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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., We used functional MRI to examine brain activation and functional connectivity during visuomotor behavior in individuals with ASD and typically developing controls. Results indicated that atypical sensorimotor behavior in ASD was linked to increased functional activation and decreased task‐dependent functional connectivity throughout the visuomotor network. Our results suggest that atypical modulation of sensory feedback information during precision refinement of ongoing motor behavior contributes to multiple developmental disruptions in affected individuals.

Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features.Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values0.94 between B-SNIP1 and B-SNIP2).Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups.Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

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.

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.

Social-emotional information processing (SEIP) is critical for appropriate human interaction. It is composed of processes that underlie how we behave towards others, especially in response to adverse social threat. We conducted a study in 26 healthy participants who completed a validated Video-SEIP (V-SEIP) task in the fMRI scanning environment. The V-SEIP phases studied included encoding (ENC) of socially relevant information, hostile attribution (HA) of motive, and the negative emotional response (NER) the participant would have in the context of the video vignettes. The ENC phase was associated with activation of amygdala, left ventrolateral prefrontal cortex, right middle temporal gyrus, and visual cortex, the HA phase associated with activation of several brain regions including frontal and temporal cortex as well as basal ganglia and cerebellum, while the NER phase was associated with activation in the midbrain with regions involving the periaqueductal gray, basal ganglia, and the cerebellum. We suggest that this V-SEIP task represents a novel neuro-biomarker for the study of SEIP and that it can be extended for use in a number of psychiatric conditions in which anger, irritability, and impulsive aggressive are prominent features.

Impaired emotional processing and cognitive functioning are common in schizophrenia, schizoaffective disorder, and bipolar disorders, causing significant socioemotional disability. While a large body of research demonstrates abnormal cognition/emotion interactions in these disorders, previous studies investigating abnormalities in the emotional scene response using event-related potentials (ERPs) have yielded mixed findings, and few studies compare findings across psychiatric diagnoses. The current study investigates the effects of emotion and repetition on ERPs in a large, well-characterized sample of participants with schizophrenia-bipolar syndromes. Two ERP components that are modulated by emotional content and scene repetition, the early posterior negativity (EPN) and late positive potential (LPP), were recorded in healthy controls and participants with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, and bipolar disorder without psychosis. Effects of emotion and repetition were compared across groups. Results displayed significant but small effects in schizophrenia and schizoaffective disorder, with diminished EPN amplitudes to neutral and novel scenes, reduced LPP amplitudes to emotional scenes, and attenuated effects of scene repetition. Despite significant findings, small effect sizes indicate that emotional scene processing is predominantly intact in these disorders. Multivariate analyses indicate that these mild ERP abnormalities are related to cognition, psychosocial functioning, and psychosis severity. This relationship suggests that impaired cognition, rather than diagnosis or mood disturbance, may underlie disrupted neural scene processing in schizophrenia-bipolar syndromes.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

Background Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum. Methods We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability. Results All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability. Conclusions We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities.

