White matter deficits in schizophrenia are global and don't progress with age.

INTRODUCTION: Diffusion tensor imaging has revealed differences in all examined white matter tracts in schizophrenia, with a range of explanations for why this may be. The distribution and timing of differences may help explain their origin; however, results are usually dependent on the analytical method. We therefore sought to examine the extent of differences and their relationship with age using two different methods. METHODS: A combined voxel-based whole-brain study and a tract-based spatial-statistics study of 104 patients with schizophrenia and 200 matched healthy controls, aged between 17 and 63 years. RESULTS: Fractional anisotropy was reduced throughout the brain in both analyses. The relationship of fractional anisotropy with age differed between patients and controls, with controls showing the gentle fractional anisotropy decline widely noted but patients showing an essentially flat relationship: younger patients had lower fractional anisotropy than controls, but the difference disappeared with age. Mean diffusivity was widely increased in patients. CONCLUSION: Reduction in fractional anisotropy and increase in mean diffusivity would be consistent with global disruption in myelination; the relationship with age would suggest this is present already at the onset of their illness, but does not progress.

Effects of risk for bipolar disorder on brain function: A twin and family study.

Bipolar disorder (BPD) is associated with altered regional brain function during the performance of cognitive tasks. The relative contribution of genetic and environmental risk factors for BPD to these changes has not yet been quantified. We sought to address this issue in a functional neuroimaging study of people who varied in their risk for BPD. Functional magnetic resonance imaging was used to study 124 subjects (29 twin and 9 sibling pairs with at least one member with BPD, and 24 healthy twin pairs) performing a working memory task. We assessed the influence of risk for BPD on regional brain function during the task in a two stage process. Firstly, we identified areas where there were group differences in activation. Secondly, we estimated the heritability and phenotypic correlation of activation and BPD using genetic modeling. BPD was associated with increased activation in the anterior cingulate, orbitofrontal, medial prefrontal, and left precentral cortices, and in the precuneus. Within these regions, activation in the orbitofrontal cortex rendered the most significant heritability estimate (h2=0.40), and was significantly correlated with BPD phenotype (rph=0.29). A moderate proportion of the genetic influences (rg=0.69) acting on both BPD and on the degree of orbitofrontal activation were shared. These findings suggest that genetic factors that confer vulnerability to BPD alter brain function in BPD.

Familial and environmental influences on brain volumes in twins with schizophrenia.

BACKGROUND: Reductions in whole brain and grey matter volumes are robust features of schizophrenia, yet their etiological influences are unclear. METHODS: We investigated the association between the genetic and environmental risk for schizophrenia and brain volumes. Whole brain, grey matter and white matter volumes were established from structural MRIs from twins varying in their zygosity and concordance for schizophrenia. Hippocampal volumes were measured manually. We conducted between-group testing and full genetic modelling. RESULTS: We included 168 twins in our study. Whole brain, grey matter, white matter and right hippocampal volumes were smaller in twins with schizophrenia. Twin correlations were larger for whole brain, grey matter and white matter volumes in monozygotic than dizygotic twins and were significantly heritable, whereas hippocampal volume was the most environmentally sensitive. There was a significant phenotypic correlation between schizophrenia and reductions in all the brain volumes except for that of the left hippocampus. For whole brain, grey matter and the right hippocampus the etiological links with schizophrenia were principally associated with the shared familial environment. Lower birth weight and perinatal hypoxia were both associated with lower whole brain volume and with lower white matter and grey matter volumes, respectively. LIMITATIONS: Scan data were collected across 2 sites, and some groups were modest in size. CONCLUSION: Whole brain, grey matter and right hippocampal volume reductions are linked to schizophrenia through correlated familial risk (i.e., the shared familial environment). The degree of influence of etiological factors varies between brain structures, leading to the possibility of a neuroanatomically specific etiological imprint.

Experiences of women in secure care who have been prescribed clozapine for borderline personality disorder.

BACKGROUND: Clozapine is an atypical antipsychotic medicine which can cause significant side-effects. It is often prescribed off-license in severe cases of borderline personality disorder contrary to national treatment guidelines. Little is known about the experiences of those who take clozapine for borderline personality disorder. We explored the lived-experience of women in secure inpatient care who were prescribed clozapine for borderline personality disorder. FINDINGS: Adult females (N = 20) participated in audio-taped semi-structured interviews. Transcripts were subject to thematic analysis. The central themes related to evaluation, wellbeing, understanding and self-management; for many, their subjective wellbeing on clozapine was preferred to prior levels of functioning and symptomatology, sometimes profoundly so. The negative and potentially adverse effects of clozapine were explained as regrettable but relatively unimportant. CONCLUSIONS: When psychological interventions are, at least initially, ineffective then clozapine treatment is likely to be evaluated positively by a group of women with borderline personality disorder in secure care despite the potential disadvantages.

White Matter Microstructural Organization Is Higher with Age in Adult Superior Cerebellar Peduncles.

