Dissociable auditory mismatch response and connectivity patterns in adolescents with schizophrenia and adolescents with bipolar disorder with psychosis: A magnetoencephalography study

BACKGROUND: There is overlap between schizophrenia and bipolar disorder regarding genetic risk as well as neuropsychological and structural brain deficits. Finding common and distinct event-response potential (ERP) responses and connectivity patterns may offer potential biomarkers to distinguish the disorders. OBJECTIVE: To examine the neuronal auditory response elicited by a roving mismatch negativity (MMN) paradigm using magnetoencephalography (MEG). PARTICIPANTS: 15 Adolescents with schizophrenia (ASZ), 16 adolescents with bipolar disorder with psychosis (ABP), and 14 typically developing individuals (TD) METHODS: The data were analysed using time-series techniques and dynamic causal modelling (DCM). OUTCOME MEASURES: MEG difference wave (deviant - standard) at primary auditory (~90ms), MMN (~180ms) and long latency (~300ms). RESULTS: The amplitude of difference wave showed specific patterns at all latencies. Most notably, it was significantly reduced ABP compared to both controls and ASZ at early latencies. In contrast, the amplitude was significantly reduced in ASZ compared to both controls and ABP. The DCM analysis showed differential connectivity patterns in all three groups. Most notably, inter-hemispheric connections were strongly dominated by the right side in ASZ only. CONCLUSIONS: Dissociable patterns of the primary auditory response and MMN response indicate possible developmentally sensitive, but separate biomarkers for schizophrenia and bipolar disorder

Adsorption of C-82 on Si(100)

The interactions between C82 molecules and the Si(1 0 0) surface have been explored via ab initio total energy calculations. Configurations which have the cage located within the dimer trench bonded to four dimers (t4) and upon the dimer row bonded to two dimers (r2) have been investigated, as these were found to be most stable for the C60 molecule. It is found that the interactions between the surface and the C82 molecule are weaker than for the corresponding configurations for C60. The C82 cage has a far lower symmetry than the C60 cage and this gives many more unique rotational orientations of C82 compared with C60. We have, thus, investigated the binding energy when the local area of the C82 binding to the surface is the same but the cage orientation varies. We show that the binding energy can vary strongly within the configurations investigated. Bader analysis has been used to explain the relative binding energies of the different configurations

Interaction of C-60 molecules on Si(100)

The interactions between pairs of C60 molecules adsorbed upon the Si(1 0 0) surface have been studied via a series of DFT calculations. Configurations which have the fullerene cage located within the dimer trench bonded to four dimers (t4) have been investigated, as these have previously been found to be among the most stable for the C60 molecule. These t4 configurations are explored with all possible pairs of fullerene configuration combinations considered. We have looked at two distinct groups of separation distances between the two C60 molecules. These have the fullerene bonding sites as either adjacent to one another or separated by one Si surface dimer. Comparisons between the two groups confirm the trend of the combinations becoming more favourable at a greater fullerene separation. In the systems with adjacent bonding sites the combined pair of fullerenes were in general less favourable than the two isolated cases. At the longer fullerene separation distance this trend was reversed. The longer fullerene separation distance reflects the experimental separation observed by Moriarty et al. [P. Moriarty, Y.R. Ma, M.D. Upward, P.H. Beton, Surf. Sci. 407 (1998) 27]

Towards a clinical staging for bipolar disorder: defining patient subtypes based on functional outcome.

BACKGROUND: The functional outcome of Bipolar Disorder (BD) is highly variable. This variability has been attributed to multiple demographic, clinical and cognitive factors. The critical next step is to identify combinations of predictors that can be used to specify prognostic subtypes, thus providing a basis for a staging classification in BD. METHODS: Latent Class Analysis was applied to multiple predictors of functional outcome in a sample of 106 remitted adults with BD. RESULTS: We identified two subtypes of patients presenting "good" (n=50; 47.6%) and "poor" (n=56; 52.4%) outcome. Episode density, level of residual depressive symptoms, estimated verbal intelligence and inhibitory control emerged as the most significant predictors of subtype membership at the p<0.05 level. Their odds ratio (OR) and confidence interval (CI) with reference to the "good" outcome group were: episode density (OR=4.622, CI 1.592-13.418), level of residual depressive symptoms (OR=1.543, CI 1.210-1.969), estimated verbal intelligence (OR=0.969; CI 0.945-0.995), and inhibitory control (OR=0.771, CI 0.656-0.907). Age, age of onset and duration of illness were comparable between prognostic groups. LIMITATIONS: The longitudinal stability or evolution of the subtypes was not tested. CONCLUSIONS: Our findings provide the first empirically derived staging classification of BD based on two underlying dimensions, one for illness severity and another for cognitive function. This approach can be further developed by expanding the dimensions included and testing the reproducibility and prospective prognostic value of the emerging classes. Developing a disease staging system for BD will allow individualised treatment planning for patients and selection of more homogeneous patient groups for research purposes

Clozapine use in childhood and adolescent schizophrenia: A nationwide population-based study

