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Original Article |

Early Sensory Contributions to Contextual Encoding Deficits in Schizophrenia FREE

Elisa C. Dias, PhD; Pamela D. Butler, PhD; Matthew J. Hoptman, PhD; Daniel C. Javitt, MD, PhD
[+] Author Affiliations

Author Affiliations: Center for Translational Schizophrenia Research, The Nathan Kline Institute for Psychiatric Research, Orangeburg, New York (Drs Dias, Butler, Hoptman, and Javitt); and the Departments of Psychiatry (Drs Dias, Butler, Hoptman, and Javitt) and Neuroscience (Dr Javitt), New York University School of Medicine, New York.


Arch Gen Psychiatry. 2011;68(7):654-664. doi:10.1001/archgenpsychiatry.2011.17.
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Published online

Context The AX version of the visual continuous performance task (AX-CPT) is widely used for investigating visual working memory dysfunction in schizophrenia. Event-related potentials (ERP) provide an objective index of brain function and can be used to evaluate brain substrates underlying impaired cognition in schizophrenia.

Objective To assess the mechanisms that underlie visual working memory dysfunction in schizophrenia relative to impairment of early visual processing.

Design Case-control study.

Setting Inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research.

Participants A total of 30 individuals with schizophrenia and 17 healthy comparison subjects.

Interventions Three versions of the AX-CPT, with parametric variations in the proportions of trial types, were used to test performance and underlying neural activity during differential challenge situations. Contrast sensitivity measures were obtained from most subjects.

Main Outcome Measures Behavioral performance was assessed using d' context scores. Integrity of stimulus- and task-related cortical activation to both cue and probe stimuli was assessed using sensory (C1, P1, N1) and cognitive (N2, contingent negative variation [CNV]) ERP components. Early magnocellular/parvocellular function was assessed using contrast sensitivity. Linear regression and path analyses were used to assess relations between physiological and behavioral parameters.

Results Patients showed reduced amplitude of both early sensory (P1, N1) and later cognitive (N2, CNV) ERP components. Deficits in sensory (N1) and cognitive (N2) component activation to cue stimuli contributed independently to impaired behavioral performance. In addition, sensory deficits predicted impaired cognitive ERP generation. Finally, deficits in performance correlated with impairments in contrast sensitivity to low, but not high, spatial frequency stimuli.

Conclusions Working memory deficits in schizophrenia have increasingly been attributed to impairments in stimulus encoding rather than to failures in memory retention. This study provides objective physiological support for encoding hypotheses. Further, deficits in sensory processing contribute significantly to impaired working memory performance, consistent with generalized neurochemical models of schizophrenia.

Figures in this Article

Deficits in cognitive processing have been extensively documented in schizophrenia and shown to correlate with poor long-term outcome.1,2 Recently, deficits in early sensory processing have been demonstrated as well, using methods such as contrast sensitivity,3 functional magnetic resonance imaging (fMRI),46 and steady-state7,8 or transient9 event-related potentials (ERP). However, the relationships between sensory dysfunction and higher-order cognitive impairments have been investigated only to a limited degree.1013 The present study uses variations of the AX-type continuous performance test (AX-CPT) combined with high-density ERPs to investigate contributions of early visual dysfunction to impaired cognitive processing in schizophrenia.

The AX-CPT is a well-established behavioral paradigm that elicits a consistent pattern of impairments in performance in both patients with schizophrenia1420 and unaffected first-degree relatives21 compared with controls. In AX-CPT, letters are presented sequentially on a computer screen and subjects must respond to a cue-target sequence consisting of the letter A followed by the letter X (AX sequences), while ignoring all other cue-probe sequences. Invalid sequences include those with invalid cues (collectively referred to as B) followed by the letter X (BX sequences), invalid probes (collectively referred to as Y) following the letter A (AY sequences), or sequences with both invalid cues and invalid probes (BY sequences).

In the most widely used version of the task (termed AX-70),15,16,1820 70% of the trials consist of AX sequences, creating a strong prepotency to respond whenever the probe X is presented. Following an invalid cue (B), therefore, subjects need to use local (within-trial) information to overcome this global prepotency. Thus, correct AX-CPT performance requires that cue information be correctly encoded and then retained across the delay to guide behavior.15,22,23 In the AX-70, patients with schizophrenia show not only significant reductions in hit rate to AX trials but also an increase in false alarm to BX, suggesting a specific deficit in the ability to use cue information to guide subsequent target response.

The initial use of the AX-70 version of the task in schizophrenia was based largely on dopaminergic theories,2426 which postulated that patients would be particularly impaired when retaining the local information online owing to specific dysfunction of prefrontal dopamine-recipient prefrontal regions. In addition, interpretation of these models is derived from cognitive models that postulate discrete input, association, context, and response stages.15,22 Recent developments in schizophrenia and cognitive neuroscience research have challenged both sets of hypotheses.

First, deficits in working memory in schizophrenia have increasingly been attributed to failures of encoding rather than memory retention.19,27,28 Second, schizophrenialike deficits in AX-CPT performance may be reproduced by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine to healthy volunteers,20 consistent with glutamatergic29,30 and other distributed neural theories31 of schizophrenia.

