Characterization of Neurophysiologic and Neurocognitive Biomarkers for Use in Genomic and Clinical Outcome Studies of Schizophrenia

Abstract

BackgroundEndophenotypes 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.MethodsParticipants (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.ResultsMost 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.ConclusionsThe 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.

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…In accordance with clinical EEG observations using a similar sensory gating paradigm (Light et al . 2012), we observed a response suppression of the second pulse ( anova main effect of pulse order, P  < 0.001, F  = 12.61 and P  < 0.001, F  = 11.91 for PCs and interneurones respectively). However, there was no significant difference in sensory gating between genotypes ( P  > 0.05 for both cell types for the anova interaction effect between genotype and pulse number; Fig.…”

“…2007, Light et al . 2012). On a mechanistic level, we found deficient function of putative GABAergic FSIs during pre‐attentive processing of auditory information.…”

“…2012). Deficits at this perceptual level can be probed by back‐translational auditory stimulation paradigms, such as the ‘paired click paradigm’ or ‘auditory steady‐state responses (ASSR)’ (Hamm et al .…”

Review paper. Neuropsychological dimension of schizophrenia - evaluation possibilities and therapeutic implications

“…It has already been demonstrated that in patients with schizophrenia, gating processes do not function properly, and they among other factors are responsible for cognitive deficits. One of the testing methods of the efficiency of gating processes is testing of the so-called auditory evoked potentials [59,60]. So far, various studies have confirmed the irregularity of these processes based on the analysis of the waves P50, P200, N100, N200, P300 in patients and their healthy first-line relatives, which make them potential "candidates" to the name of endophenotypes or markers in schizophrenia [ 59,61,62].…”

“…One of the testing methods of the efficiency of gating processes is testing of the so-called auditory evoked potentials [59,60]. So far, various studies have confirmed the irregularity of these processes based on the analysis of the waves P50, P200, N100, N200, P300 in patients and their healthy first-line relatives, which make them potential "candidates" to the name of endophenotypes or markers in schizophrenia [ 59,61,62]. Based on the analysis of auditory evoked potentials researchers conclude that in patients suffering from schizophrenia, there is hyper sensitivity of neurons to stimuli, and hence, reduced initial selection of information occurs [63,64].…”