This study addressed two related questions: 1) Are there selective impairments of specific auditory ERP measures; 2) Do these specific impairments reflect a single underlying auditory processing deficit? With respect to the first question, the answer appears to be “yes”. N100 amplitude, pitch MMN and P3b amplitude were differentially impaired in this patient sample. With respect to the second question, the factor analysis indicates that these abnormalities coalesce into two distinct and relatively independent auditory processing deficits. One, encompassing the N100 and MMN, appears to be a relatively focal disturbance of early sensory processing at the level of the auditory cortex, which can be linked clinically to the positive symptom of thought disorder and the reciprocal negative symptom of alogia. The other, represented by abnormal P300 amplitude, denotes a disturbance of higher-order cognitive processes of stimulus evaluation, discrimination and salience detection, which is linked to clinical disturbances in motivation, attention and reality testing. Our results indicate, therefore, that there are at least 2 distinct auditory processing deficits in schizophrenia, one early and one late, and that these are likely to reflect different neurobiological and/or genetic substrates that contribute to the heterogeneity of the illness (Turetsky et al., 2007
This finding of two discrete deficits is consistent with the relatively limited data that exist concerning the co-aggregation of auditory ERP abnormalities in schizophrenia. Two recent studies examined P50 gating, P300 and MMN in the same subjects, one in schizophrenia patients and their unaffected 1st
-degree relatives (Price et al., 2006
) and one in healthy monozygotic and dizygotic twins (Hall et al., 2006
). Although all three measures were found to be both heritable and abnormal in patients, none of them were correlated with each other. Four studies have examined P50 gating and PPI in the same subjects, one in schizophrenia patients (Braff et al., 2006) and three in healthy individuals (Schwarzkopf et al., 1993
; Oranje et al., 1999
; Oranje et al., 2006
). Again, there were no consistent associations between the two measures, even though both have been conceptualized as indices of inhibitory failure in schizophrenia. Unfortunately, although there have been numerous studies of P300 in schizophrenia, and N100 amplitude measures are routinely acquired during these studies and often reported as abnormal (e.g., Ford et al., 2001
), we are unaware of any previous investigations of the relationship between these 2 patient abnormalities. Our data, though, suggest that the N100 amplitude decrement is similarly independent of other auditory ERP abnormalities, except for MMN.
There are a number of caveats and possible limitations of this study that must be emphasized. In particular, there is our failure to observe any patient abnormalities in either P50 auditory sensory gating or PPI - two measures that have been commonly reported as abnormal in schizophrenia - despite there being significant deficits in other measures of auditory sensory processing. As detailed in , the principal difference between our measurements and those of previous studies was reduced PPI and P50 gating in control subjects, rather than increased PPI and P50 gating in patients. This suggests that methodological differences, rather than patient biases, may have contributed most to our failure to observe a patient deficit. There are a number of ways in which this study differed from prototypical P50 and PPI studies.
First, these measures were not acquired in isolation, but as part of a more extensive battery of auditory processing tasks. We employed a fixed test order that was selected to minimize carryover effects from one task to another and maintain the psychophysiological construct validity of each measure. Nevertheless, the use of multiple tests in this particular order may have affected measures that are relatively sensitive to state effects. It is notable, in this regard, that a recent study employing a broad test battery found significant effects of test order on PPI in a healthy control sample (Swerdlow et al., 2007
). Specifically, PPI was reduced in healthy men when testing occurred later in the test battery. This is especially pertinent since PPI was the last experiment in our protocol. Similarly, P50 has been shown to be altered in a state-dependent manner, in healthy subjects, by changes in levels of arousal and stress (Johnson and Adler, 1993
). It may be that control subjects, who have no intrinsic deficit, are more sensitive to the disruptive effects of such state factors than schizophrenia patients.
