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.

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.

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.

Biotyping in psychosis: using multiple computational approaches with one data set.

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.

Cognitive Impairment and Diminished Neural Responses Constitute a Biomarker Signature of Negative Symptoms in Psychosis.

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.

Associating Psychotic Symptoms with Altered Brain Anatomy in Psychotic Disorders Using Multidimensional Item Response Theory Models.

Reduced cortical thickness has been demonstrated in psychotic disorders, but its relationship to clinical symptoms has not been established. We aimed to identify the regions throughout neocortex where clinical psychosis manifestations correlate with cortical thickness. Rather than perform a traditional correlation analysis using total scores on psychiatric rating scales, we applied multidimensional item response theory to identify a profile of psychotic symptoms that was related to a region where cortical thickness was reduced. This analysis was performed using a large population of probands with psychotic disorders (N = 865), their family members (N = 678) and healthy volunteers (N = 347), from the 5-site Bipolar-Schizophrenia Network for Intermediate Phenotypes. Regional cortical thickness from structural magnetic resonance scans was measured using FreeSurfer; individual symptoms were rated using the Positive and Negative Syndrome Scale, Montgomery-Asberg Depression Rating Scale, and Young Mania Rating Scale. A cluster of cortical regions whose thickness was inversely related to severity of psychosis symptoms was identified. The regions turned out to be located contiguously in a large region of heteromodal association cortex including temporal, parietal and frontal lobe regions, suggesting a cluster of contiguous neocortical regions important to psychosis expression. When we tested the relationship between reduced cortical surface area and high psychotic symptoms we found no linked regions describing a related cortical set.

Early and late auditory information processing show opposing deviations in aniridia.

Aniridia is a congenital disorder, predominantly caused by heterozygous mutations of the PAX6 gene. While ocular defects have been extensively characterized in this population, brain-related anatomical and functional abnormalities are emerging as a prominent feature of the disorder. Individuals with aniridia frequently exhibit auditory processing deficits despite normal audiograms. While previous studies have reported hypoplasia of the anterior commissure and corpus callosum in some of these individuals, the neurophysiological basis of these impairments remains unexplored. This study provides direct assessment of neural activity related to auditory processing in aniridia. Participants were presented with tones designed to elicit an auditory steady-state response (ASSR) at 22 Hz, 40 Hz, and 84 Hz, and infrequent broadband target tones to maintain attention during electroencephalography (EEG) recording. Persons with aniridia showed increased early cortical responses (P50 AEP) in response to all tones, and increased high-frequency oscillatory entrainment (84 Hz ASSR). In contrast, this group showed a decreased cortical integration response (P300 AEP to target tones) and reduced neural entrainment to cortical beta-band stimuli (22 Hz ASSR). Collectively, our results suggest that subcortical and early cortical auditory processing is augmented in aniridia, while functional cortical integration of auditory information is deficient in this population.

Psychosis subgroups differ in intrinsic neural activity but not task-specific processing.

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.

Intrinsic neural activity differences among psychotic illnesses.

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.

Stimulus train duration but not attention moderates γ-band entrainment abnormalities in schizophrenia.

Electroencephalographic (EEG) studies of auditory steady-state responses (aSSRs) non-invasively probe gamma-band (40-Hz) oscillatory capacity in sensory cortex with high signal-to-noise ratio. Consistent reports of reduced 40-Hz aSSRs in persons with schizophrenia (SZ) indicate its potential as an efficient biomarker for the disease, but studies have been limited to passive or indirect listening contexts with stereotypically short (500ms) stimulus trains. An inability to modulate sensorineural processing in accord with behavioral goals or within the sensory environmental context may represent a fundamental deficit in SZ, but whether and how this deficit relates to reduced aSSRs is unknown. We systematically varied stimulus duration and attentional contexts to further mature the 40-Hz aSSR as biomarker for future translational or mechanistic studies. Eighteen SZ and 18 healthy subjects (H) were presented binaural pure-tones with or without sinusoidal amplitude modulation at 40-Hz. Stimulus duration (500-ms or 1500-ms) and attention (via a button press task) were varied across 4 separate blocks. Evoked potentials recorded with dense-array EEGs were analyzed in the time-frequency domain. SZ displayed reduced 40-Hz aSSRs to typical stimulation parameters, replicating previous findings. In H, aSSRs were reduced when stimuli were presented in longer trains and were slightly enhanced by attention. Only the former modulation was impaired in SZ and correlated with sensory discrimination performance. Thus, gamma-band aSSRs are modulated by both attentional and stimulus duration contexts, but only modulations related to physical stimulus properties are abnormal in SZ, supporting its status as a biomarker of psychotic perceptual disturbance involving non-attentional sensori-cortical circuits.

Neural correlates of the impact of control on decision making in pathological gambling.

Perceived control over a gambling outcome leads individuals to accept more and larger bets, increased risk-taking. Pathological gamblers, however, do not diminish risk-taking when control is absent, suggesting an illusion of control. To evaluate neural correlates of perceived control in gamblers, this study compared magnetoencephalography responses of 36 pathological (PG) and 36 non-pathological gamblers (NPG) during the Georgia Gambling Task. PGs exhibited greater activity in bilateral primary sensory regions. An interaction between pathology and control over the gambling task was observed bilaterally throughout dorsal and ventral visual processing streams, and lateral PFC. NPGs showed decreased activity when control was absent. Groups did not differ in response to potential bet cost. These findings provide neurophysiological evidence that PGs suffer from the pattern of risk-taking associated with perceived control, even when no control exists. They suggest that gambling pathology contributes to differential processing of gambling stimuli other than potential costs or rewards.