Background Psychiatry aspires to the molecular understanding of its disorders and, with that knowledge, to precision medicine. Research supporting such goals in the dimension of psychosis has been compromised, in part, by using phenomenology alone to estimate disease entities. To this end, we are proponents of a deep phenotyping approach in psychosis, using computational strategies to discover the most informative phenotypic fingerprint as a promising strategy to uncover mechanisms in psychosis. Methods Doing this, the Bipolar–Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has used biomarkers to identify distinct subtypes of psychosis with replicable biomarker characteristics. While we have presented these entities as relevant, their potential utility in clinical practice has not yet been demonstrated. Results Here we carried out an analysis of clinical features that characterize biotypes. We found that biotypes have unique and defining clinical characteristics that could be used as initial screens in the clinical and research settings. Differences in these clinical features appear to be consistent with biotype biomarker profiles, indicating a link between biological features and clinical presentation. Clinical features associated with biotypes differ from those associated with DSM diagnoses, indicating that biotypes and DSM syndromes are not redundant and are likely to yield different treatment predictions. We highlight 3 predictions based on biotype that are derived from individual biomarker features and cannot be obtained from DSM psychosis syndromes. Conclusions In the future, biotypes may prove to be useful for targeting distinct molecular, circuit, cognitive, and psychosocial therapies for improved functional outcomes.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a “biomarker signature” for NS. Finally, distinct biomarker profiles for 2 NS domains (“diminished expression” vs “avolition/apathy”) were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response and provides an index of neural processing speed. Latency is prolonged in schizophrenia, is 90% heritable, and predicts conversion to schizophrenia in a high-risk population. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium investigates neurobiological features found in psychotic disorders spanning diagnostic criteria for schizophrenia (SCZ), schizoaffective disorder (SAD), and psychotic bipolar disorder (BP). We investigated whether differences in startle latency and prepulse inhibition (PPI) occur in probands, their first-degree relatives, and neurobiologically defined subgroups of the probands (Biotypes). METHODS: 1143 subjects were included from the B-SNIP cohort: 143 with SCZ, 178 SCZ relatives (SCZ-Fam), 123 with SAD, 152 SAD relatives (SAD-Fam), 138 BP, 183 BP relatives (BP-Fam), and 226 controls (CON). A Biopac system recorded the eyeblink component of the startle reflex during startle testing. RESULTS: Latency differed by diagnosis (F(3,620)=5.10, p=0.002): SCZ, SAD, and BP probands had slower latency than CON, with relatives intermediate. Biotypes 1 and 2 had slower latency than CON (p

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.

Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.

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 (PRS(CAD)) were quantified for each participant across 13 p-value thresholds (P(T) 0.5-5e(−8)). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS(CAD) was examined in relation to the BACS and the optimized P(T) was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS(CAD)-cognition associations. Multiple regression analyses examined PRS(CAD) under the optimal P(T) and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRS(CAD) was associated with lower BACS composite scores (p=0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p

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. Refereed/Peer-reviewed

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P

Deviant auditory steady-state responses (aSSRs) in the gamma range (30–90 Hz) may be translational biomarkers for schizophrenia (SZ). This study tests whether aSSR deviations are (i) specific to SZ across the psychosis dimension, (ii) specific to particular frequency bands, and (iii) present in bipolar I disorder without psychosis (BDNP). Methods Beta (20-), low- (40-), and high-gamma (80-Hz) aSSRs were measured with EEG and compared across 113 SZ, 105 schizoaffective disorder (SAD), 99 bipolar disorder with psychosis (BDP), 68 BDNP, and 137 healthy comparison subjects (HC). Standard aSSR measures (single-trial power [STP] and inter-trial phase coherence [ITC]), as well as evoked responses to stimulus onsets/offsets and pre-stimulus power, were quantified. Multivariate canonical discriminant analysis was used to summarize variables that efficiently and maximally differentiated groups. Results (i) Psychosis groups showed reduced responses on ITC 20 Hz, STP/ITC 40 Hz, STP/ITC 80 Hz, indicating dimensional reductions in aSSR across the psychosis spectrum not specific to aSSR frequency. For the 40- and 80-Hz ITCs there was greater reduction in SZ compared to SAD, possibly indexing cortical disruptions linked to psychosis without mood symptoms. (ii) All probands had elevated pre-stimulus power, possibly compromising neural entrainment to the steady-state stimuli. (iii) Onset/Offset and 80 Hz ITC responses were most important for group discrimination and showed dimensional reduction across the schizo-bipolar spectrum. Conclusions Deviant aSSRs were found across the schizo-bipolar spectrum at multiple frequencies with psychosis status and severity linked to greatest reductions at low and high gamma.