Third, recent studies of visual processing suggest that sensory input to prefrontal regions arises via 2 distinct pathways: a rapid, low-resolution“perception for action” system that receives input primarily from the magnocellular visual system and projects primarily via the dorsal stream visual pathway and a slower, higher-resolution“perception for identification” system that projects primarily via the ventral visual system.32,33 Deficits in magnocellular/dorsal stream processing have been demonstrated consistently in schizophrenia3,4,69 and contribute significantly to impairments in processes such as perceptual closure33 and face recognition.12 However, potential involvement of sensory systems in deficits on cognitive tasks such as AX-CPT has been understudied. This is the first study to obtain neurophysiological measures to evaluate the integrity of initial sensory responses during AX-CPT.

We used an ERP paradigm that has been validated based on both dipole mapping and direct intracranial recording in monkeys that were awake and performing a version of AX-CPT.17,34 In this paradigm, early components including P1 and N1 index function at the level of dorsal- and ventral-stream visual cortex located in middle occipital gyrus,13,35 while later components including N2 and the contingent negative variation (CNV) index function of frontal brain regions such as the dorsolateral prefrontal and medial prefrontal cortex, including the anterior cingulate cortex.36

Our study also used unique parametric variations of the AX-CPT in which visual stimuli and task instructions remain the same but stimulus probabilities change, leading to a different global response set (Table 1).17 These variations permit subfractionation of underlying cognitive processes. Based on prior research, we hypothesized that sensory processes, as indexed by sensory P1 and N1 components, would be impaired across task versions in schizophrenia and would contribute significantly to overall impairments in task performance. We hypothesized that amplitude of frontal N2 and CNV potentials would be reduced as well, consistent with impaired encoding of cue-related information.17

Table Graphic Jump LocationTable 1. Trial Type Probabilities for Each Variant of AX-CPT

Finally, we evaluated basic visual processing using contrast sensitivity to low- vs mid/high–spatial frequency (SF) sine-wave stimuli along with AX-CPT performance in a subgroup of subjects. Low-SF stimuli are processed preferentially by the magnocellular visual system, while high-SF stimuli are processed preferentially by the parvocellular system. We have previously observed that patients with schizophrenia show preferential deficits in magnocellular function.4,7 For this study, we hypothesized that preferential deficits in detection of low-SF stimuli would again be observed and would correlate with impaired AX-CPT performance, consistent with early visual contributions to overall cognitive impairment in schizophrenia.

PARTICIPANTS

Thirty patients who met DSM-IV criteria for schizophrenia and 17 healthy volunteers participated. Patients were recruited from inpatient and outpatient facilities associated with the Nathan Kline Institute for Psychiatric Research. Diagnoses were obtained using the Structured Clinical Interview for DSM-IV (SCID)37 and available clinical information. Controls were recruited through the Volunteer Recruitment Pool at the Nathan Kline Institute. All subjects provided informed consent and received cash compensation for their time. This study was approved by the Nathan Kline Institute internal review board. Healthy volunteers with a history of SCID-defined Axis I psychiatric disorder were excluded. Patients and controls were excluded if they had any neurological or ophthalmological disorders that might affect performance or if they met criteria for alcohol or substance dependence within the last 6 months or abuse within the last month. All patients were receiving antipsychotic medication at the time of testing. Chlorpromazine equivalents were calculated as described previously.38 All participants had normal or corrected-to-normal visual acuity. Clinical and demographic information are included in Table 2. Data from 3 patients and 2 controls were discarded owing to excessive movement artifacts. Contrast sensitivity was assessed in a subgroup of 20 patients and 9 controls who had no significantly different characteristics, using previously described methods.44

During recordings, subjects sat in a comfortable chair inside a darkened, electrically shielded recording chamber, facing a computer monitor. Subjects were instructed to respond quickly and accurately by pressing a button on a response pad. They had a practice block of trials before the recordings were initiated.

PARADIGM

Cue-probe sequences were presented sequentially on a computer screen located 137 cm from subject's eyes using Presentation software (Neurobehavioral Systems, Inc, Albany, California). Letters subtended approximately 2° of visual arc and were presented for 100 milliseconds, white on black, using Helvetica font.

The interval between onset of cue and onset of probe letters was 1240 milliseconds, and the interval between successive cue-probe sequences was 1390 milliseconds. Subjects were instructed to respond by pressing a button following an AX sequence while ignoring all other cue-probe sequences. Invalid (B) cues and invalid (Y) probes consisted of letters other than A and X. The response window following target presentation was 1 second.

In each task variant, 1 trial type was presented with 70% probability, while all other sequences were presented with 10% probability, in pseudorandom order (Table 2). Performance was assessed using the parameter d' context, which reflects the ability to use the cue stimulus to determine the correct response to a subsequently presented valid target letter (AX vs BX sequence).18,19,45,46

Each subject performed 6 blocks of 93 trials for each of the 3 tasks, totaling 1674 trials. In most cases, task AX-70 was presented first because this was the condition of primary interest. Task order did not significantly affect performance either across or within group (main effect of order: F3,41 = 0.25, P = .86; group× order interaction: F3,41 = 0.76, P = .52). Subjects took breaks between blocks and did not report abnormal fatigue during the tasks.

