Sensory gating and source analysis of the auditory P50 in low and high suppressors

NeuroImage 44 (2009) 992–1000

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Sensory gating and source analysis of the auditory P50 in low and high suppressors Verner Knott a,⁎, Anne Millar b, Derek Fisher c a b c

University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada K1Z 7K4 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1S 5B6 Department of Psychology, Institute of Neuroscience, Carleton University, Ottawa, ON, Canada K1H 8M5

a r t i c l e

i n f o

Article history: Received 24 July 2008 Revised 24 September 2008 Accepted 6 October 2008 Available online 1 November 2008 Keywords: Auditory middle latency event-related potential P50 Gating Standardized Low resolution magnetic tomography

a b s t r a c t Impairments in sensory gating in schizophrenia have been reflected by diminished suppression of the scalprecorded middle latency auditory P50 event-related potential (MLAERP) elicited by the second (S2) of a pair (S1–S2) of clicks. As understanding the functional neural substrates of aberrant gating would have important implications for schizophrenia, this study examined the location and time-course of the neural generators of the P50 MLAERP and its gating on subgroups of healthy volunteers exhibiting low (n = 12) and high (n = 12) P50 suppression. Suppressor differences were observed with S1 P50 (high N low) and S2 P50 (high b low) amplitudes, and current source density analysis with standardized Low Resolution Electromagnetic Tomography (sLORETA) evidenced an S1 P50-related activation of limbic, temporal and parietal regions in the high but not the low suppressors. Distributed source localization of the Gating Difference Wave (GDW), obtained by subtracting the S2 P50 response from the S1 P50 response, also revealed a later and sustained frontal activation to characterize high suppressors. These findings suggest that impaired gating of the kind evident in schizophrenia may involve the deficient functioning of multiple interconnected and temporally overlapping activated brain regions. Crown Copyright © 2008 Published by Elsevier Inc. All rights reserved.

Introduction Alterations in cerebral structure and function in schizophrenia suggest that the onset of this syndrome is associated with early neurodevelopmental disturbances in sensory processing (Lafargue and Brasic, 2000). Owing in part to the high prevalence of auditory hallucinations, which are associated with auditory cortex activation (Shergill et al., 2000), disturbances in the auditory system have long been suspected to be present in schizophrenia patients (Shi, 2007). Dysfunctional auditory sensory processing, in the form of aberrant gating of middle latency auditory event-related brain potentials (MLAERP), has been viewed as an endophenotypic marker of schizophrenia (Freedman et al., 1987; Freedman et al., 1991; Freedman et al., 1997; Myles-Worsley et al., 1996). This elementary deficit in auditory sensory gating is typically observed in a paired auditory stimulus (click) paradigm where the first (S1) of the closely (b1000 ms) paired clicks (presented at long [8–10 s] inter-pair intervals) is said to initiate or “condition” an active inhibitory process in the brain, and the second click (S2) “tests” the strength of the inhibition as indexed by the amplitude suppression of an electroencephalographically (EEG)derived vertex (Cz) positive MLAERP at ~ 50 ms (P50) post-stimulus. In non-patient populations, P50 suppression (reflected as the ratio of ⁎ Corresponding author. Royal Ottawa Mental Health Centre, 1145 Carling Avenue, Ottawa, ON, Canada K1Z 7K4. Fax: +1 613 798 2981. E-mail address: [email protected] (V. Knott).

S2 to S1 P50 amplitude [rP50] or as the subtractive difference [dP50] between S1 and S2 amplitude values) is typically robust at 55% (i.e. S2/S1 gating ratio ~.45) while suppression in unmedicated patients with schizophrenia is approximately 20% (i.e. S2/S1 ratio ~ .80) (Bramon et al., 2004; Freedman et al., 1987; Light and Fraff, 1999; Patterson et al., 2008; Potter et al., 2006). Although this P50 suppression deficit has been described as a failure to inhibit the S2 response, there is also evidence that it may be a result of decreased S1 amplitude without further reduction of the S2-elicited P50, resulting in a profile of equal amplitude for S1 and S2 in schizophrenia (Freedman et al., 1983; Jin et al., 1997; Clementz and Blumenfeld, 2001). One of the most widely recognized neuroelectrophysiologic endophenotypes for schizophrenia, P50 suppression deficits have been reported in recent-onset patients (Yee et al., 1998), 50% of firstdegree relatives and other family samples of schizophrenia (Clementz et al., 1998a,b; Freedman et al., 1997; Siegel et al., 1984; Waldo et al., 1991), individuals with schizotypical personality disorder (Cadenhead et al., 2000) and, more recently, in genetically high risk adolescent offspring and high risk prodromal adolescents (Myles-Worsley et al., 2004). Although aberrant P50 suppression is one of the strongest and most reliable electrophysiological findings in schizophrenia, relatively modest effect size differences, a consequence, in part, of the varied clinical presentation of this illness, indicate considerable overlap between patients and healthy comparison groups, and thus implicate P50 suppression deficits in only a subset of patients (Heinreichs, 2004).