BACKGROUND: Oxytocin (OT) and arginine vasopressin (AVP) exert sexually dimorphic effects on cognition and emotion processing. Abnormalities in these hormones are observed in schizophrenia and may contribute to multiple established sex differences associated with the disorder. Here we examined sex-dependent hormone associations with resting brain activity and their clinical associations in schizophrenia patients. METHODS: OT and AVP serum concentrations were assayed in 35 individuals with schizophrenia (23 men) and 60 controls (24 men) from the Chicago BSNIP study site. Regional cerebral function was assessed with resting state fMRI by measuring the amplitude of low-frequency fluctuations (ALFF) which are believed to reflect intrinsic spontaneous neuronal activity. RESULTS: In female patients, lower OT levels were associated with lower ALFF in frontal and cerebellar cortices (p’s

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.

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E−9). The inclusion of anticholinergic burden improved association models (P

Schizophrenia, schizoaffective disorder, and bipolar disorder with psychotic features include varying degrees of psychosis and mood symptoms. As such, these disorders may represent three points on a spectrum rather than three categorically distinct disorders. This chapter outlines the key role of psychosis in characterizing these disorders and reviews the conceptual history of this characterization as embodied in the different editions of the Diagnostic and Statistical Manual of Mental Disorders. The inherent practical and conceptual problems associated with a categorical system for these diagnoses and for defining psychosis symptoms are emphasized. Finally, specific symptoms and their qualitative and quantitative features are compared and contrasted among schizophrenia, schizoaffective disorder, and psychotic bipolar disorder.

Focusing on biomarker identification and using biomarkers individually or in clusters to define biological subgroups in psychiatry requires a re-orientation from behavioral phenomenology to quantifying brain features, requiring big data approaches for data integration. Much still needs to be accomplished, not only to refine but also to build support for the application and customization of such an analytical phenotypic approach. In this review, we present some of what Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has learned so far to guide future applications of multivariate phenotyping and their analyses to understanding psychosis. This paper describes several B-SNIP projects that use phenotype data and big data computations to generate novel outcomes and glimpse what phenotypes contribute to disease understanding and, with aspiration, to treatment. The source of the phenotypes varies from genetic data, structural neuroanatomic localization, immune markers, brain physiology, and cognition. We aim to see guiding principles emerge and areas of commonality revealed. And, we will need to demonstrate not only data stability but also the usefulness of biomarker information for subgroup identification enhancing target identification and treatment development.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

Highlights • Transdiagnostic evidence for neural disruption in psychotic hallucinations. • Hallucinations associated increased connectivity in auditory association cortex. • Brain regions for auditory-verbal language comprehension linked to hallucinations. • Interhemispheric connectivity alterations related to subgroup-specific findings. • Hallucinations link to auditory rs-connectivity tested in 243 psychosis patients., Background Auditory hallucinations are prevalent across the major psychotic disorders, but their underlying mechanism is poorly understood. Limited prior work supports a hypothesis of altered auditory/language brain systems. To more definitively assess this, we examined whether alterations in resting state connectivity of auditory and language cortices are associated with hallucination severity in a large sample of individuals in the schizo-bipolar spectrum. Methods Whole brain resting state connectivity of auditory and language cortex (primary auditory cortex, unimodal auditory association cortex, Wernicke’s area [speech and heteromodal association cortex] and Broca’s area [speech production motor]) was evaluated for 243 subjects with schizophrenia, schizoaffective, or bipolar disorder with psychosis and 186 healthy controls from the Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Regression analyses were conducted to evaluate whether resting state connectivity of auditory and language cortex was a significant predictor of current overall hallucination severity (information about specific modality of hallucinations experienced was not available). Results Increased connectivity between lower and higher order regions of left temporal-parietal auditory/language processing cortex was associated with worse hallucination severity for all psychosis patients. Additionally, within bipolar subjects, increased interhemispheric connectivity between higher order temporal-parietal auditory/language regions was related to greater hallucination severity. When patients were categorized by B-SNIP biomarker-based Biotype groups, interhemispheric connectivity between left auditory association cortex and right core auditory cortex was related to greater hallucination severity for Biotype 1 patients. Exploratory analyses resulted in different patterns of connectivity of auditory/language cortex in patients and controls, unrelated to current hallucination severity. Conclusions Although the findings cannot be precisely attributed to auditory hallucination severity or possible differences in such experiences between groups, increased connectivity among the left hemisphere auditory and receptive language cortex may represent a significant factor contributing to hallucination severity across psychotic disorders, and additional subgroup specific connectivity alterations may also be present.