ERP RECORDING
Data Acquisition

Continuous electroencephalography was acquired using an ActiveTwo system (Biosemi, Amsterdam, the Netherlands) from 168 scalp electrodes and digitized at 512 Hz. The continuous data were separated into epochs (−100 to 750 milliseconds) surrounding the digital event tags, baseline corrected from−100 milliseconds to stimulus onset, and an artifact rejection criterion of±80μV was applied. Epochs for the correct trials were averaged separately for each trial type, for cue and probe periods, and for each subject, and a nasal reference was applied to the averaged data. Subjects with fewer than 25 accepted trials in any condition were removed from the analysis. For the remaining subjects, the mean (SD) percentage of accepted sweeps was 77.9% (12.5%) for controls and 72.0% (15.1%) for patients. Grand mean averages for each group were obtained by averaging the data from all subjects. Electrode placement was highly consistent across subjects owing to the use of an electrode cap that constrained interelectrode spacing and placement. An averaged version of the electrode locations on the head was used for group topographic data.

ERP Analysis

Spatiotemporal windows for peak detection were determined based on previous results.17,35 The averaged ERP were filtered (low pass, cutoff value, 45 Hz; zero phase shift, 48 dB), and for each component, peak amplitude was obtained from the median of 6 electrodes that covered the area of scalp where this component was best represented (Figure 1). Time windows were C1, 60 to 120 milliseconds; P1, 75 to 130 milliseconds; N1, 100 to 200 milliseconds; N2, 220 to 350 milliseconds; and CNV, 1200 to 1250 milliseconds. Peaks amplitudes were chosen as the dependent measure because of the large latency difference between patients and controls.

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Figure 1. Electrode distribution on the scalp. Posterior (A) and top (B and C) view, with electrodes used for statistics highlighted for each component measured. For reference, corresponding electrode locations form the 10-20 system are given.

Contrast Sensitivity

Horizontal sine-wave gratings were presented for 32 milliseconds at spatial frequencies of 0.5, 7, or 21 cycles per degree.3 A spatial 2-alternative forced-choice procedure was used. On each trial, a sine-wave grating was presented on one side of a monitor and a uniform field of average luminance was presented simultaneously on the opposite side. Sides were randomly varied across trials. The viewing distance was 160 cm, and the grating and uniform field together subtended 5.7°× 5.7° of visual angle. Participants stated which side of the display contained the grating. An up-down transform rule was used to determine contrast sensitivity associated with 79.4% correct responses for each SF in steps of 1.5 dB. The mean of 8 reversals was used to estimate a threshold.

STATISTICAL ANALYSIS

Between-group analyses were conducted using repeated-measures multivariate analysis of variance with diagnostic group as a between-subject factor and cue type (A vs B), probe type (X vs Y), preceding cue type (A vs B preceding probe stimuli), and task variant (AX-70, AY-70, BX-70) as within-subject factors, as appropriate. The relationship between variables was determined using stepwise multivariate regression analysis, with statistical significance determined using r change parameter. Further relationship among variables was evaluated by path analysis, as implemented in AMOS 18.0 (SPSS Inc, Chicago, Illinois) (eAppendix). Effect sizes were calculated using the Cohen's d statistic.47 All tests were 2-tailed with a preset level of significance of P < .05. Unless otherwise noted, data in text represent mean (standard deviation).

BEHAVIORAL RESULTS

As expected, patients showed increased AX errors (F1,35 = 30.3; P < .001) and greater BX, relative to AY, errors (F1,35 = 5.78; P = .02) across all task versions and in the AX-70 alone (Figure 2A). As a result, both d' (F1,35 = 28.9; P < .001) and d' context (F2,34 = 18.5; P < .001) scores were significantly reduced across task variants, with large effect size differences between groups (Figure 2B, eTable 2). The task× group interaction was also significant (F2,34 = 4.4; P = .02), reflecting greater deficits in AY-70 (F1,35 = 4.5; P = .04) and BX-70 (F1,35 = 6.7; P = .01) relative to AX-70 in patients vs controls.

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Figure 2. Behavioral results of the visual AX–continuous performance task. A, Mean (standard error of the mean [SEM]) of errors is shown for all trial types in task AX-70 for controls and patients. Errors for trials AX were omissions and for trials AY, BX, and BY were false alarms. B, d' Context across tasks is shown. Corresponding effect sizes (Cohen's d) were AX-70, d = 0.83; AY-70, d = 1.32; and BX-70, d = 1.45. *  P < .05,† P < .01,‡ P < .001.

Patients also had longer reaction times to the correct target than controls (controls: 296 [84] milliseconds; patients: 435 [105] milliseconds; F1,35 = 34.9; P < .001; d = 1.46), and reaction times varied by task (F2,34 = 54.9; P < .001) but there was no significant group× task interaction.

EVENT-RELATED POTENTIALS

Waveforms elicited in the AX-70 condition are illustrated in Figure 3 and Figure 4. Similar components were obtained in the other task variants (eFigure 1, eFigure 2, eFigure 3, and eFigure 4). Peak amplitudes for sensory (C1, P1, N1) and cognitive (N2, CNV) components were calculated for each subject in response to cue and target stimuli separately and analyzed across subjects. Probe trial types were grouped according to type of preceding cue (A or B) and type of probe (X or Y). Effect sizes are summarized in eTable 2.

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Figure 3. Sensory (P1, N1; A and B) and cognitive (N2; C) event-related potential (ERP) activity in response to cue stimuli in the AX-70 task variant. The activity is presented 2 ways. The scalp voltage distributions for each component for patients and controls are plotted over the head representation; scales are inμV per step; red is positive, and blue is negative. The plots show ERP waveforms recorded at the electrode highlighted over the scalp rendition for patients and controls and for cues A and B. Note that statistical results described in the manuscript refer to the median of the electrodes over the region analyzed (Figure 1); ms indicates milliseconds.

