Postdoctoral Researcher, UT Southwestern Medical Center
Using biological metrics to elucidate psychosis sub-groups towards individualized medicine
Disease heterogeneity in psychotic illness presents a significant challenge for researchers and physicians. The BSNIP consortium hypothesized that measures of cognition and brain activity will identify subgroups of psychosis and represent differences in underlying psychosis pathophysiology. Subsequently, we have hypothesized that neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) may uncover synaptic mechanisms and divergent intracellular traits in these novel subgroups.
A panel of cognitive, neuropsychological and neuroimaging measures were collected for individuals with psychosis (schizophrenia, schizoaffective disorder, psychotic bipolar disorder) (N=977), relatives (N=1029) and healthy comparison subjects (N=429). A subset of individuals provided dermal biopsies for additional study, which were cultured to establish patient-derived fibroblast lines. Fibroblasts were reprogrammed into iPSCs, which were validated and differentiated into neural progenitor cells and cortical-like neurons. Once mature, neurons will be used for molecular and functional measurements to assess correlates of in vivo neural activity.
Analysis of composite measures of cognitive control and sensorimotor reactivity elucidate three distinct psychosis biotypes that do not conform to traditional psychiatric diagnoses. Most prominently, biotypes demonstrate discrete differences in neurophysiology: Biotype-1/B-1, which show significant neural hypoactivity, Biotype-2/B-2, which show neural hyperactivity, and Biotype-3/B-3, which are most similar to healthy participants. The hypo- and hyper-activity measured by EEG is present both at baseline and in evoked conditions using auditory and visual paradigms. First-degree relatives of individuals in each of these biotypes demonstrate similar results, indicating a heritable, biological basis. Using molecular and electrophysiological outcomes of basal and induced activity, we expect synaptic activity in mature neurons from iPSC cells to show hypoactivity in B-1, hyperactivity in B-2 and normal activity in B-3.
These findings support the hypothesis that psychosis subtypes are biologically distinguishable and related to different underlying pathophysiologies. Leveraging patient-derived iPSCs is a promising means of investigating underlying mechanisms of synaptic and electrophysiological dysfunction, identifying new targets for medication, and potentially individualizing psychosis treatments.
Abstract: The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects.We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale.Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality.The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially.
Pub.: 10 Mar '16, Pinned: 26 Jun '17
Abstract: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown.
Pub.: 24 Oct '16, Pinned: 26 Jun '17
Abstract: Functional magnetic resonance imaging (fMRI) studies have shown altered brain dynamic functional connectivity (DFC) in mental disorders. Here, we aim to explore DFC across a spectrum of symptomatically-related disorders including bipolar disorder with psychosis (BPP), schizoaffective disorder (SAD), and schizophrenia (SZ). We introduce a group information guided independent component analysis procedure to estimate both group-level and subject-specific connectivity states from DFC. Using resting-state fMRI data of 238 healthy controls (HCs), 140 BPP, 132 SAD, and 113 SZ patients, we identified measures differentiating groups from the whole-brain DFC and traditional static functional connectivity (SFC), separately. Results show that DFC provided more informative measures than SFC. Diagnosis-related connectivity states were evident using DFC analysis. For the dominant state consistent across groups, we found 22 instances of hypoconnectivity (with decreasing trends from HC to BPP to SAD to SZ) mainly involving post-central, frontal, and cerebellar cortices as well as 34 examples of hyperconnectivity (with increasing trends HC through SZ) primarily involving thalamus and temporal cortices. Hypoconnectivities/hyperconnectivities also showed negative/positive correlations, respectively, with clinical symptom scores. Specifically, hypoconnectivities linking postcentral and frontal gyri were significantly negatively correlated with the PANSS positive/negative scores. For frontal connectivities, BPP resembled HC while SAD and SZ were more similar. Three connectivities involving the left cerebellar crus differentiated SZ from other groups and one connection linking frontal and fusiform cortices showed a SAD-unique change. In summary, our method is promising for assessing DFC and may yield imaging biomarkers for quantifying the dimension of psychosis. Hum Brain Mapp 00:000–000, 2017. © 2017 Wiley Periodicals, Inc.