Intro The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) proposed “Biotypes,” subgroups of psychosis cases with neuro-cognitive homology. Neural activity unbound to stimulus processing (nonspecific or intrinsic activity) was important for differentiating Biotypes, with Biotype-2 characterized by high nonspecific neural activity. A precise estimate of intrinsic activity (IA) was not included in the initial Biotypes characterization. This report hypothesizes intrinsic activity is a critical differentiating feature for psychosis Biotypes. Method Participants were recruited at B-SNIP sites and included probands with psychosis (schizophrenia, schizoaffective disorder, bipolar I disorder), their first-degree biological relatives, and healthy persons (N = 1338). Probands were also sub-grouped by psychosis Biotype. 10-sec inter-stimulus intervals during an auditory paired-stimuli task were used to quantify intrinsic activity from 64 EEG sensors. Single-trial power and connectivity measures at empirically derived frequency bands were quantified. Multivariate discriminant and correlational analyses were used to summarize variables that efficiently and maximally differentiated groups by conventional diagnoses and Biotypes and to determine their relationship to clinical and social functioning. Results Biotype-1 consistently exhibited low IA, and Biotype 2 exhibited high IA relative to healthy persons across power frequency bands (delta/theta, alpha, beta, gamma) and alpha band connectivity estimates. DSM groups did not differ from healthy persons on any IA measure. Discussion Psychosis Biotypes, but not DSM syndromes, were differentiated by intrinsic activity; Biotype-2 was uniquely characterized by an accentuation of this measure. Neurobiologically defined psychosis subgroups may facilitate the use of intrinsic activity in translation models aimed at developing effective treatments for psychosis-relevant deviations in neural modulation.

Individuals with psychosis often show high levels of intrinsic, or nonspecific, neural activity, but attenuated stimulus-specific activity. Clementz et al. (2016) proposed that one subgroup of psychosis cases has accentuated intrinsic activity (Biotype-2's) and a different subgroup (Biotype-1's) has diminished intrinsic activity, with both groups exhibiting varying degrees of cognitive deficits. This model was studied by assessing neural activity in psychosis probands (N=105) during baseline and a 5second period in preparation for a pro-/anti-saccade task. Steady-state stimuli allowed real-time assessment of modulation of visuocortical investment to different target locations. Psychosis probands as a whole showed poor antisaccade performance. As expected, Biotype-1 showed diminished intrinsic neural activity and the worst behavior, and Biotype-2 showed accentuated intrinsic activity and less deviant behavior. Both of these groups also exhibited less dynamic oscillatory phase synchrony. Biotype-3 showed no neurophysiological differences from healthy individuals, despite a history of psychosis. Interestingly, all psychosis subgroups showed normal (i.e., not different from healthy) preparatory modulation of visuocortical investment as a function of cognitive demands, despite varying levels of task performance. Similar analyses conducted subgrouping cases by psychotic symptomatology revealed fewer and less consistent differences, including no intrinsic activity differences between any clinical subgroup and healthy individuals. This study illustrates that (i) differences in intrinsic neural activity may be a fundamental characteristic of psychosis and need to be evaluated separately from stimulus-specific responses, and (ii) grouping patients based on multidimensional classification using neurobiological data may have advantages for resolving heterogeneity and clarifying illness mechanisms relative to traditional psychiatric diagnoses.