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Figure 4. Sensory (P1, N1) and cognitive (N2) event-related potential (ERP) activity in response to probe stimuli in the AX-70 task variant. Conventions are as in Figure 3. A, Activity following presentation of the valid probe (X) is shown. B, Activity following presentation of the invalid probe (Y) is shown; ms indicates milliseconds.

Separate repeated-measures multivariate analyses of variance were conducted for the 2 sensory (P1, N1) and 2 cognitive (N2, CNV) potentials and for cue and probe stimuli.

SENSORY POTENTIALS
Group Effects

Amplitudes of both P1 (cue: F1,35 = 5.94, P = .02; probe: F1,35 = 5.77, P = .02) and N1 (cue: F1,35 = 7.83; P = .008; probe: F1,35 = 10.9, P = .002) were significantly reduced in schizophrenia across all conditions, reflecting significant impairment in early sensory processing (Figure 5 and Figure 6). Larger N1 responses were observed to A vs B cues (F1,35 = 13.1; P = .001) (Figure 5) and X vs Y probes (F1,35 = 23.2; P < .001) (Figure 6) across tasks. However, the cue type× group (F1,35 = 0.04; P = .80) and probe type× group (F1,35 = 1.06; P = .30) interactions were not significant, suggesting similar differentiation across groups.

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Figure 5. Mean (standard error of the mean [SEM]) event-related potential (ERP) component amplitudes to cue stimuli across task variants. Early visual component P1 (A), early visual component N1 (B), difference in peak amplitudes of N2 to B- vs A-cues (C), and contingent negative variation (CNV) amplitude vs conditional probability ratio (D) are shown (Table 1). * P < .05,† P < .01,‡ P < .001.

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Figure 6. Mean (standard error of the mean [SEM]) event-related potential (ERP) component amplitudes to probe stimuli across task variants. A, P1 and N1 amplitudes to preceding cue (A or B) (A); P1 and N1 to probe type (X or Y) (B); and N2 amplitudes following A cues across task variants (C) are shown. * P < .05,† P < .01,‡ P < .001.

Task Effects

For cues, larger sensory responses were observed to A vs B cues in the BX-70 condition only (Figures 5A), as reflected in significant cue type× task interactions for both the P1 (F2,34 = 8.10, P = .001) and N1 (F2,34 = 4.69, P = .02) components. Nevertheless, the degree of modulation was similar across groups, as reflected in nonsignificant cue× task× group interactions (P1: F2,34 = 0.6, P = .50; N1: F2,34 = 0.03, P = .97).

For probes, greater P1 response amplitudes were observed to X vs Y cues in the AY-70 condition vs greater Y vs X amplitudes in other conditions, resulting in a significant probe type× task interaction (F2,34 = 10.2; P < .001). Although the probe type× task× group interaction was marginally significant (F2,34 = 2.70; P = .08), this reflected a tendency for greater (rather than reduced) differential P1 modulation in patients vs controls (Figure 6B).

Sequence Effects

Larger N1 responses were observed to probe stimuli following A than B cues across both groups and all tasks, resulting in a significant main effect of preceding cue type (F1,35 = 36.9; P < .001) (Figure 6A). The degree of N1 modulation was also significantly greater in the BX-70 vs other task variants (Figure 6A) and to X than Y probes in the AY-70 task only, resulting in a significant preceding cue× task (F2,34 = 13.2; P < .001) and preceding cue× probe type× task (F2,34 = 2.95; P = .001) interactions. Nevertheless, all interactions involving group were not significant, suggesting similar modulation in patients vs controls.

Latencies

In addition to being reduced in amplitude, both cue and probe potentials showed longer latencies in patients (cue: P1 F1,35 = 11.51, P = .002 and N1 F1,35 = 12.94, P = .001; probe: P1 F3,33 = 15.69, P < .001 and N1 F3,33 = 17.93, P < .001) (Figures 3 and 4).

C1

A weak C1 was also present over the central occipital region in both groups (controls,−2.50 [2.19]μV; patients,−1.82 [0.97]μV). As opposed to P1 and N1, peak C1 amplitudes were not statistically different between groups (F1,40 = 1.84; P = .18).

COGNITIVE POTENTIALS
N2

N2 was significantly reduced in amplitude for both cue (F1,35 = 8.34; P = .007) and probe (F1,35 = 4.88; P = .03) stimuli in patients vs controls across all conditions. Across groups, N2 was larger (more negative) to B cues in the AX-70 condition, larger to A cues in BX-70, and approximately equal to A and B cues in the AY-70 task (Figure 5C), leading to a highly significant cue type× task interaction (F2,34 = 14.1; P < .001). Patients showed significantly less difference in response to A vs B cues and significantly less modulation by task than controls, leading to a highly significant cue type× task× group interaction (F2,34 = 14.1; P < .001).

In response to probes, N2 was elicited primarily by AX sequences in the AY-70 condition, and AY trials in the AX-70 condition (Figure 6C), leading to a highly significant cue type× probe type effect (F1,35 = 24.1; P < .001). Patients showed highly significant reductions in both conditions, leading to a highly significant probe type× task× group interaction (F2,34 = 25.7; P < .001).