Pub.: 10 Mar '17, Pinned: 26 Jun '17
Abstract: 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.
Pub.: 19 Apr '17, Pinned: 26 Jun '17
Abstract: Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.
Pub.: 27 May '17, Pinned: 26 Jun '17
Abstract: Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear.To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum.Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium.Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests.Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05).Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.
Pub.: 16 May '14, Pinned: 26 Jun '17
Abstract: There is increasing evidence for phenomenological, biological and genetic overlap between schizophrenia and bipolar disorder, bringing into question the traditional dichotomy between them. Neurobiological models linked to dimensional clinical data may provide a better foundation to represent diagnostic variation in neuropsychiatric disorders.To capture the interaction between psychosis and affective symptoms dimensionally, we devised a brief descriptive scale based on the type and relative proportions of psychotic and affective symptoms over the illness course. The scale was administered to a series of 762 patients with psychotic disorders, including schizophrenia, schizoaffective and psychotic bipolar disorder assessed as part of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) study.The resulting Schizo-Bipolar Scale scores across these disorders showed neither a clear dichotomy nor a simple continuous distribution. While the majority of cases had ratings close to prototypic schizophrenia or bipolar disorder, a large group (45% of cases) fell on the continuum between these two prototypes.Our data suggest a hybrid conceptualization model with a representation of cases with prototypic schizophrenia or bipolar disorder at the extremes, but a large group of patients on the continuum between them that traditionally would be considered schizoaffective. A dimensional approach, using the Schizo-Bipolar Scale, characterized patients across a spectrum of psychopathology. This scale may provide a valuable means to examine the relationships between schizophrenia and psychotic bipolar disorder.
Pub.: 15 Oct '11, Pinned: 21 Jun '17
Abstract: Bipolar and schizophrenia network for intermediate phenotypes is a network of investigator-driven laboratories focused on developing phenotypes, genotypes, and biomarkers for psychosis. Over the last 5 years, the consortium has accomplished a dense phenotyping protocol using probands with a lifetime history of psychosis, their relatives, and healthy controls. This has established a library of biomarker information on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. The founding goal of establishing disease biomarkers for current psychotic diagnoses has been poorly met, because the cognitive, electrophysiologic, eye movement, and brain imaging biomarkers did not regularly discriminate individuals with different DSM psychosis diagnoses. In future, we will use this biomarker information to establish a pathway to biomarker-based classification in psychoses.
Pub.: 25 Feb '14, Pinned: 21 Jun '17
Abstract: It is critical for Psychiatry as a field to develop approaches to define the molecular, cellular and circuit basis of its brain diseases, especially for serious mental illnesses. Then, to use these definitions to generate biologically-based disease categories, as well as to explore disease mechanisms and illness etiologies. Our current reliance on phenomenology is inadequate to support exploration of molecular treatment targets and disease formulations. And the leap directly from phenomenology to disease biology has been limiting because of broad heterogeneity within conventional diagnoses. The questions addressed in this paper are formulated around how we can use brain biomarkers to achieve disease categories which are biologically based. We have grouped together a series of vignettes as examples of early approaches, all using the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) biomarker data base and collaborators, starting off with describing the foundational statistical methods for these goals. We use primarily criterion-free statistics to identify pertinent groups of involved genes related to psychosis, genes related to symptoms and finally, to create new biologically based disease cohorts within the psychopathological dimension of psychosis. While we do not put these results forward as final formulations, they represent a novel effort to rely minimally on phenomenology as a diagnostic tool and to fully embrace brain characteristics of structure, molecular and cellular characteristics and function to support disease definition in psychosis.
Pub.: 02 Aug '16, Pinned: 21 Jun '17
Abstract: Current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs—Biotypes—previously developed from cognitive and neurophysiologic measures (1), we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes.
Pub.: 31 Aug '16, Pinned: 21 Jun '17