This study applies modern signal processing methods to explore oscillatory signals that are suppressed during repeated stimuli. The results indicate that gating of auditory evoked oscillatory responses occurs primarily at the beta to theta frequencies when measured in single trials. Gating of the alpha-theta band marks the liability for schizophrenia and is heritable: its heritability is estimated to be at least 4-fold higher than that of the traditional P50 gating measure in the families of people with schizophrenia.
The heritability of the P50 gating measure was estimated at 0 – 0.12. Several twin studies of P50 gating in non-schizophrenia populations suggested that its heritability could be estimated to be as high as 0.40 – 0.68 by some genetic models 36–39
. However, these twin-based estimates may be misleading for family studies, because they relied on models that weighted heavily on the familial correlations of the monozygotic twins. For instance, the familial correlations of P50 gating in dizygotic twins (50% genetic sharing) were 0 36
and 0.04 38
even though the heritability estimates were reported to be 0.44 and 0.68, respectively, in these studies. Genetic sharing in first-degree family members is 50%. Therefore, data from these twin studies could have actually predicted that the P50 gating measure is unlikely to have a high heritability in family samples, which is confirmed by the recent COGS sample (h2
, and now by our sample.
Sensory gating has been considered as one of the leading endophenotypes of schizophrenia. However, the use of P50 gating as the primary index for sensory gating has been questioned due to this measure’s low test-retest reliability 9;40;41
, and is further discouraged recently by its low heritability in families of people with schizophrenia. Several alternative measures to P50 have been examined 25;26;42–49
. For example, using frequency domain analyses, it was found that gating of lower frequency response (~ 1–20 Hz) of the averaged evoked potential provided better separation between patients and controls than P50 or gamma band gating 42–44
. Another approach was to use evoked potentials occurring at the 100–200 ms post stimulus interval, namely the N1 and P2 components, which significantly separated patients from controls in some studies 41;43–45
; but produced the opposite finding in a study of first-degree relatives 50
. These prior efforts suggest that sensory gating can occur at a lower frequency and in a window after the P50 wave, even though a systematic evaluation of these alternative measures’ heritability in the families of people with schizophrenia have not been reported. Our finding of impaired single trial alpha-theta band gating at the 25–275 ms window may be viewed as consistent with these prior data. However, we have only compared the current wavelet approach with P50. It would be informative to compare it with other alternative processing approaches in the future.
While we have used sensory gating to described both P50 and alpha-theta band gating, there is a lack of direct evidence to support or refute whether P50 gating and the alpha-theta gating are measuring the same underlying information processing. There was a lack of substantial correlation between the two gating measures (Pearson’s r=0.01–0.13 in different epochs). On the other hand, P50 is a time-locked response, while the alpha-theta response includes time-locked and nonstationary responses, therefore there is likely some overlap in their underlying mechanism but additional studies are clearly needed to understand the convergent and divergent mechanisms of the two gating phenomena. The new measure of gating is based on the decomposition of evoked energy into its oscillatory components in different frequency bands. This frequency-specific oscillatory gating measure is thought to be more elementary than the traditional P50 measure that is based on the averaged signal across all frequencies. The high heritability and impairment in unaffected relatives suggest that this new oscillatory gating measure indexes a biological process associated with the genetic liability for schizophrenia.
The finding that suppression at the beta and alpha-theta frequencies is the primary event during sensory gating is supported by another recent sensory gating study using single trial independent component analysis (ICA) based approach, which showed that it was the beta, alpha, and theta activities that contributed to the N1 suppression 51
. So how might a failure in suppressing low frequency oscillations be related to schizophrenia pathology and its liability? The data from this study demonstrated a genetic effect but did not address the physiological origin of the problem, therefore we should emphasize that the following discussion is speculative. Elevated on-going low frequency activity has been shown to delay behavioral response in humans 52
, and weakens the synchronization of inter-neuronal spiking in animal recordings 15
. The sensory gating problem has long been theorized as related to the inability of people with schizophrenia to filter out unwanted sensory information, leading to psychotic symptoms1;2;53;54
. The identification of failed low frequency gating in schizophrenia may suggest that a dysfunction in suppressing alpha-theta activities in response to repeated stimulus might lead to impaired neuronal synchronization in response to subsequent sensory information. There was a modest but significant correlation between alpha-theta gating and psychotic symptoms/level of function, suggesting that this deficit maybe related to clinical functions. However, additional human and animal studies are needed to test and expand this hypothesis. We should emphasize that it was the gating of the alpha-theta response, not the actual responses that had higher heritability, implicating that the alpha-theta inhibition is perhaps indexing a more elementary or distinct biological process separated from the process of individual responses (but see limitation discussed below).
Low frequency activities are related to reduced alertness. A question is whether psychotropic medications contributed to the alpha-theta gating abnormality by their sedating effects in the patients. However, the finding of alpha-theta gating deficit in unaffected relatives is inconsistent with a direct medication or chronic disease effect.
The traditional approach of using P50 to index sensory gating is also problematic due to its measurement procedures: although the scoring is semi-automated it still requires some subjective decisions to select the P50 peak within a window where there may be more than one peak or the selection of trough, which may be affected by the descending slope of the previous wave. This may add further noise to the data. In comparison, the DWT based single trial method, while computationally intense, does not require rater intervention, thus removing potential subjective biases. However, single trial analysis also has its own inherent limitations, since it includes the background noise. The sensory gating measure happens to partially circumvent the problem because the ratio measure removes the noise that is equally present in responses to S1 and S2. However, this limitation would be present when responses to individual stimuli are analyzed and may partially contribute to their lower ability to differentiate groups and their lower heritability estimates.
In conclusion, this study supports the hypothesis that the gating deficit represents an elementary neuronal dysfunction in people with schizophrenia 55;56
. Our data demonstrate that deficit in gating of evoked responses remains a critical biomarker for the liability of schizophrenia, and is highly heritable. However, frequency-based analytic methods are needed to facilitate the use of this endophenotype in genetic studies. This finding is especially timely and relevant given the fact that a large amount of sensory gating data has already been collected across many laboratories. If our finding can be replicated by other laboratories, this or similar methods maybe used to reanalyze existing data. The neural oscillatory approach may also provide a new framework for studying the neurobiological pathway of sensory gating, and for testing novel compounds that can reverse specific oscillatory dysfunctions.