CNV

CNV was significantly reduced in patients across tasks and stimulus types (F1,35 = 8.56; P = .006). Across groups, CNV was observed primarily for A vs B cues across task variants (F1,35 = 115.5; P < .001). For A cues, CNV was larger in BX-70 vs other conditions, leading to a significant effect of task (F2,34 = 25.8; P < .001) (Figure 7). The task× group interaction was significant (F2,34 = 5.34; P = .01), suggesting less modulation of CNV by task in patients vs controls. Despite being reduced in amplitude in patients, the slope of the CNV showed a parallel time course across groups over the course of the cue-probe interval. The period 550 to 1200 milliseconds from cue onset showed no group effect of slope (F1,35 = 1.74; P = .20) (eAppendix; eTable 1).

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Figure 7. Contingent negative variation (CNV) waveform in response to cue stimuli across task variants. Waveforms reflect activity during the cue-trial interval. All spatial distributions shown at time 1248 milliseconds (ms) with the scale at 0.40μV per step. Conventions are as in Figure 3. The shaded rectangle represents the period used for the CNV slope analysis.

INTERCORRELATION AMONG MEASURES
ERP vs Performance

Primary analyses were performed using regression analysis vs performance, as indexed by d' context (Figure 8). A supplemental path analysis was performed as well to assess directional relations (eFigure 5).

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Figure 8. Correlations of performance (d' context). Shown are performance vs N1 amplitude to cue B (A), performance vs N1 amplitude to probe AY (B), performance vs N2 to cue B in task AX-70 and cue A in task BX-70 (C), and performance vs contrast sensitivity in task AX-70 (D).

Across task versions, N1 amplitude to B cues correlated significantly with performance (r = 0.28; n = 116; P = .002) (Figure 8A), as did N1 amplitude to probe Y in sequence AY (r = 0.40; n = 116; P < .001) (Figure 8B), with larger N1 amplitudes correlating with better performance. The correlation for both B cues (r = 0.20; P = .03) and AY probes (r = 0.25; P = .007) remained significant even when controlling for task type and group membership.

In the AX-70 condition, N2 to B cues correlated significantly with performance (r = 0.37; P = .02), while in the BX-70 condition, N2 to A cues correlated with performance (r = 0.47; P = .004) (Figure 8C). However, neither correlation remained significant following consideration of group status (AX-70: r = 0.23, P = .11; BX-70: r = 0.19, P = .17). Furthermore, when variables were entered simultaneously vs performance in the AX-70 condition, the contribution of N1 remained highly significant (r = 0.37; P = .004), whereas the contribution of N2 became marginal (r = 0.24; P = .05).

Path analysis showed a similar relationship, with both N1 and N2 contributing significantly to performance (eFigure 5). In addition, path analysis revealed a significant contribution of P1 to N2 amplitude and group effects at the level of both P1 and N1. Because of the small sample size, however, these findings require replication in an independent sample.

Finally, across conditions there was a significant correlation between CNV amplitude to A cues and response latency (r = 0.23; P = .01), although the correlation was no longer significant once group status was considered (r = 0.08; P = .33).

Contrast Sensitivity

Patients showed reduced contrast sensitivity at low (0.5 cycles per degree) spatial frequency vs controls (F1,27 = 10.7; P = .003) but not at middle (F1,27 = 2.28; P = .14) or high (F1,27 = 2.08; P = .16), leading to a significant main effect of group (F1,27 = 11.3; P = .002) and a significant group× SF interaction (F2,26 = 5.49; P = .01). There was a significant correlation between contrast sensitivity and performance both across conditions ( = 0.62; P = .01) and in the AX-70 condition individually ( = 0.61; P = .001) (Figure 8D). Both the overall (r = 0.53; P = .02) and AX-70 correlations (r = 0.42; P = .01) remained significant, even when controlling for group status. Finally, the correlation was significant, even in patients alone (r = 0.52; P = .02), and remained significant even when Wechsler Adult Intelligence Scale (WAIS) performance intelligence quotient (IQ) was included in the regression to control for general cognitive dysfunction (r = 0.55; P = .02).

AX-CPT is a widely used task for evaluating the neural basis of working memory and executive processing deficits in schizophrenia.14,18,19,48 Although reduced visual cortical activation has been observed across working memory/executive processing tasks in schizophrenia,36 contributions of sensory dysfunction to impairment in such tasks has not been studied systematically. The present study used ERP to investigate neural bases of impaired AX-CPT performance, focusing on both sensory and higher cognitive measures.

The primary findings are that patients showed reduced sensory responses along with reduced higher cortical activation. Furthermore, performance deficits correlated specifically with reduced ability to process low visual spatial frequency information, consistent with impaired magnocellular input.7,33 Finally, significant task- and sequence-related modulation of sensory responses were observed in this study, reflecting potential top-down modulatory control of sensory responses. Notably, however, such modulations were not significantly reduced in patients despite the reduced amplitudes of the sensory responses. Thus, these findings suggest that sensory deficits may be observed during cognitive tasks in schizophrenia even in the face of normal top-down cognitive control.

BEHAVIORAL FINDINGS

In the present study, patients showed significantly increased rates of AX errors and greater deficits in BX vs AY errors relative to controls, suggesting a specific response pattern.11,15,46 Furthermore, deficits were not limited to the most commonly used version of this task (ie, AX-70) but were observed across task versions. These findings suggest that cognitive deficits in schizophrenia are not confined to those related to frontal response inhibition.49

SENSORY EFFECTS

Sensory processing was assessed using 2 approaches. First, ERP were collected over visual regions in response to cue and probe stimuli, and amplitudes of P1 and N1 visual components were analyzed. Second, patients were assessed using contrast sensitivity, which measures the ability of individuals to detect low-contrast stimuli across a range of spatial frequencies.