Early onset schizophrenia (EOS) begins in childhood or adolescence. EOS is associated with poor treatment response and may benefit from timely use of clozapine. This study aimed to identify the predictors of clozapine use in EOS and characterize the clinical profile and outcome of clozapine-treated youths with schizophrenia. We conducted a nationwide population-based study using linked data from Danish medical registries. We examined all incident cases of EOS (i.e., cases diagnosed prior to their 18th birthday) between December 31st 1994 and December 31st 2006 and characterized their demographic, clinical and treatment profiles. We then used multivariable cox proportional hazard models to identify predictors of clozapine treatment in this patient population. We identified 662 EOS cases (1.9% of all schizophrenia cases), of whom 108 (17.6%) had commenced clozapine by December 31st 2008. Patients had on average 3 antipsychotic trials prior to clozapine initiation. The mean interval between first antipsychotic treatment and clozapine initiation was 3.2 (2.9) years. Older age at diagnosis of schizophrenia [HR=1.2, 95% CI (1.05-1.4), p=0.01], family history of schizophrenia [HR=2.1, 95% CI (1.1-3.04), p=0.02] and attempted suicide [HR=1.8, 95% CI (1.1-3.04), p=0.02] emerged as significant predictors of clozapine use. The majority of patients (n=96, 88.8%) prescribed clozapine appeared to have a favorable clinical response as indicated by continued prescription redemption and improved occupational outcomes. Our findings support current recommendations for the timely use of clozapine in EOS

Accelerated Global and Local Brain Aging Differentiate Cognitively Impaired From Cognitively Spared Patients With Schizophrenia

BACKGROUND: Accelerated aging has been proposed as a mechanism underlying the clinical and cognitive presentation of schizophrenia. The current study extends the field by examining both global and regional patterns of brain aging in schizophrenia, as inferred from brain structural data, and their association with cognitive and psychotic symptoms. METHODS: Global and local brain-age-gap-estimates (G-brainAGE and L-brainAGE) were computed using a U-Net Model from T(1)-weighted structural neuroimaging data from 84 patients (aged 16–35 years) with early-stage schizophrenia (illness duration <5 years) and 1,169 healthy individuals (aged 16–37 years). Multidomain cognitive data from the patient sample were submitted to Heterogeneity through Discriminative Analysis (HYDRA) to identify cognitive clusters. RESULTS: HYDRA classified patients into a cognitively impaired cluster (n = 69) and a cognitively spared cluster (n = 15). Compared to healthy individuals, G-brainAGE was significantly higher in the cognitively impaired cluster (+11.08 years) who also showed widespread elevation in L-brainAGE, with the highest deviance observed in frontal and temporal regions. The cognitively spared cluster showed a moderate increase in G-brainAGE (+8.94 years), and higher L-brainAGE localized in the anterior cingulate cortex. Psychotic symptom severity in both clusters showed a positive but non-significant association with G-brainAGE. DISCUSSION: Accelerated aging in schizophrenia can be detected at the early disease stages and appears more closely associated with cognitive dysfunction rather than clinical symptoms. Future studies replicating our findings in multi-site cohorts with larger numbers of participants are warranted

Parvovirus 4 Infection and Clinical Outcome in High-Risk Populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n=469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clea

Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study

Altered neuroplasticity is increasingly invoked as a mechanism underpinning dysconnectivity in schizophrenia. We used Dynamic Causal Modelling to compare connectivity during the magnetic auditory Mismatch Negativity (MMN), an index of error prediction, between schizophrenia patients and controls. Patients showed reduced intrinsic connectivity within the primary auditory cortex suggestive of impaired local neuronal adaptation and disrupted forward and backward extrinsic connectivity throughout the MMN network indicative of reduced higher order input in disambiguating activity in lower network nodes. Our study provides the first empirical description of the dysplastic changes underpinning dysconnectivity between primary sensory and higher order cortical areas in schizophrenia

Sex differences in predictors and regional patterns of brain age gap estimates

The brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data and is considered a biomarker of brain health. Understanding sex differences in brainAGE is a significant step toward precision medicine. Global and local brainAGE (G-brainAGE and L-brainAGE, respectively) were computed by applying machine learning algorithms to brain structural magnetic resonance imaging data from 1113 healthy young adults (54.45% females; age range: 22–37 years) participating in the Human Connectome Project. Sex differences were determined in G-brainAGE and L-brainAGE. Random forest regression was used to determine sex-specific associations between G-brainAGE and non-imaging measures pertaining to sociodemographic characteristics and mental, physical, and cognitive functions. L-brainAGE showed sex-specific differences; in females, compared to males, L-brainAGE was higher in the cerebellum and brainstem and lower in the prefrontal cortex and insula. Although sex differences in G-brainAGE were minimal, associations between G-brainAGE and non-imaging measures differed between sexes with the exception of poor sleep quality, which was common to both. While univariate relationships were small, the most important predictor of higher G-brainAGE was self-identification as non-white in males and systolic blood pressure in females. The results demonstrate the value of applying sex-specific analyses and machine learning methods to advance our understanding of sex-related differences in factors that influence the rate of brain aging and provide a foundation for targeted interventions

Multimodal Brain Changes in First-Episode Mania: A Voxel-Based Morphometry, Functional Magnetic Resonance Imaging, and Connectivity Study

Background: Brain structural and functional changes in bipolar disorder (BD) are well-established findings, but it is uncertain whether these changes are already present in first episode mania (FEM). Methods: We compared 31 FEM subjects, with 31 healthy individuals matched for age, sex, and premorbid IQ. Whole-brain voxel-wise morphometry, functional magnetic resonance imaging during the n-back task, and a functional connectivity analysis were performed. Results: There were no volumetric differences between the 2 groups. During the 2-back task, FEM patients did not perform differently from controls and activated similar regions, but they showed less deactivation in the ventromedial prefrontal cortex (vmPFC), the anterior hub of the default mode network (DMN). They showed preserved functional connectivity between the vmPFC and other regions of the DMN, but increased connectivity with the superior frontal gyrus. Conclusions: The absence of volumetric changes in FEM patients suggests that these changes could be related to progression of the illness. On the other hand, the failure of deactivation of the anterior hub of the DMN is present from the onset of the illness and may represent a core pathophysiological feature of BD