Interpreting abnormality: an EEG and MEG study of P50 and the auditory paired-stimulus paradigm

Abstract

Interpretation of neurophysiological differences between control and patient groups on the basis of scalp-recorded event-related brain potentials (ERPs), although common and promising, is often complicated in the absence of information on the distinct neural generators contributing to the ERP, particularly information regarding individual differences in the generators. For example, while sensory gating differences frequently observed in patients with schizophrenia in the P50 paired-click gating paradigm are typically interpreted as reflecting group differences in generator source strength, differences in the latency and/or orientation of P50 generators may also account for observed group differences. The present study examined how variability in source strength, amplitude, or orientation affects the P50 component of the scalp-recorded ERP. In Experiment 1, simulations examined the effect of changes in source strength, orientation, or latency in superior temporal gyrus (STG) dipoles on P50 recorded at Cz. In Experiment 2, within- and between-subject variability in left and right M50 STG dipole source strength, latency, and orientation was examined in 19 subjects. Given the frequently reported differences in left and right STG anatomy and function, substantial inter-subject and inter-hemispheric variability in these parameters were expected, with important consequences for how P50 at Cz reflects brain activity from relevant generators. In Experiment 1, simulated P50 responses were computed from hypothetical left- and right-hemisphere STG generators, with latency, amplitude, and orientation of the generators varied systematically. In Experiment 2, electroencephalographic (EEG) and magnetoencephalographic (MEG) data were collected from 19 subjects. Generators were modeled from the MEG data to assess and illustrate the generator variability evaluated parametrically in Experiment 1. In Experiment 1, realistic amounts of variability in generator latency, amplitude, and orientation produced ERPs in which P50 scoring was compromised and interpretation complicated. In Experiment 2, significant within and between subject variability was observed in the left and right hemisphere STG M50 sources. Given the variability in M50 source strength, orientation, and amplitude observed here in nonpatient subjects, future studies should examine whether group differences in P50 gating ratios typically observed for patient vs. control groups are specific to a particular hemisphere, as well as whether the group differences are due to differences in dipole source strength, latency, orientation, or a combination of these parameters. Present analyses focused on P50/M50 merely as an example of the broader need to evaluate scalp phenomena in light of underlying generators. The development and widespread use of EEG/MEG source localization methods will greatly enhance the interpretation and value of EEG/MEG data.

Introduction

Over the last decade, the development of whole-head magnetoencephalographic (MEG) systems and substantial improvements in electroencephalographic (EEG) and MEG source modeling techniques have fostered the study of the topography of event-related brain potentials (ERPs) in relation to the corresponding anatomical sources. In particular, the development of source localization techniques has allowed investigators to undertake a detailed investigation of the generators that determine the electrical and magnetic activity observed at the scalp (Hari, 1993, Lewine, 1995). These investigations, however, highlight limitations in traditional signal processing techniques used to study ERPs (Lewine, 1995). Using both simulated and nonsimulated data, the present paper presents a study of the adequacy of such traditional techniques through an examination of the P50 component of the ERP obtained in a prominent auditory paired-stimulus paradigm. The intent is not a substantive focus specifically on P50, its reduction as a function of repetition, or its growing use in clinical research. Rather, the intent is a particularly straightforward illustration of a much more general issue in ERP componentry. The interpretation of component differences will often benefit from, and will often require, information about the neural generator(s) of the components, especially when multiple sources contribute to the scalp ERP component. The present case study employs P50 because it is a cortical phenomenon without extensive overlap with other components, because it has multiple neural generators that are fairly well established yet very hard to identify with typical EEG methods, and because within- and between-subject variability in its generators would have major but as yet unappreciated consequences for basic and clinical research relying on it.

In the paired-click paradigm, two clicks are separated by 500 ms, and the amplitude of P50 to each click is determined. The most widely used analysis method is that employed in the first studies of P50 gating in schizophrenia (Adler et al., 1982, Freedman et al., 1983). Using EEG recorded between Cz and a distant reference such as mastoid or earlobe, the ratio of the peak amplitude of P50 to the second click (S2) to that for the first click (S1) provides an index of the degree of sensory gating. This paradigm is often used to study sensory gating in normal and patient populations and has achieved considerable prominence in studies of schizophrenia. In normal subjects a substantial suppression of the P50 response to the second click occurs (Freedman et al., 1983, Nagamoto et al., 1989, Erwin et al., 1991, Clementz et al., 1997a, Clementz et al., 1997b, Judd et al., 1992, Nabor et al., 1992, Ward et al., 1996). However, patients with schizophrenia show a marked preservation of S2, so that it is comparable to S1 or only slightly smaller (Adler et al., 1982, Freedman et al., 1983, Freedman et al., 1987, Nagamoto et al., 1989, Boutros et al., 1991, Judd et al., 1992, Clementz et al., 1997a, Clementz et al., 1997b, Jin et al., 1997; White and Yee, 1997; Yee et al., 1998; Yee and White, 2001; Clementz and Blumenfeld, 2001).