Consistent with recent studies using other sensory and cognitive paradigms,12,33,50 patients showed highly significant deficits in P1 and N1 generation. Generators of these components have been localized to the middle occipital gyrus.13,35 Notably, reduced middle occipital gyrus activation was also observed in a recent meta-analysis of fMRI studies of executive processing in schizophrenia (including some which used the AX-CPT),36 supporting our finding of reduced sensory ERP response in this task. Selective reductions in middle occipital gyrus and medial prefrontal fMRI activation have also been reported following ketamine administration in healthy subjects, suggesting a potential link to underlying NMDA dysfunction.51

In prior studies involving psychophysically precise stimuli (sine-wave gratings), we have found preferential P1 reduction to low vs high SF stimuli, consistent with preferential magnocellular vs parvocellular visual system impairment.7 In the present study, psychophysically complex stimuli (letters) were used so exact SFs could not be determined. However, readers in general use a frequency band of approximately 3 cycles per letter,52,53 suggesting that the main frequency band for letter evaluation in this task was likely centered around 1.5 cycles per degree. This frequency band is within the range of prominent magnocellular sensitivity,54 suggesting that the key stimulus-related information may have been contained within a preferential magnocellular SF band. Furthermore, performance deficits in patients correlated significantly with both reduced N1 sensory response (Figure 8A,B) and impaired contrast sensitivity to low- but not high-SF stimuli (Figure 8D), suggesting a significant contribution of impaired sensory processing to impaired behavioral performance in schizophrenia.

COGNITIVE COMPONENTS

This study also analyzed generation of 2 cognitive potentials, N2 and CNV, that have been shown to reflect activity in the prefrontal cortex (medial prefrontal and dorsolateral prefrontal cortex) based on human dipole mapping studies17,55 and direct intracranial recordings in primates.34 These regions show consistently reduced activation in fMRI studies of AX-CPT in schizophrenia,18,56 consistent with our present findings.

No significant correlation was observed with response accuracy (d' context) for either N2 or CNV, suggesting that impaired function of these regions may not be directly linked to the most prominent behavioral impairment observed on this task. Nevertheless, these findings suggest that prefrontal regions may contribute to 2 alternative AX-CPT–related processes indexed by the distinct N2 and CNV ERP components.

First, N2 was larger to B cues in the AX-70 task variant and to A cues in the BX-70 variant, and thus may index conflict between the local and global prepotency.17 In a recent fMRI study of AX-CPT using the AX-70 task version, reduced frontal activation was not related to overall accuracy but only to type of error (BX vs AX).56 Given the larger N2 response to the less frequent B vs A cues in the AX-70 task variant but to the less frequent A vs B cues in the BX-70 task variant, reduced frontal activation during AX-CPT in schizophrenia may thus reflect, at least in part, reduced conflict processing, as has been reported in other response inhibition tasks.57,58 The conflict monitoring role of N2 was underscored in this study by the fact that large N2 responses were also observed to AY sequences in the AX-70 paradigm. Notably, however, patients had no increase in AY false alarms, underscoring the separability of frontal activation vs performance.

Second, CNV amplitude was maintained throughout the cue-probe interval and varied across tasks with the conditional probability of a response, consistent with a role in maintenance of response bias across delay.59,60 The fact that CNV was significantly reduced in amplitude to cue stimuli in patients, but nevertheless showed a parallel time course in patients vs controls during the cue-probe interval, is consistent with the increasing suggestion over recent years that working memory deficits are associated with impairments in stimulus encoding11,19,27,48,61 rather than memory retention.46 Furthermore, the present study suggests that ERP, because of their high temporal resolution, may be more sensitive than fMRI to differential evaluation of encoding vs retention subcomponents during working memory tasks, and thus may offer complementary information.

TOP-DOWN MODULATION

Although the present study was not designed a priori to evaluate top-down modulations of sensory response, 3 apparent examples of top-down modulation were observed. First, in the BX-70 condition (vs other conditions), subjects showed larger sensory ERP responses to A vs B cues (Figure 5). Second, in the AY-70 task variant (vs other variants), subjects showed larger amplitude responses to X vs Y probes (Figure 6). Third, N1 was larger to all probe stimuli following A vs B cues across tasks. These context-related modulations permitted post hoc assessment of integrity of top-down control of sensory processing during this task in schizophrenia.

In the first 2 cases, the stimuli enhanced by these modulations were relatively infrequent and therefore highly informative regarding response selection. Modulation of P1 and N1 by expectation has been described previously.62 In the present study, no significant differences were observed in the degree of task-related modulation of either cue or probe responses between patients and controls, suggesting similar top-down effects across group.

In the case of probe N1 modulation by prior cue type, subjects must attend to the subsequent probe following valid cues to determine the correct response, whereas this is not true following invalid cues (ie, AX and AY sequences require different behavioral responses, whereas BX and BY sequences both require the same response). Thus, a greater degree of attention may be required following valid vs invalid cues and may result in increased N1 amplitude. The similar degree of N1 modulation as a function of prior cue in patients vs controls despite the overall reduction in N1 amplitude (Figure 6) therefore also suggests relatively intact top-down attentional control mechanisms despite impaired bottom-up sensory activation.

