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Background Deviation in level of intrinsic activity (IA; what some call "background brain state" or "resting state"), quantified from ongoing EEG/MEG, has been observed in psychosis. Neurophysiological models of psychosis have leaned on this physiological indicator as a possible core deviation. Translational models of IA deviations hold promise for identifying multiple distinct physiological mechanisms for psychosis manifestation. IA deviations may cause diminished signal-to-noise ratios, and contribute to, or at least set the stage for, psychosis-related problems like identifying stimulus salience. B-SNIP published a means for categorizing psychosis cases by neurobiological homology through use of multiple biomarkers (psychosis Biotypes) rather than by surface level clinical features. B-SNIP demonstrated the superiority of Biotypes versus DSM diagnoses for capturing neurobiological similarity through comparisons on multiple external validating measures (social functioning, measures of brain volume from structural magnetic resonance images, clinical diagnoses of the first-degree relatives, and biomarker features among clinically healthy first-degree relatives). Independent analyses since the initial publication have provided additional support for the usefulness of psychosis Biotypes, and the psychosis Biotypes have been replicated in an independent sample (B-SNIP2). In this presentation we interrogated B-SNIP1 data for whether there is evidence of differential IA patterns as a function of treatment with Clozapine (should be higher) versus Depakote (should be lower). Because Biotype-1 cases are defined by low intrinsic activity, Clozapine should bring them closer to healthy values and Depakote should take them farther from healthy values. Alternatively, because Biotype-2 cases are defined by high intrinsic activity, Clozapine should take them farther from healthy values and Depakote should take them closer to healthy values. Methods For this project, we analyzed ongoing neural activity from 64 EEG sensors during 150 intervals of 10 sec duration from over 1450 B-SNIP subjects. These data were from the inter-trial interval (ITI) of an auditory paired-stimuli task used in Biotypes construction (although the ITI data themselves were not used). Although the subjects were engaged in a task (the counting of the number of presented stimulus pairs), the data used here were not part of the task itself. Data were evaluated for single trial power (an estimate of strength of neural response on individual trials) as a function of frequency of neural oscillations (from 2–50 Hz) over the whole head. Data were then averaged over single trials to yield an estimate of the overall strength of nonspecific (unrelated to sensory processing) neural activity. Probands were also grouped by whether they were treated with either Clozapine or Depakote (but not both). Results When evaluated as a function of DSM psychosis diagnoses (schizophrenia, schizoaffective disorder, bipolar disorder), the 95% confidence intervals for all groups overlapped the healthy group means across all frequencies. When considered by psychosis Biotypes, however, differences were both obvious and statistically significant. In comparison to healthy persons, Biotype-2 probands (the most neurophysiologically activated subgroup based on previous analyses) were notably high on intrinsic neural activity, and Biotype-1 probands (the most cognitively and neurophysiologically compromised subgroup based on previous analysis) were notably low on intrinsic neural activity. Group separations on this metric were better than those obtained with the original intrinsic EEG measure used to construct psychosis Biotypes. Furthermore, Clozapine treatment was associated with higher intrinsic activity, which normalized Biotype-1 but worsened Biotype-2. Depakote treatment was associated with lower intrinsic activity, which normalized Biotype-2 but worsened Biotype-1. When these same biomarker outcomes were considered by DSM diagnoses, the results were less convincing. Conclusions Intrinsic neural activity, quantifiable in numerous ways is an effective metric for capturing a meaningful component of Biotype neurophysiology. This was true across a range of oscillatory frequencies for the probands. Biotypes subgrouping may provide a means for meaningful and clinically useful neuroscience-based predictions of treatment response in psychosis. [ABSTRACT FROM AUTHOR]

Background Evidence suggests that clinical phenomenology incompletely captures biologically meaningful differentiations in psychosis. The Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) consortium has employed cognitive and neurophysiological measures to identify three biologically distinct Biotypes, agnostic to clinical features. Biotype 1, 2, and 3, have distinctive neurobiological characteristics: Biotype 1 cases have significant neurocognitive impairment, high numbers of clinically affected relatives, and poor psychosocial functioning. Biotype 2 cases have high neural reactivity and more modest but significant cognitive impairment. Biotype 3 cases have nearly normal cognition and neural reactivity and better psychosocial functioning. As brain white matter is altered in psychosis, we aimed to externally validate the Biotype model using free-water imaging - an advanced diffusion imaging technique to compare differences across Biotypes, as well as across clinical categorization. Methods Diffusion tensor imaging (DTI) data from 69 individuals with schizophrenia, 49 with schizoaffective disorder (SAD), 42 with psychotic bipolar disorder, and 51 healthy controls (HC) from the Baltimore and Hartford sites in the B-SNIP consortium were included. Diffusion within each voxel was modeled using two compartments: isotropic free-water compartment, and a tissue compartment. Measures obtained from this model are the free-water compartment fraction (FW), and the tissue-FA fraction (FAt). Using Tract-based spatial statistics, the ENIGMA-DTI protocols were run on FAt and FW maps. The average FAt and FW within 25 bilateral white matter regions of interest was extracted. A MANCOVA model was used to test for differences in FAt and FW between diagnostic groups and Biotype groups, with age and sex as covariates. Results A significant group effect for diagnosis was observed in the corpus callosum (CC) (p<0.05, partial eta squared=0.1), whereby those diagnosed with SAD showed lower FAt in CC compared to HC. Using Biotype classification, a significant group effect was also observed for the CC, whereby Biotype 1 showed lower FAt than HC and Biotype 3 (p<0.01, partial eta squared=.13). For FW, no significant group differences were observed for diagnosis. However, group differences for Biotype were observed in the CC, whereby Biotypes 1 and 2 showed elevated FW compared to Biotype 3 and HC (p<0.01, partial eta squared = 0.1). Discussion While significant diagnosis comparisons were observed between schizoaffective disorder and HC, larger effects were observed when using Biotype classification. Patients in Biotype 1 group not only showed significant FAt reductions in the CC compared to HC, but also compared to Biotype 3. This is expected as Biotype 1 individuals were shown to be most impaired with regards to the biomarker dimensions of cognitive control and sensorimotor reactivity, whereas Biotype 3 were more comparable to healthy controls. Finally, no differences were observed for FW when grouping by diagnosis, however, when grouping by Biotype, significant elevations were observed for Biotypes 1 and 2. Aligned with our previous studies, FW appears to be a marker of acute response to psychosis, where elevations in FW are observed in individuals who were actively psychotic during scanning. Since neuroinflammation is expected to alter the extracellular FW fraction, it's possible that neuroinflammatory processes are apparent in these Biotype groups. However, further validation is required. In conclusion, grouping psychosis patients by Biotype may be a more biologically parsimonious approach for parsing heterogeneity of the disorder. [ABSTRACT FROM AUTHOR]