Although numerous studies have used this method to exam patient/nonpatient differences in the scalp-recorded P50 S1 and S2 responses, little is known about the characteristics of the generators that produce P50. Such information would be valuable, however, as between-subject variability in the generators that contribute to P50 could alter how the sensory gating deficit is interpreted. Considering even the simplest case, with just two P50 generators at homologous locations in each hemisphere, the P50 literature to date has not examined possible group differences in the generators in terms of strength, orientation, and latency. Thus, when examining P50 at Cz it is not possible to determine whether the sensory gating deficit observed in patients with schizophrenia is a bilateral or unilateral deficit and, within a particular hemisphere, which parameters contribute to the decreased S2 and/or S1 amplitude observed in schizophrenia. For example, although amplitude effects are generally interpreted as differences in generator strength, they could as readily arise from differences in orientation.

Given that P50 is consistently observed to be maximal at the midline Cz site and that its generators are bilateral, the possibility of lateralized differences in the orientation or behavior of those generators must be evaluated in order to interpret P50 ratio effects unambiguously. It is generally believed that the left and right superior temporal gyri (STG) directly produce much and perhaps essentially all of the P50 component. For example, investigators recording the ERP using either intraoperative electrocorticography (Ligeois-Chauvel et al., 1994) or chronic subdural electrodes (Lee et al., 1984) have reported that P50 is a near-field potential in the primary auditory cortex. The supratemporal origin of middle-latency ERPs is also supported by the scalp distribution of electrical potentials (Cohen, 1982) and by recordings from the pial surface over temporal and parietal lobes (Chatrian et al., 1960). However, areas such as hippocampus (Goff, 1978, Waldo et al., 1994, Freedman et al., 1996), midbrain reticular (Erwin and Buchwald, 1986a; Erwin and Buchwald, 1986b), and other midline brain regions (Kraus et al., 1992; Ninomiya et al., 1997) have been suggested as additional generators of the early auditory ERPs.

In practice, it is difficult to study the contribution of individual STG sources to the scalp-recorded ERP with traditional scalp EEG arrays, largely due to the orientation of primary current flow in the superior and inferior direction. Bilateral STG sources in left and right hemisphere generate a maximum electric potential distribution on the top of the head (near Cz) and a minimum potential somewhere near the chin and neck area, a region where electrodes are typically not placed. Accordingly, only one pole of the electric field is measured. Recorded activity from mid- and near-midline vertex electrodes will reflect the combined activity from the two STG sources. Such conditions make localization and study of the individual STG generators using typical EEG montages difficult. Very rarely, dense EEG arrays place some electrodes in the chin and upper neck areas. However, due to the complicated conductivity distribution of the chin, mouth, and neck, it remains a challenge yet to be met to accurately model the conductivity profile of those areas even with realistic head modeling techniques using the boundary element method or the finite element method.

In contrast, MEG is well suited for studying STG sources. First, the generally superior–inferior orientation of the source is favorable to MEG recordings: the magnetic signal recorded from bilateral STG to a bilateral click shows a maximum and minimum magnetic field distribution in both the left and right portion of the MEG sensor array, roughly in an anterior–posterior direction within each hemisphere, with virtually no overlap between the left- and right-hemisphere MEG fields. In addition, the head is relatively transparent to magnetic fields, making MEG insensitive to errors in modeling the conductivity profile of the head (Leahy et al., 1998, Huang et al., 1998). These reasons make MEG an ideal technique for studying bilateral STG sources related to P50.

The present study was conducted as an initial exploration of the relationship of STG generators to the Cz P50 response, using two strategies. First, realistic simulations were conducted positing various combinations of generator characteristics and computing the forward solution to determine what such generators would produce in Cz EEG. Second, MEG and EEG data were recorded simultaneously in a standard P50 paired-stimulus paradigm in a group of nonpatient subjects and analyzed to distinguish the characteristics of the lateralized STG generators in terms of source strength, orientation, and amplitude, both within subjects (comparing left- and right-hemisphere sources) and between subjects. These approaches to P50 generation served to illustrate broader issues in the measurement and interpretation of scalp-recorded ERP phenomena.