1053-8119/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2008.10.002

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Efforts to delineate the neuroanatomy and neurochemistry underlying individual differences in P50 sensory gating in normal and pathological samples, particularly as they apply to the isolation of between-subject variability in the cortical generators that contribute to P50 and to successful and impaired P50 suppression, would significantly add to our understanding of the neural mechanisms subserving this sensory deficiency in schizophrenia and their relationship to the heterogeneous nature of the clinical and cognitive symptoms characterizing the schizophrenia syndrome. To date, evidence relating to the spatial mapping of this neural response has attributed generators of the auditory P50 to both temporal lobes, with left and right superior temporal gyri (STG) producing most of the P50 component, and with intraoperative electrocorticography (LigeoisChauvel et al., 1994) and chronic subdural recordings (Lee et al., 1984) localizing P50 in the primary auditory cortex (AC). While the supratemporal origin of P50 is also seen in recordings from the pial surface over temporal/parietal lobes (Chatrian et al., 1960) and in the scalp surface distribution of MLAERPs (Cohen, 1982), conventional reference-based EEG does not easily lend itself to the identification of contributions from STG sources due to the orientation of primary current flow in the superior and inferior direction. In contrast to EEG, magnetoencephalography (MEG) recordings, which are very sensitive to tangentially oriented sources such as those in the STG, have identified M50, the MEG analogue of P50, as being generated primarily from bilateral posterior STG areas (Makela et al., 1994; Pelizzone et al., 1987; Reite et al., 1988) as well as in the frontal lobe (Weisser et al., 2001). However, simultaneous recordings of P50 and M50 suggest that they may reflect activity from different brain generators (Huotilainen et al., 1998; Onitsuka et al., 2003; Thoma et al., 2003), the inter-dependencies of which appear to vary with clinical grouping, e.g. bilateral (MEG) STG sources account for ~97% of the scalp-recorded variance of the EEG vertex (Cz) signal in the 30–100 ms latency window in normals but significantly less (86%) in schizophrenia patients (Huang et al., 2003). In contrast to our knowledge of brain structures underlying the P50 response, considerably less is known about the neuroanatomical and functional substrate of P50 suppression per se. In a rodent model, recordings of the N40, the MLAERP equivalent of the human P50 (Boutros et al., 1997), have revealed auditory gating in hippocampal and reticular thalamic neurons (Krause et al., 2003); Miller and Freedman, 1993, 1995; Moxon et al., 1999, 2003) and although P50s are not evidenced in the human hippocampus or rhinal cortex, these latter regions in humans have shown attenuated electrophysiologic responses to S2, albeit in a later temporal window distinct from that of P50 (Boutros et al., 2005). Human intracranial recordings have also reported a multi-stage gating process comprised of an early phase reflected in S2 P50 amplitude reductions in temporo-parietal and prefrontal cortical regions and a late phase mediated by the hippocampus (Grunwald et al., 2003). In a recent intracranial study of P50, the main generators of which were localized in the temporal lobes, a novel methodology found the Gating Difference Wave (GDW), an indicator of the gating process resulting in P50 amplitude reduction (obtained by digital point-by-point subtraction of the S2 waveform from the S1 waveform), to reflect neuronal activity localized at the frontal lobe (Korzyukov et al., 2007). Schizophrenia patients, particularly those with negative symptoms, have exhibited attenuated GDWs which have been attributed to reduced S1 amplitudes, thus pointing to an abnormality in readiness than in gating per se (Arnfred, 2006). The identification of generator patterns in healthy individuals with low-gating levels has recently been promoted as a translational model for elucidating the neuronal basis of P50 suppression deficits in schizophrenia and their differential response to pharmacological treatments (Csomor et al., 2007). Given that P50 and its suppression appear to be mediated by multiple generators, the activation of which may vary from individual to individual, the objective of this study, employing standardized Low Resolution Electromagnetic Tomography