Objective Neural substrates of loss of control (LOC) eating are undercharacterized. We aimed to model intermittent access to food to elicit disinhibited eating in youth undergoing neuroimaging, given evidence that restricted food access may increase subsequent food intake via enhancing reward value of food and diminishing eating-related self-control. Methods Participants were 18 preadolescents (aged 9-12 years) who were overweight/obese with recent LOC eating (OW-LOC; n = 6); overweight/obese with no history of LOC eating (OW-CON; n = 5); or non-overweight with no history of LOC eating (NW-CON; n = 7). Participants underwent functional magnetic resonance imaging during a simulated food restriction paradigm in which they were alternately given restricted or unrestricted access to milkshake solutions. Results There were no significant main effects of restricted versus unrestricted access to milkshake flavors. Group main effects revealed increased activation for OW-LOC relative to OW-CON in areas related to attentional processes (right middle frontal gyrus), inhibitory control/attentional shifts (right and left cuneus), and emotion regulation (left cingulate gyrus); and for OW-LOC relative to NW-CON in areas related to response inhibition (right inferior frontal gyrus). Significant block type × group interaction effects were found for the right middle frontal gyrus, left cingulate gyrus, and left cuneus, but these appeared to be accounted for primarily by group. Discussion There were clear group differences in neural activity in brain regions related to self-regulation during a food restriction paradigm. Elevations in these regions among OW-LOC relative to OW-CON and NW-CON, respectively, may suggest that youth with LOC eating expended more cognitive effort to regulate ingestive behavior.

Purpose Auditory hallucinations (AH), typically hearing voices, are a core symptom in schizophrenia. They may result from deficits in dynamic functional connectivity (FC) between cortical regions supporting speech production and language perception that interfere with the ability to recognize self-generated speech as not coming from external sources. We tested this hypothesis by investigating dynamic connectivity between the frontal cortex region related to language production and the temporal cortex region related to auditory processing. Methods Resting-state fMRI scans were acquired from 18 schizophrenia patients with AH (AH+), 17 schizophrenia patients without AH (AH-) and 22 healthy controls. A multiband sequence with TR = 427 ms was adopted to provide relatively high temporal resolution data for characterizing dynamic FC. Analysis focused on connectivity between speech production and language comprehension areas, eloquent language cortex in the left hemisphere. Two frequency bands of brain oscillatory activity were evaluated (0.01–0.027 Hz, 0.027–0.08 Hz) in which differential alterations that have been previously linked to schizophrenia. Conventional static FC maps of these seeds were also calculated. Results Dynamic connectivity analysis indicated that AH+ patients showed not only less temporal variability but transient lower strength in connectivity between speech and auditory areas than healthy controls, while AH- patients not. These findings were restricted to 0.027–0.08 Hz activity. In static connectivity analysis, no significant differences were observed in connectivity between speech production and language comprehension areas in either frequency band. Conclusions Reduced temporal variability and connectivity strength between key regions of eloquent language cortex may represent a mechanism for AH in schizophrenia., Highlights • Abnormal dynamic functional connectivity in schizophrenia with auditory hallucinations. • The dynamic connectivity goes wrong between expressive and receptive language regions. • The abnormality was restricted to the left hemisphere. • This abnormal dynamic connectivity was limited to a specific frequency band.

Physically healthy, adult, same-sexed twins (n = 287) from a population-based twin cohort underwent high-resolution magnetic resonance imaging (MRI) to identify fronto-limbic brain regions significantly associated with lifetime history of aggression. MRI scans used a 3D magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) sequence, for voxel-based morphometry (VBM) and history of aggressive behavior was assessed using the Life History of Aggression measure. Aggression had modest, inverse associations with grey matter volume (GMV) in medial prefrontal cortex (mPFC, b = -0.20, se = 0.05, p < 0.001) and lateral prefrontal cortex (lPFC, b = -0.23, se = 0.06, p < 0.001). These associations were not confounded by other demographic, psychiatric, or personality factors. Biometrical twin analyses revealed significant heritabilities of 0.57 for GMV in the mPFC cluster and 0.36 for GMV in the lPFC cluster. Genetic factors accounted for the majority of the phenotypic correlations between aggression and mPFC GMV (85.3%) and between aggression and lPFC GMV (63.7%). Reduced GMV of prefrontal brain regions may be a neuronal characteristic of individuals with substantial histories of aggressive behavior regardless of psychiatric diagnosis. As such, these data suggest an anatomical correlate, with a possible genetic etiology, associated with functional deficits in social-emotional information processing.