OVERALL MODELS OF COGNITIVE DYSFUNCTION

Working memory deficits in schizophrenia were, at one point, considered to reflect impairments in retention of information across delay, consistent with local dysfunction within prefrontal brain regions. In recent years, however, behavioral studies have increasingly shown that performance deficits in AX-CPT and other working memory tasks reflect primarily a failure of encoding, with limited, if any, deficit in retention.11,27 This study supports and adds to this finding and highlights the role of sensory dysfunction as a basis for encoding dysfunction. Moreover, although top-down modulations of sensory processing were observed in this paradigm, they were not significantly different between patients and controls, supporting bottom-up models.

Within the auditory system, deficits in low-level auditory processing have increasingly been shown to contribute to deficits in higher-order processing such as emotion recognition63 and P3 generation.64 This study suggests that a similar relationship may also exist in the visual system in schizophrenia. Thus, while impairments in frontal function and top-down processing undoubtedly occur, sensory deficits and bottom-up influences on cognition in schizophrenia must also be considered.

Correspondence: Daniel C. Javitt, PhD, Center for Translational Schizophrenia Research, The Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Bldg 35, Orangeburg, NY 10962 (javitt@nki.rfmh.org).

Submitted for Publication: May 17, 2010; final revision received November 18, 2010; accepted January 3, 2011.

Published Online: March 7, 2011. doi:10.1001/archgenpsychiatry.2011.17

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants R37MH49334 and P50MH086385 (Dr Javitt) and MH84848 (Dr Butler) from the National Institutes of Health.

Previous Presentations: This study was presented at the American College of Neuropsychopharmacology Annual Meeting; December 7, 2009; Hollywood, Florida; and 15th International Congress on Event-Related Potentials of the Brain (XV EPIC); April 25, 2009; Bloomington, Indiana.

Additional Contributions: The authors would like to thank Stephan Bickel, MD, PhD, for comments on the article and Jeanette Piesco for technical assistance.

Carter CS, Barch DM, Buchanan RW, Bullmore E, Krystal JH, Cohen J, Geyer M, Green M, Nuechterlein KH, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T, Heinssen R. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative.  Biol Psychiatry. 2008;64(1):4-10
PubMed   |  Link to Article
Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder.  J Clin Psychiatry. 2006;67(10):e12
PubMed   |  Link to Article
Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO, Revheim N, Silipo G, Javitt DC. Early-stage visual processing and cortical amplification deficits in schizophrenia.  Arch Gen Psychiatry. 2005;62(5):495-504
PubMed   |  Link to Article
Martínez A, Hillyard SA, Dias EC, Hagler DJ Jr, Butler PD, Guilfoyle DN, Jalbrzikowski M, Silipo G, Javitt DC. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging.  J Neurosci. 2008;28(30):7492-7500
PubMed   |  Link to Article
Green MF, Lee J, Cohen MS, Engel SA, Korb AS, Nuechterlein KH, Wynn JK, Glahn DC. Functional neuroanatomy of visual masking deficits in schizophrenia.  Arch Gen Psychiatry. 2009;66(12):1295-1303
PubMed   |  Link to Article
Wible CG, Kubicki M, Yoo SS, Kacher DF, Salisbury DF, Anderson MC, Shenton ME, Hirayasu Y, Kikinis R, Jolesz FA, McCarley RW. A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.  Am J Psychiatry. 2001;158(6):938-943
PubMed   |  Link to Article
Butler PD, Schechter I, Zemon V, Schwartz SG, Greenstein VC, Gordon J, Schroeder CE, Javitt DC. Dysfunction of early-stage visual processing in schizophrenia.  Am J Psychiatry. 2001;158(7):1126-1133
PubMed   |  Link to Article
Schechter I, Butler PD, Silipo G, Zemon V, Javitt DC. Magnocellular and parvocellular contributions to backward masking dysfunction in schizophrenia.  Schizophr Res. 2003;64(2-3):91-101
PubMed   |  Link to Article
Butler PD, Martinez A, Foxe JJ, Kim D, Zemon V, Silipo G, Mahoney J, Shpaner M, Jalbrzikowski M, Javitt DC. Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments.  Brain. 2007;130(pt 2):417-430
PubMed   |  Link to Article
Javitt DC, Liederman E, Cienfuegos A, Shelley AM. Panmodal processing imprecision as a basis for dysfunction of transient memory storage systems in schizophrenia.  Schizophr Bull. 1999;25(4):763-775
PubMed   |  Link to Article
Javitt DC, Shelley AM, Silipo G, Lieberman JA. Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern.  Arch Gen Psychiatry. 2000;57(12):1131-1137
PubMed   |  Link to Article
Butler PD, Abeles IY, Weiskopf NG, Tambini A, Jalbrzikowski M, Legatt ME, Zemon V, Loughead J, Gur RC, Javitt DC. Sensory contributions to impaired emotion processing in schizophrenia.  Schizophr Bull. 2009;35(6):1095-1107
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Figures

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Figure 1. Electrode distribution on the scalp. Posterior (A) and top (B and C) view, with electrodes used for statistics highlighted for each component measured. For reference, corresponding electrode locations form the 10-20 system are given.

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Figure 2. Behavioral results of the visual AX–continuous performance task. A, Mean (standard error of the mean [SEM]) of errors is shown for all trial types in task AX-70 for controls and patients. Errors for trials AX were omissions and for trials AY, BX, and BY were false alarms. B, d' Context across tasks is shown. Corresponding effect sizes (Cohen's d) were AX-70, d = 0.83; AY-70, d = 1.32; and BX-70, d = 1.45. *  P < .05,† P < .01,‡ P < .001.