993

(sLORETA), is to extend information on P50, gating and their cortical sources in normal controls stratified for low and high gating levels. To this end, low and high P50 amplitude suppressors were characterized with respect to: a) Cz surface recordings of S1 P50 and S2 P50 amplitudes and indices of P50 suppression and b) sLORETA-based cortical source density (CSD) distributions of S1 P50, which is purported to initiate the inhibitory process, and GDW, which may index the inhibition itself. High suppressors were generally predicted to have greater S1 P50 amplitudes and suppression indices, including the suppression indexed by the GDW. Although no specific predictions were made with respect to group difference in generator locations, generator activations were expected to be greater in the high than in the low suppression group. As there are suggestions that gating may involve a multi-stage process (Boutros et al., 2005; Grunwald et al., 2003), the activation time-courses of the neural generators of GDW were also examined. Methods Study participants A sample of 24 (13 male) right-handed, healthy volunteers between 18–40 years of age were recruited via a screening interview which excluded individuals with medical illnesses and with a current or past neurological (including seizures and head trauma) or psychiatric (including drug/alcohol abuse) history. As smoking status has been shown to influence P50 suppression (Crawford et al., 2002; Croft et al., 2004; Wan et al., 2006, 2007a,b), only non-smokers, who were defined as having smoked no more than a lifetime maximum of 10 cigarettes (none in the past year), were included in the study. All participants were medication-free and reported normal hearing. Volunteers signed a consent form prior to participation in the study which was approved by the Research Ethics Board of the Royal Ottawa Health Care Group. Procedure/recording Participants arrived at the laboratory at 8:00 a.m. having been instructed to abstain overnight (beginning at 12:00 a.m.) from food, nicotine, caffeine, alcohol and drugs. As personality dimensions can influence mid-latency MLAERPs (Houston and Stanford, 2001), they completed the Eysenck Personality (EPQ) Questionnaire (Eysenck and Eysenck, 1975) which was scored for neuroticism (N), extraversion (E) and psychoticism (P) dimensions, and the Sensation Seeking (SSS-V) Scale (Zuckerman, 1994), the scoring of which was limited to Experience Seeking (ES) and Disinhibition (DIS) factors. Volunteers were seated in a dimly lit, sound-attenuated chamber where electrodes were applied and auditory stimuli were presented for P50 recordings. Thirty-two 85 dB (SPL) click pairs, with 100 μs click durations and 500 ms inter-click intervals, were presented binaurally through headphones at 10 s inter-pair intervals. Eyes-open EEG was collected with Ag+/Ag+Cl- electrodes from 28 scalp sites (Fp1, Fp2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T7, T8, P7, P8, Fz, Cz, Pz, Oz, Fc1, Fc2, Cp1, Cp2, Fc5, Fc6, Cp5, Cp6) using a common average reference and a ground electrode positioned between Fpz and Fz sites. Electrodes were also placed on the supra- and sub-orbital ridges of the right eye as well as on the external canthus of both eyes to monitor vertical (VEOG) and horizontal electro-oculographic (HEOG) activity, respectively. Electrode impedances were maintained below 5 kΩ and electrical activities, recorded with Brain Vision Recorder and Quickamp® (Brain Products, Germany) amplifier bandpass filters set at 0.1– 120 Hz, were digitized continuously at 500 Hz. P50 processing Off line analysis with Brain Vision Analyser® (Brain Products, Germany) software included digital re-referencing to linked mastoids, bandpass filtering (10–49 Hz: 24 dB/octave — roll-off), epoch