Using diffusion tensor imaging, we conducted an exploratory investigation of the relationship between white matter tract microstructure and age in 200 healthy adult subjects using tract-based spatial statistics (TBSS). Though most tracts showed the slight decline in microstructural organization with age widely noted, in both superior cerebellar peduncles (SCP) it correlated positively with age, a result not previously reported. We confirmed this by using an alternative method, and by repeating our TBSS analysis in an additional sample of 133 healthy adults. In exploring this surprising result we considered the possibility that this might arise from the continual cognitive and motor refinement that is enacted in the cerebellum: we found that tract microstructure in both SCPs was also strongly correlated with IQ, again in contrast with all other tracts, and its relationship with age mediated by IQ, as a training model would predict.

Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder.

Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.

The Predictive Validity of the Short-Term Assessment of Risk and Treatability (START) for Multiple Adverse Outcomes in a Secure Psychiatric Inpatient Setting.

The Short-Term Assessment of Risk and Treatability (START) aims to assist mental health practitioners to estimate an individual's short-term risk for a range of adverse outcomes via structured consideration of their risk ("Vulnerabilities") and protective factors ("Strengths") in 20 areas. It has demonstrated predictive validity for aggression but this is less established for other outcomes. We collated START assessments for N = 200 adults in a secure mental health hospital and ascertained 3-month risk event incidence using the START Outcomes Scale. The specific risk estimates, which are the tool developers' suggested method of overall assessment, predicted aggression, self-harm/suicidality, and victimization, and had incremental validity over the Strength and Vulnerability scales for these outcomes. The Strength scale had incremental validity over the Vulnerability scale for aggressive outcomes; therefore, consideration of protective factors had demonstrable value in their prediction. Further evidence is required to support use of the START for the full range of outcomes it aims to predict.

Predictive validity of the HCR-20 for violent and non-violent sexual behaviour in a secure mental health service.

BACKGROUND: Violent and non-violent sexual behaviour is a fairly common problem among secure mental health service patients, but specialist sexual violence risk assessment is time-consuming and so performed infrequently. AIMS: We aimed to establish whether a commonly used violence risk assessment tool, the Health Clinical Risk management 20(HCR-20), has predictive validity specifically for inappropriate sexual behaviour. METHODS: A pseudo-prospective cohort design was used for a study in the adult wards of a large provider of specialist secure mental health services. Routine clinical team HCR-20 assessments were extracted from records, and incidents involving inappropriate sexual behaviour were recorded for the 3 months following assessment. RESULTS: Of 613 patients, 104 (17%) had engaged in at least one inappropriate sexual behaviour; in 65 (10.6%), the sexual act was violent. HCR-20 total score, clinical and risk management subscales, predicted violent and non-violent sexual behaviour. The negative predictive value of the HCR-20 for inappropriate sexual behaviour was over 90%. CONCLUSIONS: Prediction of violent sexual behaviour may be regarded as well within the scope of the HCR-20 as a structured professional judgement tool to aid violence risk prediction, but we found that it also predicts behaviours that may be of concern but fall below the violence threshold. High negative predictive values suggest that HCR-20 scores may have some utility for screening out patients who do not require more specialist assessment for inappropriate sexual behaviour. Copyright © 2015 John Wiley & Sons, Ltd.

Intrusive prospective imagery, posttraumatic intrusions and anxiety in schizophrenia.

Trauma exposure and intrusive thoughts are commonly reported in both schizophrenia and posttraumatic stress disorder (PTSD). Information processing accounts suggest that intrusions occur in the two conditions as a result of insufficient state and/or trait contextual processing in long-term memory. Most research has focused on intrusions about past events, while growing evidence suggests that intrusions about prospective imagined events warrants further investigation. Prospective intrusive imagery has yet to be examined in psychotic disorders but could provide crucial information regarding the aetiology and maintenance of psychotic symptoms. The current study examines the role of prospective intrusive imagery, posttraumatic intrusions and anxiety in schizophrenia. Fifty-seven participants (30 patients and 27 healthy controls) completed measures of trauma, PTSD, anxiety, general non-affective use of imagery, and intrusive prospective imagery. Patients reported significantly more intrusive prospective imagery relative to control participants but, importantly, not greater use of general non-affective imagery. Intrusive prospective imagery was associated with posttraumatic intrusions and anxiety in schizophrenia. The findings are consistent with information processing models of intrusions and psychosis, and provide novel insights for theoretical accounts, clinical formulation and therapeutic targets for psychotic symptoms in schizophrenia.

Differential predictive validity of the Historical, Clinical and Risk Management Scales (HCR-20) for inpatient aggression.