Background Flat and inappropriate affect and emotional labiality are features of psychosis syndromes and could involve impairments in neural processing of emotional stimuli. Studies have reported abnormal electrophysiological (EEG) responses to emotional stimuli in schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar I disorder with psychosis (BDP). The Bipolar-Schizophrenia Network on Intermediate Phenotypes (BSNIP) has identified three psychosis Biotypes (abbreviated B1, B2 & B3) which display differing patterns of neural activity, but emotional processing has not been assessed in these groups. Methods 814 participants (HC = 197, SZ = 230, SAD = 212, BDP = 175; B1 = 198, B2 = 176, B3 = 243) from the 5-site BSNIP consortium viewed pleasant, neutral, and unpleasant scenes from the IAPS while EEG was recorded from 64 sensors. Using a spatial PCA, two components reduced EEG data to one waveform per component. Spatial components were weighted in the occipital and centroparietal scalp regions and accounted for 56% and 42% of the variance, respectively. Early, mid-latency, and late time bins of interest (80–140 ms, 200–400 ms, & 400–1000 ms) were identified by visual inspection. Data were averaged across bins for each spatial component, yielding 6 spatiotemporal measures. Mixed-design ANOVAs were calculated using DSM and Biotype as between-subjects variables and task as the within-subjects variable. Follow up Tukey tests were conducted as appropriate. Results There were no significant DSM by Biotype interactions for any component/time combination (F = 1.39, 1.40,.92, 1.27, 1.34, 1.08, all p >.05). There was a main effect of DSM for the centroparietal component during the early time bin (F = 5.82, p <.01), with significant differences from HC and BDP to SZ and SAD (all p <.05). There was also a significant DSM by task interaction at the late time bin of the centroparietal component (F = 2.60, p =.04), where response to emotional images distinguished HC from SZ (p =.02,.03). There were main effects of Biotype for the early time bin at both components (F = 6.33, 11.77, both p <.001), with significant differences from HC and B3 to B1 and B2 (all p <.01). The mid-latency time bin displayed main effects of Biotype and Biotype by task interactions for both components (main effects: F = 7.74, 5.66, interactions: F = 2.65, 5.50, all p <.05). For all stimulus types, B1 significantly differed from all other groups at the occipital component and from HC and B3 at the centroparietal component (all p <.05). There was also a Biotype by task interaction at the late time bin of the centroparietal component, with reactivity to neutral images differing between B1 and B3 (p =.04) and reactivity to emotional images differing between B2 and HC (p =.04,.03). Discussion Distinguishing patients by Biotype yielded new information regarding emotional scene perception in psychosis. Only one neural measure distinguished between DSM-defined groups and did not interact with emotional scene content. However, these same measures and other components of the neural emotional response presented a complex pattern of differences within psychosis Biotypes. Results indicate the most profound disruptions in scene processing are found in B1. B1 is also associated with reductions in amygdala volume, which could result in abnormal aversive and appetitive reactions captured by these scalp measures of the emotional response. This external measure of neural function provides novel evidence that psychosis Biotypes identified by the BSNIP consortium provide better separation between psychosis subtypes than current DSM categories. Future research will examine habituation to scenes, medication effects, subjective reports of emotional experience, and clinical and phenotypic correlates. [ABSTRACT FROM AUTHOR]

Background The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subsets of the disease. In the present study, we hypothesized that disruption of protein quality control can lead to protein insolubility for a subset of patients with schizophrenia. Methods Prefrontal cortex or superior temporal gyrus from autopsy brains provided by the University of Pittsburgh, University of Texas Southwestern, and Harvard were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. All pellet samples were analyzed to quantify insoluble protein levels and ubiquitin reactivity, normalized to total homogenate protein. We then performed mass spectrometry analysis to identify the contents of the insoluble pellets. The potential biological relevance of the detected proteins was assessed using Gene Ontology Enrichment Analysis and Ingenuity Pathway Analysis. Results A subset of patients with schizophrenia showed an increase in protein insolubility and ubiquitination in the insoluble protein fraction. Mass spectrometry of the insoluble fraction revealed that cases with increased insolubility and ubiquitination showed a similar pattern of peptide clustering by principal component analysis. The proteins that were significantly altered in the insoluble pellet were enriched for terms relating to axon target recognition as well as nervous system development and function. Discussion This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Understanding the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways, circuitry, and symptoms seen in some patients with major mental illness and could lead to improved nosology and novel therapeutic targets. [ABSTRACT FROM AUTHOR]