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segmentation (150 ms, beginning 50 ms pre-stimulus onset), EOG correction (Gratton et al., 1983), artifact rejection (excluding EEG epochs with voltages exceeding ±75 μV), baseline correction and finally, selective averaging for each (S1, S2) stimulus of the click pairs. Surface P50 measures were limited to the central vertex site as previous work had supported the use of the Cz site alone for best differentiating between schizophrenia and control groups (Clementz et al., 1998a,b). The P50 was identified semi-automatically using criteria described by Boutros et al. (2004). First, in a post-stimulus latency range of 15–80 ms, P50 was chosen as the second of two positive peaks, appearing as the largest positivity between 40–80 ms and preceding an earlier positive (Pa) peak in the 15–40 ms range. Second, P50 had to be present in at least one additional recording channel besides Cz. For the present data set, all amplitudes were ≥0.5 μV and the latency of P50 peaks elicited by S2 stimuli were within ±10 ms of their paired S1 P50 peaks. P50 peaks from Cz were scored for latency and amplitude. Although P50 amplitude is frequently assessed as a peak-to-trough index, i.e. the voltage difference between P50 and the preceding negative (N40) peak (~30–50 ms), P50 amplitude in our recordings was measured with respect to the average pre-S1 baseline amplitude due to the relative inconsistent appearance of the N40 which was frequently obscured by P30. Auditory P50 suppression (i.e. gating) indices included both rP50 (amplitude of the S2 P50 divided by the amplitude of the S1 P50, multiplied by 100), and dP50 (amplitude of S2 P50 subtracted from amplitude of S1-P50). Participants were separated into low and high suppressors on the basis of their dP50 scores as this index has consistently been shown to be more reliable in repeated testing as compared with the rP50 (Smith et al., 1994; Fuerst et al., 2007a,b; Johannesen et al., 2005; Rentzsch et al., 2007). Volunteers were divided into low and high suppressor groups on the basis of dP50 scores lying below and above the median, respectively. In addition to these gating indices, the GDW suppression index was computed for each participant via point-by-point digital subtraction of their S2 waveform from their S1 waveform (Korzyukov et al., 2007). The resulting positive component was scored at Cz for latency and amplitude. Source localization With the cortex modeled as a collection of volume elements (voxels) in the digitized Talairach atlas provided by the Brain Imaging Centre, Montreal Neurological Institute (MNI; Talairach & Tournoux, 1988), sLORETA, on the basis of scalp-recorded electrical potential distributions, was used to solve the non-unique ‘inverse’ problem (i.e. computation of electric sources from surface data), estimating the 3dimensional intracerebral current density distribution (numerically, and ultimately visually using scaled colour intensity) in 6239 voxels with a spatial resolution of 5 mm (Pascual-Marqui et al., 1994, 2002, 2002). Validation of this distributed source localization technique has been replicated by Yao and He (2001) and by Phillips et al. (2002) and cross-modal validation has come from studies combining nonstandardized LORETA with functional MRI (fMRI) (Mulert et al., 2004; Vitaccio et al., 2002), structural MRI (Worrell et al., 2000) and PET (Pizzagalli et al., 2004; Gamma et al., 2004) as well as from epilepsy studies where sLORETA-defined localization of circumscribed epileptic activity corresponded to the localization of epileptic discharges given by fMRI, subdural and intracerebral EEG recordings, and the MRI-defined epilepticogenic seizure (Lantz et al., 1997; Seeck et al., 1998; Worrell et al., 2000). Drawing on known electrophysiological evidence of highly synchronized activity of neighboring cortical neurons (Llinas, 1988; Gray et al., 1989; Silva et al., 1991) necessary for generating the EEG (Pascual-Marqui et al., 2002), sLORETA is based on the neurophysiological assumption of coherent coactivation of neighboring cortical areas and, accordingly, it computes the “smoothest” of all possible activity distributions (i.e. no assumption is made about the number of discernable source regions). As a direct consequence of the smoothness constraint, the

sLORETA solution results in relatively low spatial resolution, producing a “blurred-localized” image of a point source that conserves the location of maximal activity, but with a certain degree of dispersion (Molert et al., 2005). The 3-dimensional solution space in which the inverse problem is solved (i.e. computation of current source density) is restricted to the cortical gray matter and hippocampus. Ventricles are not included in the sLORETA solution space and only voxels in which the probability of being gray matter was at least 0.33 (maximum 1.00), and for which the probability also exceeded that of a) being white matter and b) being cerebrospinal fluid were labeled as gray matter. This study used sLORETA with a three-shell spherical head model registered to the MNI 152 template (Mazziotta et al., 2001), and electrode coordinates were calculated by cross-registration of spherical and realistic geometry following Towle et al., 1993. In the initial stage, the voxel-based data were created from the MLAERP data (28 sites) for a single time frame that corresponded to the peak value of P50. The GDW peaks later than the P50 and appears as a somewhat broader component than the P50 therefore, in line with our intention to probe temporal dynamics, CSDs of GDW and S1 P50 were examined in 4 segmental timeframes (52–56 ms, 56–60 ms, 60–64 ms and 64– 68 ms), activation at each timeframe being compared to time zero for within-group analyses. These results were visualized on statistical map overlaid on a model structured MRI scan, not on individual MRIdefined brain anatomy and thus are accurate for groups but not for individual subjects. Statistical analysis Group characteristics (age, EPQ, SSS-V) were analyzed with a oneway Analysis of Variance (ANOVA) comparing low and high suppressors, as were the amplitude and latency of the GDW, and the two raw gating MLAERP indices, including rP50 and dP50. Amplitudes and latencies of the P50 derived from the raw non-subtracted MLAERP waveforms were analyzed with separate mixed-ANOVAs, with group (low, high) serving as the between-group factor and stimulus (S1, S2) as the within-group factor. Greenhouse–Geisser corrected significant (p b .05) interactions were followed up with pairwise comparisons. For the exploratory analysis of CSD distributions for P50 and GDW, data created for each participant in each group was statistically analyzed using sLORETA's built-in voxelwise non-parametric t-tests. Comparisons, each involving 2394 permutations, were of two types: a) within-group comparisons (dependent t-tests) contrasting density values at the time of peak S1 P50 and at the four time segments of GDW, all being compared with density values at stimulus onset and b) between-group comparisons (independent t-tests) contrasting low vs high suppressors with respect to current source density values at the S1 P50 peak time point as well as at each of the four post-stimulus time windows for GDW. The former comparisons aimed to describe the CSD distribution of P50 and GDW per se within each of the two subgroups while the latter investigated group differences in CSD distributions. The voxel-by-voxel t-tests were Bonferroni corrected for multiple comparisons (Holmes et al., 1996; Nichols and Holmes, 2002) and voxels with p b 0.05 values were accepted as statistically significant and were identified by LORETA-KEY software in terms of specific brain region and Brodmann area (BA). Results Mean (±SE) characteristics for the low and high suppressor groups are shown in Table 1. No significant subgroup differences were observed for any of the measures. P50 amplitudes Grand average vertex waveforms depicting P50 for both stimuli in each group are shown in Fig. 1. Analysis of P50 amplitudes yielded a

