Pons-to-Cerebellum Hypoconnectivity Along the Psychosis Spectrum and Associations With Sensory Prediction and Hallucinations in Schizophrenia.

BACKGROUND: Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking. METHODS: We examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity. RESULTS: Compared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia. CONCLUSIONS: Deficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum.

Differentiating Biomarker Features and Familial Characteristics of B-SNIP Psychosis Biotypes.

Idiopathic psychosis shows considerable biological heterogeneity across cases. B-SNIP used psychosis-relevant biomarkers to identity psychosis Biotypes, which will aid etiological and targeted treatment investigations. Psychosis probands from the B-SNIP consortium (n = 1907), their first-degree biological relatives (n = 705), and healthy participants (n = 895) completed a biomarker battery composed of cognition, saccades, and auditory EEG measurements. ERP quantifications were substantially modified from previous iterations of this approach. Multivariate integration reduced multiple biomarker outcomes to 11 "bio-factors". Twenty-four different approaches indicated bio-factor data among probands were best distributed as three subgroups. Numerical taxonomy with k-means constructed psychosis Biotypes, and rand indices evaluated consistency of Biotype assignments. Psychosis subgroups, their non-psychotic first-degree relatives, and healthy individuals were compared across bio-factors. The three psychosis Biotypes differed significantly on all 11 bio-factors, especially prominent for general cognition, antisaccades, ERP magnitude, and intrinsic neural activity. Rand indices showed excellent consistency of clustering membership when samples included at least 1100 subjects. Canonical discriminant analysis described composite bio-factors that simplified group comparisons and captured neural dysregulation, neural vigor, and stimulus salience variates. Neural dysregulation captured Biotype-2, low neural vigor captured Biotype-1, and deviations of stimulus salience captured Biotype-3. First-degree relatives showed similar patterns as their Biotyped proband relatives on general cognition, antisaccades, ERP magnitudes, and intrinsic brain activity. Results extend previous efforts by the B-SNIP consortium to characterize biologically distinct psychosis Biotypes. They also show that at least 1100 observations are necessary to achieve consistent outcomes. First-degree relative data implicate specific bio-factor deviations to the subtype of their proband and may inform studies of genetic risk.

Double dissociation between P300 components and task switch error type in healthy but not psychosis participants.

Event-related potentials (ERPs) during oddball tasks and the behavioral performance on the Penn Conditional Exclusion Task (PCET) measure context-appropriate responding: P300 ERPs to oddball targets reflect detection of input changes and context updating in working memory, and PCET performance indexes detection, adherence, and maintenance of mental set changes. More specifically, PCET variables quantify cognitive functions including inductive reasoning (set 1 completion), mental flexibility (perseverative errors), and working memory maintenance (regressive errors). Past research showed that both P300 ERPs and PCET performance are disrupted in psychosis. This study probed the possible neural correlates of 3 PCET abnormalities that occur in participants with psychosis via the overlapping cognitive demands of the two study paradigms. In a two-tiered analysis, psychosis (n = 492) and healthy participants (n = 244) were first divided based on completion of set 1 - which measures subjects' ability to use inductive reasoning to arrive at the correct set. Results showed that participants who failed set 1 produced lower parietal P300, independent of clinical status. In the second tier of analysis, a double dissociation was found among healthy set 1 completers: frontal P300 amplitudes were negatively associated with perseverative errors, and parietal P300 was negatively associated with regressive errors. In contrast, psychosis participants showed global P300 reductions regardless of PCET performance. From this we conclude that in psychosis, overall activations evoked by the oddball task are reduced while the cognitive functions required by PCET are still somewhat supported, showing some level of independence or compensatory physiology in psychosis between neural activities underlying the two tasks.

Clinical characterization and differentiation of B-SNIP psychosis Biotypes: Algorithmic Diagnostics for Efficient Prescription of Treatments (ADEPT)-1.

