Cortical electrophysiologic event-related potentials are multidimensional measures of information processing that are well-suited for efficiently parsing automatic and controlled components of cognition that span the range of deficits evidenced in schizophrenia patients. These information processes are key cognitive measures that are recognized as informative and valid targets for understanding the neurobiology of schizophrenia. These measures may be used in concert with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) neurocognitive measures in the development of novel treatments for schizophrenia and related neuropsychiatric disorders. The employment of novel event-related potential paradigms designed to carefully characterize the early spectrum of perceptual and cognitive information processing allows investigators to identify the neurophysiologic basis of cognitive dysfunction in schizophrenia and to examine the associated clinical and functional impairments.

Although sensory processing abnormalities contribute to widespread cognitive and psychosocial impairments in schizophrenia (SZ) patients, scalp-channel measures of averaged event-related potentials (ERPs) mix contributions from distinct cortical source-area generators, diluting the functional relevance of channel-based ERP measures. SZ patients (n = 42) and non-psychiatric comparison subjects (n = 47) participated in a passive auditory duration oddball paradigm, eliciting a triphasic (Deviant-Standard) tone ERP difference complex, here termed the auditory deviance response (ADR), comprised of a mid-frontal mismatch negativity (MMN), P3a positivity, and re-orienting negativity (RON) peak sequence. To identify its cortical sources and to assess possible relationships between their response contributions and clinical SZ measures, we applied independent component analysis to the continuous 68-channel EEG data and clustered the resulting independent components (ICs) across subjects on spectral, ERP, and topographic similarities. Six IC clusters centered in right superior temporal, right inferior frontal, ventral mid-cingulate, anterior cingulate, medial orbitofrontal, and dorsal mid-cingulate cortex each made triphasic response contributions. Although correlations between measures of SZ clinical, cognitive, and psychosocial functioning and standard (Fz) scalp-channel ADR peak measures were weak or absent, for at least four IC clusters one or more significant correlations emerged. In particular, differences in MMN peak amplitude in the right superior temporal IC cluster accounted for 48% of the variance in SZ-subject performance on tasks necessary for real-world functioning and medial orbitofrontal cluster P3a amplitude accounted for 40%/54% of SZ-subject variance in positive/negative symptoms. Thus, source-resolved auditory deviance response measures including MMN may be highly sensitive to SZ clinical, cognitive, and functional characteristics.

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.