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Table 1 Mean (±SD) group characteristics Measure

High suppressors

Low suppressors

M/F Age EPQ-E EPQ-N EPQ-P SSS-ES SSS-DSS

6/6 34.4 (5.2) 14.0 (6.4) 10.3 (3.9) 7.1 (2.7) 5.6 (1.5) 3.4 (2.0)

7/5 25.1 (3.9) 15.1 (6.2) 11.5 (6.2) 8.3 (2.7) 6.3 (2.1) 4.9 (2.5)

M = male; F = female; EPQ = Eysenck personality questionnaire; E = extraversion; N = neuroticism; P = psychoticism; ES = experience seeking; DIS = disinhibition.

significant stimulus (F1,22 = 97.9, p b .0001) and a stimulus × group interaction (F1,22 = 41.5, p b .0001) effect. Mean (±SE) amplitudes for S1 were significantly (p b .01) greater for the high (M = 4.0 μV, ±.38) compared to the low suppressor group (M = 2.4 μV, ±.42), but the opposite effect (p b .001) was observed for S2-elicited P50, where amplitudes of the high suppressors were smaller (M = .15 μV, ±.40) than the low suppressors (M = 1.5 μV, ±.30). Relative to S1 P50 amplitudes, both the high (p b .0001) and low (p b .02) suppressor groups exhibited significant reductions in S2 P50 amplitudes. The latency of P50, the overall mean of which was 55.5 ms (±.92), did not vary with stimuli or groups.

Fig. 2. Grand averaged gating difference waves (GDW) in low (LS) and high suppressors.

P50 suppression As would be expected, analysis of the suppression indices observed significantly larger (F1,22 = 41.5, p b .0001) dP50 values for the high (M = 4.1 μV) versus the low suppressors (M = .9 μV). Similarly, the rP50 index was lower (F1,22 = 13.7, p b .001) in high (M = 19.3%) relative to low suppressors (M = 73.8%). Analysis of the GDWs, exhibited in Fig. 2, also found larger (F1,22 = 6.97, p b .02) amplitudes for the high suppressor group (M = 3.4 μV), relative to the low suppressor group (M = 1.8 μV). The mean latency of the GDW was 59.4 ms, with no differences being observed between suppressor groups. CSD distributions sLORETA applied to the peak amplitude of S1 P50 in high suppressors found, as shown in Fig. 3 and Table 2, the maximal CSD

value in the right posterior cingulate of the limbic lobe. Additional significant activations, all limited to the right hemisphere, were observed in the cingulate gyrus, the superior and middle temporal gyrus of the temporal lobe, the insula and in parietal (precuneus supramarginal gyrus, inferior parietal lobule) and occipital lobe (lingual gyrus) regions. For the time-course analysis of the GDW within the high suppressor group, activations were limited to the frontal lobe region, with an early activation, at the precentral gyrus, for example, being observed at the 52–56 ms post-stimulus, peaking at 56–60 ms and, although remaining active, declined at 60–64 ms and was non-active at 64–68 ms. All these activations were apparent in the left hemisphere (see Fig. 4 and Table 2). No significant GDW-related CSD activation was observed in the left or right hemisphere in the low suppressor group at any of these post-stimulus times, and no

Fig. 1. Grand averaged waveforms exhibiting P50 components elicited by S1 and S2 in low and high suppressors.