The Historical, Clinical and Risk Management Scales (HCR-20) may be a better predictor of inpatient aggression for selected demographic and clinical groups but homogeneity of study samples has prevented definitive conclusions. The aim of this study, therefore, was to test the predictive validity of the HCR-20 as a function of gender, diagnosis, age, and ethnicity while controlling for potential covariates. A pseudo-prospective cohort study (n=505) was conducted in a UK secure/forensic mental health setting using routinely collected data. The HCR-20 predicted aggression better for women than men, and for people with schizophrenia and/or personality disorder than for other diagnostic groups. In women, the presence of the risk management items (R5) was important while men׳s aggression was best predicted solely by current clinical features from the C5 scale. R5 items were better than C5 items for predicting aggression in people with organic and developmental diagnoses. Our data provide additional information on which HCR-20 raters can formulate overall summary judgements about risk for inpatient aggression based on important demographic and clinical characteristics.

Predictive validity of the HCR-20 for inpatient self-harm.

BACKGROUND: Few instruments have been developed to assess the risk of self-harm by psychiatric patients and the evidence for their predictive validity is limited. Given that individuals who self-harm may also engage in other-directed aggression, and that the behaviour can be a precursor to violence, we tested whether, and for which groups, the commonly used violence risk assessment HCR-20 demonstrated predictive validity for self-harm. PROCEDURES: A pseudo-prospective cohort study (N=504) was conducted in a UK secure/forensic mental health setting using routinely collected data. HCR-20 assessments were completed by the clinical team and incidents of self-harm during the 3months following assessment were coded from patient records. FINDINGS: The HCR-20 total score, H10 and R5 subscales, and SJ for violence significantly predicted self-harm; however, AUC values did not demonstrate large effect sizes (range .345 to .749). Personality disorder and impulsivity were the strongest predictors of self-harm, but the R5 scale contained the greatest proportion of relevant items. Predictive efficacy was superior for women compared with men and for those with schizophrenia or personality disorder compared with organic and developmental disorders. CONCLUSIONS: The HCR-20 appears to be a significant predictor of self-harm. It may be possible to supplement HCR-20 ratings with case specific knowledge and additional known risk factors for self-harm to make a valuable summary judgement about the behaviour and thus minimise the need for multiple assessment tools.

Gender influence on white matter microstructure: a tract-based spatial statistics analysis.

BACKGROUND: Sexual dimorphism in human brain structure is well recognised, but less is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore gender differences in fractional anisotropy (FA), an index of microstructural integrity. We previously found increased FA in the corpus callosum in women, and increased FA in the cerebellum and left superior longitudinal fasciculus (SLF) in men, using a whole-brain voxel-based analysis. METHODS: A whole-brain tract-based spatial statistics analysis of 120 matched subjects from the previous analysis, and 134 new subjects (147 men and 107 women in total) using a 1.5T scanner, with division into tract-based regions of interest. RESULTS: Men had higher FA in the superior cerebellar peduncles and women had higher FA in corpus callosum in both the first and second samples. The higher SLF FA in men was not found in either sample. DISCUSSION: We confirmed our previous, controversial finding of increased FA in the corpus callosum in women, and increased cerebellar FA in men. The corpus callosum FA difference offers some explanation for the otherwise puzzling advantage in inter-callosal transfer time shown in women; the cerebellar FA difference may be associated with the developmental motor advantage shown in men.

Facial emotion processing in borderline personality disorder: a systematic review and meta-analysis.

A body of work has developed over the last 20 years that explores facial emotion perception in Borderline Personality Disorder (BPD). We identified 25 behavioural and functional imaging studies that tested facial emotion processing differences between patients with BPD and healthy controls through a database literature search. Despite methodological differences there is consistent evidence supporting a negative response bias to neutral and ambiguous facial expressions in patients. Findings for negative emotions are mixed with evidence from individual studies of an enhanced sensitivity to fearful expressions and impaired facial emotion recognition of disgust, while meta-analysis revealed no significant recognition impairments between BPD and healthy controls for any negative emotion. Mentalizing studies indicate that BPD patients are accurate at attributing mental states to complex social stimuli. Functional neuroimaging data suggest that the underlying neural substrate involves hyperactivation in the amygdala to affective facial stimuli, and altered activation in the anterior cingulate, inferior frontal gyrus and the superior temporal sulcus particularly during social emotion processing tasks. Future studies must address methodological inconsistencies, particularly variations in patients' key clinical characteristics and in the testing paradigms deployed.

A case series of clozapine for borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a common, debilitating disorder for which the evidence base for treatment is modest. This case series aimed to explore preliminary evidence of clozapine's effectiveness for patients with severe BPD. METHODS: We examined the case notes of 22 female inpatients with a primary diagnosis of BPD who had started treatment with clozapine. Baseline routine clinical data were extracted from the records and at 6 monthly intervals thereafter, up to a maximum of 18 months after starting treatment. Patients also were interviewed about their experiences. RESULTS: We found evidence for a beneficial effect of clozapine across several clinical domains. Symptom severity, need for enhanced observations, use of additional medication, and the number of aggressive incidents all significantly improved after clozapine. The greatest improvements appeared within the first 6 months of initiating treatment. There also was a significant increase in weight. CONCLUSIONS: The results suggest that clozapine, with suitable health monitoring, may be beneficial for this clinical population. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings.

Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity.

The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.

Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia.

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.