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.

Lesion network guided delta frequency neuromodulation improves cognition in patients with psychosis spectrum disorders: A pilot study.

BACKGROUND: Transcranial electric stimulation (tES) may improve cognition in psychosis spectrum disorders. However, few studies have used novel tES approaches, such as high definition tES (HD-tES) to target specific brain circuits. Recently, the extrastriate visual cortex (V5/MT) has been causally linked to visual hallucinations through lesion network mapping and this may be a promising approach for improving cognition. OBJECTIVE: We aim to determine if causal lesion network guided HD-tES to V5/MT improves cognitive performance as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: A single-blind pilot study with a within-subjects crossover design was performed to characterize the effect of cathodal HD-transcranial direct current stimulation (tDCS) and 2 Hz HD-transcranial alternating current stimulation (tACS) on cognition. Enrolled patients received 20 mins of HD-tES twice daily for 5 consecutive days applied bilaterally to V5/MT with a washout between conditions. BACS assessments were performed at baseline, day-5, and 1-month. RESULTS: 6 participants with psychosis spectrum disorder were enrolled. 6 individuals received cathodal HD-tDCS. 4 individuals received 2 Hz HD-tACS. HD-tACS resulted in significant (p < 0.1 baseline to 1-month improvements for Digit Sequencing, Verbal Fluency, and Tower of London. HD-tDCS did not result in significant improvement on any task. CONCLUSIONS: HD-tACS targeting V5/MT may be a promising treatment to improve cognitive abilities in individuals with psychosis. By promoting delta oscillations, tACS may enhance cortico-cortico communications across brain networks to improve verbal working memory, processing speed, and executive function. Large-scale investigations are needed to replicate these results.

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.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.

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.

Auditory Oddball Responses Across the Schizophrenia-Bipolar Spectrum and Their Relationship to Cognitive and Clinical Features.

OBJECTIVE: 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. METHODS: 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 values >0.94 between B-SNIP1 and B-SNIP2). RESULTS: 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. CONCLUSIONS: 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.

Humor and emotion: Quantitative meta analyses of functional neuroimaging studies.

Humor is a ubiquitous aspect of human behavior that is infrequently the focus of neuroscience research. To localize human brain structures associated with the experience of humor, we conducted quantitative activation likelihood estimate (ALE) meta analyses of 57 fMRI studies (n = 1248) reporting enhanced regional brain activity evoked by humorous cues versus matched control cues. We performed separate ALE analyses of studies that employed picture-driven, text-based, and auditory laughter cues to evoke humor. A primary finding was that complex humor activates supramodal areas of the brain strongly associated with emotional processes, including bilateral amygdala and inferior frontal gyrus. Moreover, activation in brain regions associated with language, semantic knowledge, and theory of mind were differentially modulated by text and picture-driven humor cues, while hearing laughter enhances activation in auditory association cortex. The identification of humor-driven brain networks has the potential to expand brain-derived models of human emotion and could provide useful targets in translational research and therapy.

Neural Processing of Repeated Emotional Scenes in Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder.

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.

Testing Psychosis Phenotypes From Bipolar-Schizophrenia Network for Intermediate Phenotypes for Clinical Application: Biotype Characteristics and Targets.

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.

Auditory paired-stimuli responses across the psychosis and bipolar spectrum and their relationship to clinical features.

Background: EEG responses during auditory paired-stimuli paradigms are putative biomarkers of psychosis syndromes. The initial iteration of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP1) showed unique and common patterns of abnormalities across schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar disorder with psychosis (BDP). This study replicates those findings in new and large samples of psychosis cases and extends them to an important comparison group, bipolar disorder without psychosis (BDNP). Methods: Paired stimuli responses from 64-sensor EEG recording were compared across psychosis (n = 597; SZ = 225, SAD = 201, BDP = 171), BDNP (n = 66), and healthy (n = 415) subjects from the second iteration of B-SNIP. EEG activity was analyzed in voltage and in the time-frequency domain. Principal component analysis (PCA) over sensors (sPCA) was used to efficiently capture EEG voltage responses to the paired stimuli. Evoked power was calculated via a Morlet wavelet procedure. A frequency PCA divided evoked power data into three frequency bands: Low (4-17 Hz), Beta (18-32 Hz), and Gamma (33-55 Hz). Each time-course (ERP Voltage, Low, Beta, and Gamma) were then segmented into 20 ms bins and analyzed for group differences. To efficiently summarize the multiple EEG components that best captured group differences we used multivariate discriminant and correlational analyses. This approach yields a reduced set of measures that may be useful in subsequent biomarker investigations. Results: Group ANOVAs identified 17 time-ranges that showed significant group differences (p < .05 after FDR correction), constructively replicating B-SNIP1 findings. Multivariate linear discriminant analysis parsimoniously selected variables that best accounted for group differences: The P50 response to S1 and S2 uniquely separated BDNP from healthy and psychosis subjects (BDNP > all other groups); the S1 N100 response separated groups along an axis of psychopathology severity (HC > BDNP > BDP > SAD > SZ); the S1 P200 response indexed psychosis psychopathology (HC/BDNP > SAD/SZ/BDP); and the preparatory period to the S2 stimulus separated SZ from other groups (SZ > SAD/BDP>HC/BDNP).Canonical correlation identified an association between the neural responses during the S1 N100, S1 N200 and S2 preparatory period and PANSS positive symptoms and social functioning. The neural responses during the S1 P50 and S1 N100 were associated with PANSS Negative/General, MADRS and Young Mania symptoms. Conclusions: This study constructively replicated prior B-SNIP1 research on auditory deviations observed during the paired stimuli task in SZ, SAD and BDP. Inclusion of a group of BDNP allows for the identification of biomarkers more closely related to affective versus nonaffective clinical phenotypes and neural distinctions between BDP and BDNP. Findings have implications for nosology and future translational work given that some biomarkers are shared across all psychosis and some are unique to affective syndromes.

Electrophysiological correlates of emotional scene processing in bipolar disorder.

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.

Intrinsic neural activity differences in psychosis biotypes: Findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium.

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 psychosisrelevant deviations in neural modulation.