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Fig. 3. Horizontal, sagittal and coronal slices of sLORETA statistical image, derived from voxel-by-voxel t-tests, for the S1 P50 (vs. baseline) in high suppressors. Increased activity (p b .05) is indicated and is maximal at right posterior cingulate.

inter-group differences were observed with GDW source densities (Table 3). Discussion Although numerous P50 studies, based on observations of smaller S2/S1 amplitude ratios in normal control subjects than in patients with schizophrenia, have suggested that this MLAERP sensory gating index may be a sufficiently reliable endophenotype, the finding that P50 gating ratios for approximately 40% of controls are within the schizophrenic range raises questions about the specificity and normal individual variability of this measure (Patterson et al., 2008). However, investigations into individual differences in P50 gating in controls, with a particular emphasis on inefficient P50 gaters, can be a useful alternative strategy for exploring the functional correlates of gating abnormalities without the contaminating influences of clinical status and medication that characterize the study of gating deficits in schizophrenia (Light and Braff, 2003). In this study, the average S2/S1 gating ratio was 33.2%, reflecting a degree of P50 suppression which is similar to that observed in multiple studies of normal controls (Fuerst et al., 2007a,b) and is below 1 S.D. of the mean of means reported for patients with schizophrenia (Patterson et al., 2008). Utilizing the dP50 subtraction index of gating, which is highly correlated with the rP50 ratio index but possesses greater test– retest reliability (Fuerst et al., 2007a,b), the S2/S1% gating ratios of low suppressors (i.e. those with reduced dP50 subtraction indices that are below the median split) averaged 73.8%, a gating index which is well within 1 S.D. (24.3) of the mean ratio of 79.9% typically seen in schizophrenics (Patterson et al., 2008). In addition to exhibiting a high gating ratio approximating that of patients with schizophrenia, these low suppressors also exhibited smaller S1 amplitudes than high suppressors. Reduced S1-elicited P50 amplitudes have also been observed in schizophrenia and, combined with an equivalent S2elicited P50 amplitude which failed to evidence suppression following S1, have been thought by some to underlie defective gating in this disorder (Freedman et al., 1983; Jin et al., 1997; Clementz and Blumenfeld, 2001). Significant S2 P50 amplitude suppression was seen in both the low and high suppressors, the degree of suppression being more evident in the high suppressors, resulting in smaller S2elicited P50 amplitudes in this group than in the low suppressors. This observation of gating even in those with attenuated S1 P50 amplitudes suggests that the triggering of significant inhibitory processes may not necessarily be completely dependent on normal S1 P50 responsivity and that the reasons for impaired gating in schizophrenia may extend beyond aberrant inhibitory mechanisms initiated by S1 P50 generation. As expected, GDW amplitudes were also reduced in low (versus high) suppressors and although these findings implicate a greater S1-

induced central inhibitory process in high (versus low) suppressors as a result of larger S1 P50 amplitudes in this group, an effect which is supported by earlier observations of a significant correlation between S1 P50 amplitude and dP50 subtraction indices (Fuerst et al., 2007a,b), it should be noted that S1 P50 amplitudes do not necessarily predict S2/ S1 gating ratios (Fuerst et al., 2007a,b). Inter-group comparisons of MLAERP source densities did not yield any significant differences between low and high suppressors and this may have been related to the reduced statistical power associated with our relatively small subgroup samples. Cortical source density distributions of S1 P50 revealed by sLORETA also failed to show any regional cortical activations in low suppressors, but within the high suppressors maximum activation was observed in the limbic lobe (posterior cingulate), with additional activations being seen in temporal (middle and superior temporal gyrus), parietal (precuneus and inferior parietal lobule) and occipital (lingual gyrus) areas, all activations being limited to the right hemisphere. These multiple regional activations parallel observations of supratemporal and frontal auditory P50 sources that have been reported both with intracranial EEG and MEG recordings in human subjects and with single unit recordings in animals, with the latter implicating diverse (e.g. hippocampal, rhinal, amygdaloid and medial prefrontal) cortices outside of the primary auditory pathway to be part of the complex neurocircuitry computing and responding to auditory input (Cromwell et al., 2008). As this regional activational pattern characterizing high suppressors emerged with within- but not with between-group (high versus low) suppressor comparisons, it may suggest that a similar brain circuitry may be active in low suppressors, but at a near