Clinically defined psychosis diagnoses are neurobiologically heterogeneous. The B-SNIP consortium identified and validated more neurobiologically homogeneous psychosis Biotypes using an extensive battery of neurocognitive and psychophysiological laboratory measures. However, typically the first step in any diagnostic evaluation is the clinical interview. In this project, we evaluated if psychosis Biotypes have clinical characteristics that can support their differentiation in addition to obtaining laboratory testing. Clinical interview data from 1907 individuals with a psychosis Biotype were used to create a diagnostic algorithm. The features were 58 ratings from standard clinical scales. Extremely randomized tree algorithms were used to evaluate sensitivity, specificity, and overall classification success. Biotype classification accuracy peaked at 91 % with the use of 57 items on average. A reduced feature set of 28 items, though, also showed 81 % classification accuracy. Using this reduced item set, we found that only 10-11 items achieved a one-vs-all (Biotype-1 or not, Biotype-2 or not, Biotype-3 or not) area under the sensitivity-specificity curve of .78 to .81. The top clinical characteristics for differentiating psychosis Biotypes, in order of importance, were (i) difficulty in abstract thinking, (ii) multiple indicators of social functioning, (iii) conceptual disorganization, (iv) severity of hallucinations, (v) stereotyped thinking, (vi) suspiciousness, (vii) unusual thought content, (viii) lack of spontaneous speech, and (ix) severity of delusions. These features were remarkably different from those that differentiated DSM psychosis diagnoses. This low-burden adaptive algorithm achieved reasonable classification accuracy and will support Biotype-specific etiological and treatment investigations even in under-resourced clinical and research environments.

Methamphetamine enhances neural activation during anticipation of loss in the monetary incentive delay task.

Stimulants like methamphetamine (MA) affect motivated behaviors via actions on circuits mediating mood, attention, and reward. Few studies examined the effects of single doses of stimulants on reward circuits during anticipation and receipt of rewards and losses. Here, we examined the effects of MA (20 mg) or placebo in a within-subject, double-blind study with healthy adults (n = 43). During 2 fMRI sessions, participants completed the monetary incentive delay task. Primary outcome measures were BOLD activation in selected regions of interest during anticipation and receipt of monetary rewards and losses. Secondary analyses included behavioral measures, whole brain analysis, and arterial spin labeling. MA produced its expected behavioral effects and increased neural activation in the ventral striatum and anterior insula during anticipation of monetary loss versus non-loss. MA did not affect activation during anticipation of gains, or during receipt of wins or losses. MA significantly reduced cerebral blood flow in the striatum and insula. The present finding that a stimulant enhances the responses of striatal and insular regions to upcoming loss suggests that this system may be sensitive to the salience of upcoming events. The finding adds to a complex body of evidence regarding the effects of stimulant drugs on neural processes during motivated behaviors.

Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis.

INTRODUCTION: High-inflammation subgroups of patients with psychosis demonstrate cognitive deficits and neuroanatomical alterations. Systemic inflammation assessed using IL-6 and C-reactive protein may alter functional connectivity within and between resting-state networks, but the cognitive and clinical implications of these alterations remain unknown. We aim to determine the relationships of elevated peripheral inflammation subgroups with resting-state functional networks and cognition in psychosis spectrum disorders. METHODS: Serum and resting-state fMRI were collected from psychosis probands (schizophrenia, schizoaffective, psychotic bipolar disorder) and healthy controls (HC) from the B-SNIP1 (Chicago site) study who were stratified into inflammatory subgroups based on factor and cluster analyses of 13 cytokines (HC Low n = 32, Proband Low n = 65, Proband High n = 29). Nine resting-state networks derived from independent component analysis were used to assess functional and multilayer connectivity. Inter-network connectivity was measured using Fisher z-transformation of correlation coefficients. Network organization was assessed by investigating networks of positive and negative connections separately, as well as investigating multilayer networks using both positive and negative connections. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia. Linear regressions, Spearman correlations, permutations tests and multiple comparison corrections were used for analyses in R. RESULTS: Anterior default mode network (DMNa) connectivity was significantly reduced in the Proband High compared to Proband Low (Cohen's d = -0.74, p = 0.002) and HC Low (d = -0.85, p = 0.0008) groups. Inter-network connectivity between the DMNa and the right-frontoparietal networks was lower in Proband High compared to Proband Low (d = -0.66, p = 0.004) group. Compared to Proband Low, the Proband High group had lower negative (d = 0.54, p = 0.021) and positive network (d = 0.49, p = 0.042) clustering coefficient, and lower multiplex network participation coefficient (d = -0.57, p = 0.014). Network findings in high inflammation subgroups correlate with worse verbal fluency, verbal memory, symbol coding, and overall cognition. CONCLUSION: These results expand on our understanding of the potential effects of peripheral inflammatory signatures and/or subgroups on network dysfunction in psychosis and how they relate to worse cognitive performance. Additionally, the novel multiplex approach taken in this study demonstrated how inflammation may disrupt the brain's ability to maintain healthy co-activation patterns between the resting-state networks while inhibiting certain connections between them.

