Neural anomalies during vigilance in schizophrenia: Diagnostic specificity and genetic associations

Abstract

Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N = 48), bipolar disorder patients (N = 26), first-degree biological relatives of schizophrenia patients (N = 55) and bipolar disorder patients (N = 28), as well as healthy controls (N = 68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.

Keywords: Bipolar disorder; Electrophysiology; Endophenotype; Evoked potential; Genetic liability; Schizophrenia; Vigilance.

Fig. 1

The Degraded Stimulus Continuous Performance Test. Each trial was composed of a single-digit numeral (4.3° × 3.4° visual angle in size) presented for 29 msec followed by a 971-msec white display. During “just look” trials, subjects passively viewed 80 trials of task stimuli. After a pause the experimenter instructed each subject to “press to every” stimulus for 80 trials. After completing control trials, subjects were instructed to press the button only when they thought they saw the numeral “0.” Twenty-five percent of the stimuli were targets (“0”), and 75% were nontargets (numerals “1” to “9”). After 160 practice trials, subjects were given a rest and then presented 480 continuous test trials over three blocks (160 trials per block) in a fixed-pseudorandom order. (adapted from K. H. Nuechterlein and Asarnow, 1999).

Fig. 2

Grand averaged N1 to targets at O2. Topographies depict peak N1 amplitude across the N1 window (140–200 msec) in control subjects. (A) SZRel had greater peak amplitude compared to HC (FDR corrected p = .035) and SZ (FDR corrected p = .015. (B) BPRel had greater peak amplitude compared to BP (FDR corrected p = .014) but not HC (FDR corrected p = .119). (C) N1 amplitudes across groups and conditions at O2 (error bars ± SEM). (D and E) N1 amplitude to targets at O2 was positively associated with the number of false alarms (r(48) = 0.33, FDR corrected p = .04; D) and dˊ in block 1 (r(48) = -0.30, FDR corrected p = .04) and block 2 (r(48) = -0.29, FDR corrected p = .05; E) in SZ. * indicates p < .05 | ** indicates p < .01.

Fig. 3

Grand averaged N2 difference waveforms (targets – nontargets) at Cz. Topography depicts mean N2 difference amplitudes across the N2 time window (320–400 msec) in control subjects. (A) SZ had reduced peak amplitudes compared to HC (FDR corrected p < .01). (B) There were no observed group differences in peak N2 difference waveforms between BP, BPRel and HC. (C) N2 amplitudes were positively associated with average dˊ in SZRel (r(54) = -0.275, FDR corrected p = .05). * indicates p < .05 | ** indicates p < .01.

Fig. 4

Grand averaged P3b amplitude to targets at P7. Topography depicts mean P3b amplitudes across the P3b time window (320–400 ms) in control subjects. (A) SZ had reduced peak amplitudes compared to HC (FDR corrected p < .01). (B) There were no observed group differences in peak P3b amplitudes between BP, BPRel and HC at P7 alone.(C) P3b amplitudes were positively associated with average dˊ across all five groups (r(2 2 5) = 0.37, FDR corrected p < .01). (D) P3b amplitudes were positively associated with the number of SimDiff errors in BP (r(25) = 0.619, FDR corrected p < .01). * indicates p < .05 | ** indicates p < .01.