Table 2 Local sLORETA maximum activations for the S1 P50 in high suppressors Brain region Limbic lobe R posterior cingulate R cingulate gyrus Sub-lobar R insula Temporal lobe R superior temporal gyrus R middle temporal gyrus Parietal lobe R precuneus R supramarginal gyrus R inferior parietal lobule Occipital lobe R lingual gyrus

Brodmann area

x

y

z

t-test values (t.05 = 1.57)

30 31

20 20

− 60 − 44

10 24

2.03 1.89

13

39

− 44

21

2.01

39 4

39 40

− 55 − 62

24 16

1.88 2.87

31 40 40

10 42 40

− 62 − 45 − 35

21 35 35

1.68 1.63 1.60

19

19

− 65

2

1.72

MNI — Montreal Neurological Institute.

MNI coords.

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Fig. 4. Horizontal, sagittal and coronal slices of sLORETA statistical images (p b .05) at 52–56 ms (max: precentral gyrus), 56–60 ms (max: middle frontal gyrus), 60–64 ms (max: precentral gyrus) and 64–68 ms (n.s.) for the gating difference wave (GDW; vs. baseline) in high suppressors.

sub-threshold level, and it may well be uniquely influenced with pharmacological maneuvers targeting gating-sensitive neurotransmitters, including the nicotinic receptor system, the activation of

which has been shown to correct deficient infrahuman (Metzger et al., 2007) and schizophrenic gating (Olincy et al., 2006). Interestingly, these low and high normal suppressors were found to be differentially

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Table 3 Local sLORETA maximum activations for the GDW in high suppressors (52–68 ms poststimulus): focus on the time-course Brain region 52–56 ms (t.05 = 1.97) L precentral gyrus L precentral gyrus L postcentral gyrus 56–60 ms (t.05 = 1.95) L middle frontal gyrus L precentral gyrus L middle frontal gyrus L middle frontal gyrus 60–64 ms (t.05 = 1.52) L precentral gyrus L middle frontal gyrus L precentral gyrus L middle frontal gyrus 64–68 ms (t.05 = 1.74) n.s.

Brodmann area

MNI coords. x

y

z

t-test values

6 4 1

− 55 − 56 − 67

−5 −9 −22

45 45 37

2.11 2.06 2.00

6 4 8 9

− 55 − 49 − 51 − 50

0 −8 5 5

45 45 45 41

2.25 2.13 2.13 2.12

6 9 4 8

− 45 − 51 − 50 − 51

0 5 −12 −51

40 50 51 7

1.75 1.68 1.56 1.68

GDW — Gating difference wave; MNI — Montreal Neurological Institute; n.s. — nonsignificant.

sensitive to dopamine, with P50 gating being disrupted and enhanced by the dopamine antagonist haloperidol in high and low suppressors, respectively (Csomor et al., 2007). In the present study, time-course analysis of GDW with sLORETA provided the opportunity to analyze the temporal dynamics of the gating process. Although analysis of the difference waveform GDW is relatively new in the area of auditory sensory gating, this waveform subtraction procedure is commonly used in event-related functional imaging studies using PET and fMRI to isolate brain activity associated with specific cognitive operations (Arnfred, 2006), and it has been routinely employed in ERP research to produce mismatch negativity (MMN) and processing negativity (PN) difference waveform components in the study of auditory sensory memory (Näätänen et al., 2007) and selective attention (Näätänen, 1982), respectively. Shown to be attenuated in schizophrenics with a predominance of negative symptoms (Arnfred, 2006), the GDW, when recorded intracranially and analyzed with non-standardized LORETA in non-schizophrenic epilepsy patients, was found to have a greater contribution from electrical generators in the frontal lobe, bilaterally, than in the temporal lobe (Korzyukov et al., 2007). The logic behind the use of the GDW in this latter study was to isolate a portion of the S2-elicited ERP activity so as to determine whether the gating phenomenon is distinct, spatially and temporally, from processes generating S1 P50. Accordingly, gating related changes linked to a GDW with a peak latency matching S1 P50 latency can be assumed to reflect S1 P50 amplitude changes and the activation of its neural generators, while a GDW with peak latency dissimilar to P50 latency may indicate a gating neurobiology that may be distinct from that occurring during S1 P50 generation. The average latency of GDW tended overall to be somewhat slower (M = 59.4 ms) than the S1 P50 peak latency (M = 55.5 ms) and although this temporal distinction was not reflected in GDW (M = 57.8 ms) and S1 P50 (M = 56.6 ms) latencies of low suppressors, it was evident in high suppressors, where GDW and S1 P50 peaked at 61.4 ms and 56.6 ms, respectively. The later appearance of the GDW in high suppressors corresponds with the observed maximal activation seen in the middle frontal gyrus of this group at the 60–64 ms post-stimulus time frame. The activation of this gating-associated, left-lateralized region was of relatively brief duration and was preceded and immediately followed by lessened activation in the precentral and middle frontal gyrus and was completely absent at 64–68 ms post-stimulus. Reduced left precentral gyrus activation has been reported in schizophrenics during selective attention tasks (Carter et al., 1997) and the middle frontal gyrus, with its left hemisphere being shown to be smaller in schizophrenics (Suzuki et