Second, because the profile and factor analyses require that each subject have data on all measures of interest, we did not exclude so-called “non-responders”, as is often done for PPI and P50 (e.g. Braff et al., 2007
). Rather, we measured responses in all subjects without regard for a threshold response level. The inclusion of subjects with relatively small P50 and PPI amplitudes would likely result in increased mean gating ratios, due to smaller denominator values. Although this remains a possibility, we would note that none of the subjects in our sample would have been excluded using the thresholds specified by Braff et al. (2007)
(P50 < 1.0 μV, startle amplitude < 13 μV).
Third, there may have been undetected effects of other potential confounds, such as smoking and nicotine withdrawal, female menstrual cycle, and psychotropic medications other than antipsychotics. Consistent with the standard practice for most PPI and P50 studies, we allowed subjects to maintain their usual smoking habits prior to arrival at the laboratory, but we did not allow any smoking breaks during the test session. It may be that any effects of acute nicotine withdrawal were exacerbated by our more protracted test session. However, this was unlikely to have contributed to our atypical control subject measures, as only 4 of the 22 healthy subjects smoked at all. Similarly, although antidepressants and anxiolytics can alter both PPI and P50 (e.g., Schächinger et al., 1999
; Quednow et al., 2004
; Hammer et al., 2007
), only 4 of 23 patients were actually taking these types of medications. So, the likelihood that the use of these medications substantially affected our measurements is small. Phase of the female menstrual cycle can also affect PPI (Jovanovic et al., 2004
), with PPI being reduced in the luteal phase. We did not assess menstrual phase in our female subjects; rather, we treated it as a random factor that was not expected to contribute to any between-group differences. This is fairly standard practice. However, we cannot rule out the possibility that undetected differences in menstrual phase between female patients and female controls contributed to our failure to observe a group difference.
In addition to these potential confounds, a selection bias may have contributed to the lack of a patient deficit. Our sample was a community-based outpatient sample with quite low levels of acute symptomatology and relatively high levels of functioning. Most of the published studies have examined chronic patients with greater levels of clinical impairment. Finally, a recent meta-analysis of published P50 studies noted large variability in P50 gating among healthy control subjects, and sensitivity of the measure to fairly subtle differences in experimental methodology. Overall, approximately 40% of control subjects had P50 gating ratios within 1 standard deviation of the patient mean (Patterson et al., in press
). So, relatively low statistical power may have also contributed to our failure to detect a deficit.
It should also be noted that, despite these various confounds, our PPI data are in at least one respect representative of the literature. The small group of unmedicated patients in our sample exhibited a nearly complete failure of PPI, which was offset by normal PPI (relative to this control sample) among the medicated patients. Normalization of PPI with atypical antipsychotic medication has been observed previously (Kumari et al., 2002
; Swerdlow et al., 2006
), although not uniformly for all agents (Oranje et al., 2002
). It is likely that this, too, contributed to the lack of an observed abnormality in our sample. Some studies have also reported partial-to-full normalization of P50 gating with other atypical antipsychotics, in addition to clozapine (Yee et al., 1998
; Light et al., 2000
; Adler et al., 2004
). Although we did not observe a robust effect of medication on P50 in our sample, the use of atypical antipsychotics may have also partially attenuated the gating deficit in these subjects - which was, in fact, in the expected direction.
Nevertheless, even in this sample of patients with relatively low levels of clinical symptomatology, active treatment with atypical antipsychotic medications, potential confounds, and normal PPI and P50 gating, there were robust deficits in both early auditory sensory and subsequent cognitive processing that were entirely independent of our assessment of PPI and P50. The clustering of these deficits suggests two discrete independent neurobiological substrates that may represent different illness subtypes. In particular, early sensory processing deficits at the level of the primary and secondary auditory cortex may be an index of the physiological abnormality underlying clinical symptoms of impaired language and verbal processing, while later deficits in cognitive stimulus evaluation may index more frontally mediated impairments in motivation and attention. Future studies should similarly focus on the assessment of multiple measures in the same individuals, to enable us to better understand both the heterogeneity and underlying etiologic mechanisms of the disorder.