Individuals with psychosis have been reported to show either reduced or augmented brain responses under seemingly similar conditions. It is likely that inconsistent baseline-adjustment methods are partly responsible for this discrepancy. Using steady-state stimuli during a pro/antisaccade task, this study addressed the relationship between nonspecific and stimulus-related neural activity, and how these activities are modulated as a function of cognitive demands. In 98 psychosis probands (schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis), neural activity was assessed during baseline and during a 5-s period in preparation for the pro/antisaccade task. To maximize the ability to identify meaningful differences between psychosis subtypes, analyses were conducted as a function of subgrouping probands by standard clinical diagnoses and neurobiological features. These psychosis "biotypes" were created using brain-based biomarkers, independent of symptomatology (Clementz et al., ). Psychosis probands as a whole showed poor antisaccade performance and diminished baseline oscillatory phase synchrony. Psychosis biotypes differed on both behavioral and brain measures, in ways predicted from Clementz et al. (). Two biotype groups showed similarly deficient behavior and baseline synchrony, despite diametrically opposed neural activity amplitudes. Another biotype subgroup was more similar to healthy individuals on behavioral and brain measures, despite the presence of psychosis. This study provides evidence that (a) consideration of baseline levels of activation and synchrony will be essential for a comprehensive understanding of neural response differences in psychosis, and (b) distinct psychosis subgroups exhibit reduced versus augmented intrinsic neural activity, despite cognitive performance and clinical similarities.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a "biomarker signature" for NS. Finally, distinct biomarker profiles for 2 NS domains ("diminished expression" vs "avolition/apathy") were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.

Background Symptoms of mental diseases can be cross-diagnostic. For example psychosis is not limited to schizophrenia (SZ), but can be also present in bipolar (BPP) and schizoaffective (SA) disorders. Morphometric findings are often also cross-diagnostic, For example, volume decreases of the hippocampus (HP), essential to memory functions, is affected in both schizophrenia and bipolar disorder. Biotyping, grouping of patients according to biomarker-based categories is one attempt to approach cross-diagnostic features in the hope of better classification and ultimately tailored interventions. Here we combine biotyping, in addition to traditional diagnosing, with analysis of the HP volume. Furthermore, we explore the HP according to its anterior (aHP) versus posterior (pHP) anatomical division, following the functional division of this medial temporal lobe structure. Our hypothesis is that aHP and pHP are differentially affected in biotypes and diagnostic groups and reflective of differences in cognitive functions affected in each biotype and/or diagnostic group. Methods The sample included 450 probands (age 35±12.0 yo) and 325 healthy controls (HC; 37±12.0 yo). Of the probands 187 were diagnosed with SZ, 150 with BPP (psychosis type), 113 with SA disorders; after biotyping the same probands were categorized into three biotypes: 118 biotype 1 (BP1), 142 biotype 2 (BP2), 187 biotype 3 (BP3). 3T MRI data were quality checked and processed with FreeSurfer 6.0. The HP measures extracted were: the whole HP, and further HP subfields according to aHP and pHP. aHP and pHP subfields were reconstituted into left and right aHP and pHP. BACS cognitive data and PANSS, SAPS, MADRS and mania clinical ratings were collected. Results Analysis According to Diagnoses: There were no aHP or pHP volume differences among diagnostic groups, but all diagnostic groups demonstrated volume decreases of the left and right aHP compared to HC with effect sizes (Cohen’s d) between 0.3 and 0.6. Further, SA had decreases of the left and right pHP as well and SZ of the left pHP (effect sizes 0.3–0.4) compared to HC. BPP pHP volume were not different than pHP volumes measured in HC. Analysis According to Biotyping: Decreases of left and right aHP and pHP volumes were present in BP1 compared to HC while decreases of left pHP and left and right aHP were present in BT2 compared to HC. Only aHP was affected in BT3 compared to HC. Left and right aHP and pHP distinguished BT1 and BT3. BT1 had further decreased left pHP volume compared to BP2. Several anterior portions of the subfields volumes were driving the aHP vs pHP differences among biotypes while differences of the posterior portions of the subfields were fewer. aHP differences between BP1 and BP2 were driven by the anterior portion of the right subiculum. Discussion Biotypes are more effective than diagnoses in discriminating abnormalities of the HP across psychosis categories. Further, analysis of the aHP versus the pHP demonstrates that the HP should be analyzed not as a whole, or as its subfields, but according to anterior versus posterior divisions of its subfields and to the sum of anterior versus posterior subfields in aHP and pHP. Further studies need to elucidate the cognitive functional correlates of aHP- pHP differences across psychoses and healthy populations.