Stimulant-like subjective effects of alcohol are not related to resting-state connectivity in healthy men.

Individual differences in subjective, stimulant-like effects of alcohol are associated with the risk of developing alcohol use disorder. Specifically, individuals who experience more pronounced stimulant-like effects from alcohol are more likely to continue and escalate their usage. The neural basis for these individual differences in subjective response is not yet known. Using a within-subject design, 27 healthy male social drinkers completed three fMRI scans after ingesting a placebo, 0.4 and 0.8 g/kg alcohol, in a randomized order under double-blind conditions. Subjective stimulant effects of alcohol were assessed at regular intervals during each session. Seed-based and regional homogeneity analyses were conducted to evaluate changes in resting-state functional connectivity in relation to the stimulant effect of alcohol. Results indicated that 0.4 g/kg alcohol increased the connectivity to thalamus, and 0.8 g/kg alcohol decreased the connectivity to ventral anterior insula, primarily from the superior parietal lobule. Both doses reduced regional homogeneity in the superior parietal lobule but without an exact overlap with clusters showing connectivity changes in the seed-based analyses. The self-reported stimulant effect of alcohol was not significantly related to changes in seed-based connectivity or regional homogeneity. These findings suggest that alcohol-induced stimulation effects are not related to these indices of neural activity.

Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

Characterization of childhood trauma, hippocampal mediation and Cannabis use in a large dataset of psychosis and non-psychosis individuals.

BACKGROUND: Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP volumes, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS). METHODS: Cross-sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n = 1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS). RESULTS: In survival analysis, CT and CA exposure interact to be associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage. DISCUSSION: CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis. FUNDING: MH077945; MH096942; MH096913; MH077862; MH103368; MH096900; MH122759.

Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders.

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.

Inflammation subtypes in psychosis and their relationships with genetic risk for psychiatric and cardiometabolic disorders.

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n â€‹= â€‹86 psychosis, n â€‹= â€‹36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p â€‹= â€‹0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR â€‹= â€‹2.037, p â€‹= â€‹0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness.

A subtype of institutionalized patients with schizophrenia characterized by pronounced subcortical and cognitive deficits.

Some patients with schizophrenia have severe cognitive impairment and functional deficits that require long-term institutional care. The patterns of brain-behavior alterations in these individuals, and their differences from patients living successfully in the community, remain poorly understood. Previous cognition-based studies for stratifying schizophrenia patients highlight the importance of subcortical structures in the context of illness heterogeneity. In the present study, subcortical volumes from 96 institutionalized patients with long-term schizophrenia were evaluated using cluster analysis to test for heterogeneity. These data were compared to those from two groups of community-dwelling individuals with schizophrenia for comparison purposes, including 68 long-term ill and 126 first-episode individuals. A total of 290 demographically matched healthy participants were included as normative references at a 1:1 ratio for each patient sample. A subtype of institutionalized patients was identified based on their pattern of subcortical alterations. Using a machine learning algorithm developed to discriminate the two groups of institutionalized patients, all three patient samples were found to have similar rates of patients assigned to the two subtypes (approximately 50% each). In institutionalized patients, only the subtype with the identified pattern of subcortical alterations had greater neocortical and cognitive abnormalities than those in the similarity classified community-dwelling patients with long-term illness. Thus, for the subtype of patients with a distinctive pattern of subcortical alterations, when the distinct pattern of subcortical alterations is present and particularly severe, it is associated with cognitive impairments that may contribute to persistent disability and institutionalization.

Neuronal responses in social-emotional information processing in impulsive aggressive individuals.

How we perceive and interpret signals from others' behavior, known as social-emotional information processing (SEIP), is key when responding to social threat. Impulsively aggressive individuals, behaviorally, demonstrate impaired SEIP for encoding relevant social stimuli, attribution of intent of the other person in the interaction, and responding negatively to potentially threatening social situations. In this study, we sought to explore how neural processing differs between healthy controls (HC) and individuals with impulsive aggressive behavior (individuals with Intermittent Explosive Disorder, I-IED), during a validated SEIP paradigm. Forty-five adults (19 I-IED, 26 HC) participants underwent a validated SEIP tasks during an fMRI scan. The task utilized video clips depicting a socially ambiguous, but possibly aggressive (AGG), act by one person to another and control video clips in which where possibly aggressive act does not occur (CON). Behavioral anomalies in SEIP are also manifest in altered neural activation in distributed networks/brain regions in each phase of SEIP examined. Overall, neural responses during the SEIP paradigm were characterized as reduced discrimination of the AGG vs. CON videos for I-IEDs compared to HCs. These data suggest the presence of compromised neural circuits underlying impaired social cognition in individuals with IED and highlights potential neural targets of intervention for impaired social cognition in I-IED and other behavioral disorders as well.