al., 2005) and their first-degree relatives (Delisi et al., 2006), has been shown to be critical for sustaining attention and working memory and for regulating response inhibition. This temporally distinct frontal gating reflected in the scalp-derived GDW mirrors the latency of the intracranially recorded GDW which also peaked at 60.4 ms and, with LORETA-based source reconstruction of local maxima of gating-related changes reflected in the GDW, exhibited generator activity localized beyond the temporal–parietal locus underlying P50 generation, (Korzyukov et al., 2007). Although evidence for the role of frontal processes as early as 50 ms in auditory input and output functions is somewhat lacking, frontal regions are involved in the processing of temporal auditory patterns (Griffiths et al., 2000) and may be required for successful inhibition in the paired-click paradigm (Griffiths et al., 2000). Evidence for the existence of a frontal brain region involvement in P50 suppression was seen with the reporting of reduced P50 suppression in patients with prefrontal lesions (Knight et al., 1999), and with MEG recordings which identified a medial frontal source for P50 which was functionally distinct from the auditory cortex P50, as it peaked later and showed larger suppression (Weisser et al., 2001). Keeping in mind that analysis of the source reconstruction of GDW does not specifically reflect location changes in the brain in response to S1 or S2, but assesses changes occurring before, during and after S2 presentation, thus providing insight in to brain locations where activity changes at the moment of gating (Korzyukov et al., 2007), these findings from GDW suggest that frontal lobe mechanisms characterize the gating in high suppressors. However, given the inhibitory processes attributed to S1 P50 and seeing as our study and MEG studies report gating-related changes in the temporal (and limbic/parietal) lobe (Thoma et al., 2003; Huang et al., 2003), it is reasonable to suggest, as has been done previously by Korzyukov et al (2007), that frontal and temporal mechanisms are required to work in concert to produce efficient gating-induced reductions in S2 P50 amplitude. Aberrant activity in one or both of these cortical structures may underly inefficient gating and gating impairments in schizophrenia and, given that responses in the auditory cortex can be influenced by sensory, motor and executive/cognitive systems (Zatorre, 2007), gating inefficiencies and deficits may also reflect a dysfunction in the connectivity within this distributed gating network. Whether these dual mechanisms are not activated concurrently, but are executed with varying latencies, or as expressed previously, are activated in a consecutive manner (Grunwald et al., 2003), is unknown, but the later appearance of the GDW, relative to the S1 P50initiated inhibitory processes, would suggest a multi-stage operation involving temporal sequencing (of these regional specific gating processes), a frontal executive operation which is markedly impaired in schizophrenia (Kerns et al., 2008). This study is the first to examine individual differences in P50 source densities using a time-course analysis. These preliminary observations should be treated with appropriate caution due to the limitations of the study which include relatively small sample sizes, subgrouping with an dP50 gating index, and baseline-to-peak measurement of P50. Further research, accounting for these factors and perhaps adopting the same approach in schizophrenic samples, i.e. separating patients on the basis of gating efficiency, are warranted to draw more definitive conclusions on the neural sources of impaired gating. References Arnfred, S., 2006. Exploration of auditory P50 gating in schizophrenia by way of difference waves. Behav. Brain Functions 2, 6. Boutros, N., Bonnet, K., Millana, R., Liu, J., 1997. A parametric study of the N40 auditory evoked response in rats. Biol. Psychiatry 42, 1051–1059. Boutros, N., Korzyukov, O., Jansen, B., Feingold, A., Bell, M., 2004. Sensory gating deficits during the mid-latency phase of information processing in medicated schizophrenia patients. Psychiatry Res. 126, 203–215. Boutros, N., Trautner, P., Rosburg, T., Korzyukov, O., Grunwald, T., Schaller, C., Elger, C., Kurthen, M., 2005. Sensory gating in the human hippocampal and rhinal regions. Clin. Neurophysiol. 166, 1967–1974.

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