Background The practice of “microdosing,” or the use of repeated, very low doses of lysergic acid diethylamide (LSD) to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. Methods The present study was designed to examine the effects of a single low dose of LSD (13 μg) versus placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, 18 to 35 years old, participated in 2 functional magnetic resonance imaging scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state blood oxygen level–dependent and arterial spin labeling scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. Results LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala–middle frontal gyrus connectivity strength. Conclusions These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug’s purported antidepressant effect.

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.

Description: Experiencing behavioral control over stress can have long lasting and generalizing effects. The controllability of a physical threat, for example, affects the processing of subsequent social stress. Animal research has shown that the vmPFC plays a critical role in behavioral control and orchestrating subcortical responses. However, translational research on these neural systems in humans is sparse and we therefore aimed to develop a paradigm to test the generalization effect of behavioral control on vmPFC functioning. A pilot study was performed in which subjects (n=18) were first randomly assigned to one of two versions of a signal detection task, where feedback was either paired with a controllable or an uncontrollable mild shock. Subsequently, subjects underwent a social evaluative threat fMRI paradigm to measure their response to the anticipation of speaking in public. The analyses tested whether the controllability manipulation influenced behavioral and physiological responses and vmPFC network topology. Results showed that overall subjects were faster to respond to potential shock trials in the signal detection task, and there was a trend significant difference between the controllable or uncontrollable group. No significant differences between the two groups were observed on other behavioral or physiological responses. fMRI results showed higher vmPFC efficiency in the controllable threat group at baseline and recovery but similar to the uncontrollable group during speech anticipation. The current report establishes the feasibility of the protocol and adequately-powered follow-up research is needed to further evaluate the generalization effect on the behavioral, physiological and neural level.

Emotional dysfunction is a core feature of bipolar I disorder (BD). Behavioral data suggest that emotional processing may differ based on history of psychosis, but physiological studies frequently disregard this differentiating feature. Face processing studies indicate that emotion-related components of event-related potentials (ERPs) are abnormal in BD, but fMRI data using emotional scenes are mixed. The current study used ERPs to examine emotional scene perception in BD with and without a history of psychosis (BDP, BDNP). 386 participants from the PARDIP consortium (HC = 181, BDP = 130, BDNP = 75) viewed neutral, pleasant, and unpleasant scenes from the International Affective Picture System (IAPS) during continuous EEG recording. The early posterior negativity (EPN) and late positive potential (LPP) were examined for group and stimulus effects. Analyses were conducted for groups on and off medications to examine associations between medication status, psychosis, and ERP response. Group differences were found between HC and BD in emotional modulation of the EPN and between HC and BDP in the LPP to pleasant images. There was a significant interaction between psychosis history and anticonvulsant status in the EPN, but no other medication associations were found. The relationship between neural/self-reported emotional responses and clinical symptoms were examined with canonical correlations, but no significant associations were found. Results from this large well characterized sample indicate mild deviations in neural reactivity related to medication, mood, and psychosis history. However, processing of emotional scenes appears mostly intact in individuals with BD regardless of symptom severity.

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.