Using psychosis biotypes and the Framingham model for parsing psychosis biology.

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has invested in the collection and use of multiple biomarkers in individuals with psychosis. We expect psychosis biology and its distinctive types to be reflected in the biomarkers, as they are the 'behaviors' of the brain. Like infectious diseases, we expect the etiologies of these biomarker-driven entities to be multiple and complex. Biomarkers have not yet been annotated with disease characteristics and need to be. As a model, we seek to adopt aspects of the Framingham Heart Study (FHS) to guide and organize these observations.

An opportunity for primary prevention research in psychotic disorders.

An opportunity has opened for research into primary prevention of psychotic disorders, based on progress in endophenotypes, genetics, and genomics. Primary prevention requires reliable prediction of susceptibility before any symptoms are present. We studied a battery of measures where published data supports abnormalities of these measurements prior to appearance of initial psychosis symptoms. These neurobiological and behavioral measurements included cognition, eye movement tracking, Event Related Potentials, and polygenic risk scores. They generated an acceptably precise separation of healthy controls from outpatients with a psychotic disorder. METHODS: The Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) measured this battery in an ancestry-diverse series of consecutively recruited adult outpatients with a psychotic disorder and healthy controls. Participants include all genders, 16 to 50 years of age, 261 with psychotic disorders (Schizophrenia (SZ) 109, Bipolar with psychosis (BPP) 92, Schizoaffective disorder (SAD) 60), 110 healthy controls. Logistic Regression, and an extension of the Linear Mixed Model to include analysis of pairwise interactions between measures (Environmental kernel Relationship Matrices (ERM)) with multiple iterations, were performed to predict case-control status. Each regression analysis was validated with four-fold cross-validation. RESULTS AND CONCLUSIONS: Sensitivity, specificity, and Area Under the Curve of Receiver Operating Characteristic of 85%, 62%, and 86%, respectively, were obtained for both analytic methods. These prediction metrics demonstrate a promising diagnostic distinction based on premorbid risk variables. There were also statistically significant pairwise interactions between measures in the ERM model. The strong prediction metrics of both types of analytic model provide proof-of-principle for biologically-based laboratory tests as a first step toward primary prevention studies. Prospective studies of adolescents at elevated risk, vs. healthy adolescent controls, would be a next step toward development of primary prevention strategies.

Subtyping Schizophrenia Patients Based on Patterns of Structural Brain Alterations.

Schizophrenia is a complex and heterogeneous syndrome. Whether quantitative imaging biomarkers can identify discrete subgroups of patients as might be used to foster personalized medicine approaches for patient care remains unclear. Cross-sectional structural MR images of 163 never-treated first-episode schizophrenia patients (FES) and 133 chronically ill patients with midcourse schizophrenia from the Bipolar and Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium and a total of 403 healthy controls were recruited. Morphometric measures (cortical thickness, surface area, and subcortical structures) were extracted for each subject and then the optimized subtyping results were obtained with nonsupervised cluster analysis. Three subgroups of patients defined by distinct patterns of regional cortical and subcortical morphometric features were identified in FES. A similar three subgroup pattern was identified in the independent dataset of patients from the multi-site B-SNIP consortium. Similarities of classification patterns across these two patient cohorts suggest that the 3-group typology is relatively stable over the course of illness. Cognitive functions were worse in subgroup 1 with midcourse schizophrenia than those in subgroup 3. These findings provide novel insight into distinct subgroups of patients with schizophrenia based on structural brain features. Findings of different cognitive functions among the subgroups support clinical differences in the MRI-defined illness subtypes. Regardless of clinical presentation and stage of illness, anatomic MR subgrouping biomarkers can separate neurobiologically distinct subgroups of schizophrenia patients, which represent an important and meaningful step forward in differentiating subtypes of patients for studies of illness neurobiology and potentially for clinical trials.

Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder.

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging, we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9-35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and contralateral middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar-cortical sensorimotor and nonsensorimotor networks show delayed maturation.

Psychosis Biotypes: Replication and Validation from the B-SNIP Consortium.

Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called "B-SNIP1" with 711 psychosis and 274 healthy persons, and the "replication sample" with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r's from .96-.99) and temporally stable (r's from .76-.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%-89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations.

Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders.

BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.