Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures

Abstract

In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are "impaired" in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

Fig. 1

The acoustic startle response to 110-dB SPL white noise burst, recorded from EMG electrodes situated over the OO muscle. The magnitude of the startle response is reduced when the startle pulse is preceded by a lower intensity auditory prepulse. In this example, an 85-dB white noise prepulse was presented 100 ms prior to the startle stimulus. Schizophrenia patients typically exhibit less attenuation of the acoustic startle response following the prepulse.

Fig. 2

Auditory evoked responses of 3 control subjects (left) and 3 subjects with schizophrenia (right). Stimuli were a conditioning auditory stimulus and an identical test stimulus delivered 500 ms apart. Arrows mark the location of the P50 wave in the tracings. Positive polarity is downward. Test-to-conditioning (T/C) ratio is indicated for each subject. P50 response to the second stimulus is attenuated in control subjects. As illustrated, schizophrenia patients typically exhibit less attenuation of the P50 response to this “test” click.

Fig. 3

Infrared tracings of eye position during 2 trials of a prototypical AS task. The participant is asked to generate a saccade in the opposite direction of the AS cue. In the first trial (A), the participant generates a correct AS, looking away from the cue. In the second trial (B), the participant initially makes an incorrect response (prosaccade error) to the AS cue and then quickly generates a large corrective saccade to the appropriate location. Position of the AS cue varies unpredictably from trial to trial. This particular version of the task has a 200-ms overlap between central fixation and the AS cue. Schizophrenia patients typically make more of these prosaccade errors than healthy subjects.

Fig. 4

MMN response to an auditory pitch-deviant stimulus. The MMN elicited by a 2000-Hz deviant tone is seen as a negative deflection between 100 and 150 ms poststimulus, with maximum deflection at Fz. The repeating standard, in this case, was a 1000-Hz tone presented every 500 ms, and the deviant tone comprised 5% of the stimuli. Top: grand average waveforms for 20 control subjects. Bottom: grand average waveforms for 19 patients. As shown, schizophrenia patients typically exhibit smaller MMN amplitudes than healthy subjects.

Fig. 5

P300 response to an infrequent salient auditory stimulus. The P300 response to a target stimulus appears as a broad positive ERP component between 300 and 400 ms poststimulus, with maximum amplitude at the Pz electrode. In this example, subjects made a button press to a 2000-Hz target tone. The standard tone was 1000 Hz. Tones were presented every 1.8 seconds. Top: grand average waveforms for 38 control subjects. Bottom: grand average waveforms for 52 patients. As shown, schizophrenia patients typically exhibit smaller P300 amplitudes than healthy subjects.