Clinical and biobehavioral phenotypic assessments and data harmonization for the RE-JOIN research consortium: Recommendations for common data element selection.

Background: The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium is part of the Helping to End Addiction Long-term® (HEAL) Initiative. HEAL is an ambitious, NIH-wide initiative to speed scientific solutions to stem the national opioid public health crisis. The RE-JOIN consortium's over-arching goal is to define how chronic joint pain-mediating neurons innervate different articular and peri-articular tissues, with a focus on the knee and temporomandibular joints (TMJ) across species employing the latest neuroscience approaches. The aim of this manuscript is to elucidate the human data gathered by the RE-JOIN consortium, as well as to expound upon its underlying rationale and the methodologies and protocols for harmonization and standardization that have been instituted by the RE-JOIN Consortium. Methods: The consortium-wide human models working subgroup established the RE-JOIN minimal harmonized data elements that will be collected across all human studies and set the stage to develop parallel pre-clinical data collection standards. Data harmonization considerations included requirements from the HEAL program and recommendations from the consortium's researchers and experts on informatics, knowledge management, and data curation. Results: Multidisciplinary experts - including preclinical and clinical researchers, with both clinician-scientists- developed the RE-JOIN's Minimal Human Data Standard with required domains and outcome measures to be collected across projects and institutions. The RE-JOIN minimal data standard will include HEAL Common Data Elements (CDEs) (e.g., standardized demographics, general pain, psychosocial and functional measures), and RE-JOIN common data elements (R-CDE) (i.e., both general and joint-specific standardized and clinically important self-reported pain and function measures, as well as pressure pain thresholds part of quantitative sensory testing). In addition, discretionary, site-specific measures will be collected by individual institutions (e.g., expanded quantitative sensory testing and gait biomechanical assessments), specific to the knee or TMJ. Research teams will submit datasets of standardized metadata to the RE-JOIN Data Coordinating Center (DCG) via a secure cloud-based central data repository and computing infrastructure for researchers to share and conduct analyses on data collected by or acquired for RE-JOIN. RE-JOIN datasets will have protected health information (PHI) removed and be publicly available on the SPARC portal and accessible through the HEAL Data Ecosystem. Conclusion: Data Harmonization efforts provide the multidisciplinary consortium with an opportunity to effectively collaborate across decentralized research teams, and data standardization sets the framework for efficient future analyses of RE-JOIN data collected by the consortium. The harmonized phenotypic information obtained will significantly enhance our understanding of the neurobiology of the pain-pathology relationships in humans, providing valuable insights for comparison with pre-clinical models.

Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses.

OBJECTIVE: Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients. METHODS: 410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA. RESULTS: SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli. CONCLUSIONS: MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Demand and modality of directed attention modulate "pre-attentive" sensory processes in schizophrenia patients and nonpsychiatric controls.

BACKGROUND: Mismatch negativity (MNN) and P3a are event related potential (ERP) measures of early sensory information processing. These components are usually conceptualized as being "pre-attentive" and therefore immune to changes with variations in attentional functioning. This study aimed to determine whether manipulations of attention influence the amplitudes and latencies of MMN and P3a and, if so, the extent to which these early sensory processes govern concurrent behavioral vigilance performance in schizophrenia patients and normal subjects. METHODS: Schizophrenia patients (SZ; n = 20) and Nonpsychiatric Control Subjects (NCS; n = 20) underwent auditory ERP testing to assess MMN and P3a across 4 EEG recording sessions in which attentional demand (low vs. high) and sensory modality of directed attention (visual vs. auditory) were experimentally varied. RESULTS: Across conditions, SZ patients exhibited deficits in MMN and P3a amplitudes. Significant amplitude and latency modulation were observed in both SZ and NCS but there were no group-by-condition interactions. The amount of MMN amplitude attenuation from low- to high-demand tasks was significantly associated with increased vigilance performance in both SZ and NCS groups (r = -0.67 and r = -0.60). Several other robust associations were also observed among neurophysiologic, clinical and cognitive variables. CONCLUSIONS: Attentional demand and modality of directed attention significantly influence the amplitude and latencies of "pre-attentive" ERP components in both SZ and NCS. Deficits in MMN and P3a were not "normalized" when attention was directed to the auditory stimuli in schizophrenia patients. The adaptive modulation of early sensory information processing appears to govern concurrent attentional task performance. The temporal window reflecting automatic sensory discrimination as indexed as MMN and P3a may serve as a gateway to some higher order cognitive operations necessary for psychosocial functioning.

Disentangling early sensory information processing deficits in schizophrenia.

OBJECTIVE: The disentangling of early sensory information processing deficits and examination of their relationships to demographic and clinical factors are important steps for the validation of potential biomarkers and/or endophenotypes of schizophrenia. The aims of the present study were to characterize commonly used sensory event-related potential deficits, to determine whether they are (1) distinct from one another and (2) independently associated with important clinical characteristics. METHODS: MMN, P3a and RON event-related potentials (ERP) were recorded from schizophrenia patients (SZ; n=429) and nonpsychiatric comparison subjects (NCS; n=286). Subgroup analyses on demographic and clinical variables were performed. RESULTS: Schizophrenia patients exhibited robust ERP deficits at frontocentral electrodes (MMN: d=1.10; P3a: d=0.87; RON: d=0.77), consistent with previous studies. Each ERP component uniquely accounted for variance in amplitude and schizophrenia deficits. Amplitude reductions occurred with increasing age in both NCS and SZ patients. A small subset of patients prescribed combinations of 1st and 2nd generation antipsychotics exhibited significantly reduced MMN amplitude relative to other medication-defined subgroups. CONCLUSIONS: MMN, P3a, and RON are dissociable deficits with distinct relationships to age and medication status in schizophrenia patients, potentially reflecting divergent pathophysiological processes. Reduced MMN in patients taking multiple antipsychotic medications appear to be attributable to greater severity of symptoms and functional impairments, rather than a medication effect. SIGNIFICANCE: Independent information processing deficits in schizophrenia patients may differentially contribute to the commonly observed deficits in neurocognitive and psychosocial functioning.

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

BACKGROUND: Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. METHODS: Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. RESULTS: Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. CONCLUSIONS: The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research.