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Figure 3. Sensory (P1, N1; A and B) and cognitive (N2; C) event-related potential (ERP) activity in response to cue stimuli in the AX-70 task variant. The activity is presented 2 ways. The scalp voltage distributions for each component for patients and controls are plotted over the head representation; scales are inμV per step; red is positive, and blue is negative. The plots show ERP waveforms recorded at the electrode highlighted over the scalp rendition for patients and controls and for cues A and B. Note that statistical results described in the manuscript refer to the median of the electrodes over the region analyzed (Figure 1); ms indicates milliseconds.

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Figure 4. Sensory (P1, N1) and cognitive (N2) event-related potential (ERP) activity in response to probe stimuli in the AX-70 task variant. Conventions are as in Figure 3. A, Activity following presentation of the valid probe (X) is shown. B, Activity following presentation of the invalid probe (Y) is shown; ms indicates milliseconds.

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Figure 5. Mean (standard error of the mean [SEM]) event-related potential (ERP) component amplitudes to cue stimuli across task variants. Early visual component P1 (A), early visual component N1 (B), difference in peak amplitudes of N2 to B- vs A-cues (C), and contingent negative variation (CNV) amplitude vs conditional probability ratio (D) are shown (Table 1). * P < .05,† P < .01,‡ P < .001.

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Figure 6. Mean (standard error of the mean [SEM]) event-related potential (ERP) component amplitudes to probe stimuli across task variants. A, P1 and N1 amplitudes to preceding cue (A or B) (A); P1 and N1 to probe type (X or Y) (B); and N2 amplitudes following A cues across task variants (C) are shown. * P < .05,† P < .01,‡ P < .001.

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Figure 7. Contingent negative variation (CNV) waveform in response to cue stimuli across task variants. Waveforms reflect activity during the cue-trial interval. All spatial distributions shown at time 1248 milliseconds (ms) with the scale at 0.40μV per step. Conventions are as in Figure 3. The shaded rectangle represents the period used for the CNV slope analysis.

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Figure 8. Correlations of performance (d' context). Shown are performance vs N1 amplitude to cue B (A), performance vs N1 amplitude to probe AY (B), performance vs N2 to cue B in task AX-70 and cue A in task BX-70 (C), and performance vs contrast sensitivity in task AX-70 (D).

Tables

Table Graphic Jump LocationTable 1. Trial Type Probabilities for Each Variant of AX-CPT

References

Carter CS, Barch DM, Buchanan RW, Bullmore E, Krystal JH, Cohen J, Geyer M, Green M, Nuechterlein KH, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T, Heinssen R. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative.  Biol Psychiatry. 2008;64(1):4-10
PubMed   |  Link to Article
Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder.  J Clin Psychiatry. 2006;67(10):e12
PubMed   |  Link to Article
Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO, Revheim N, Silipo G, Javitt DC. Early-stage visual processing and cortical amplification deficits in schizophrenia.  Arch Gen Psychiatry. 2005;62(5):495-504
PubMed   |  Link to Article
Martínez A, Hillyard SA, Dias EC, Hagler DJ Jr, Butler PD, Guilfoyle DN, Jalbrzikowski M, Silipo G, Javitt DC. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging.  J Neurosci. 2008;28(30):7492-7500
PubMed   |  Link to Article
Green MF, Lee J, Cohen MS, Engel SA, Korb AS, Nuechterlein KH, Wynn JK, Glahn DC. Functional neuroanatomy of visual masking deficits in schizophrenia.  Arch Gen Psychiatry. 2009;66(12):1295-1303
PubMed   |  Link to Article
Wible CG, Kubicki M, Yoo SS, Kacher DF, Salisbury DF, Anderson MC, Shenton ME, Hirayasu Y, Kikinis R, Jolesz FA, McCarley RW. A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.  Am J Psychiatry. 2001;158(6):938-943
PubMed   |  Link to Article
Butler PD, Schechter I, Zemon V, Schwartz SG, Greenstein VC, Gordon J, Schroeder CE, Javitt DC. Dysfunction of early-stage visual processing in schizophrenia.  Am J Psychiatry. 2001;158(7):1126-1133
PubMed   |  Link to Article
Schechter I, Butler PD, Silipo G, Zemon V, Javitt DC. Magnocellular and parvocellular contributions to backward masking dysfunction in schizophrenia.  Schizophr Res. 2003;64(2-3):91-101
PubMed   |  Link to Article
Butler PD, Martinez A, Foxe JJ, Kim D, Zemon V, Silipo G, Mahoney J, Shpaner M, Jalbrzikowski M, Javitt DC. Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments.  Brain. 2007;130(pt 2):417-430
PubMed   |  Link to Article
Javitt DC, Liederman E, Cienfuegos A, Shelley AM. Panmodal processing imprecision as a basis for dysfunction of transient memory storage systems in schizophrenia.  Schizophr Bull. 1999;25(4):763-775
PubMed   |  Link to Article
Javitt DC, Shelley AM, Silipo G, Lieberman JA. Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern.  Arch Gen Psychiatry. 2000;57(12):1131-1137
PubMed   |  Link to Article
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re: Dias et al Contectual Encoding in Schizophrenia
Posted on September 21, 2011
Stefan P. Kruszewski, MD
Stefan P. Kruszewski, MD & Associates, P.C.,
Conflict of Interest: None Declared
In their July 2011 article on the encoding deficits in schizophrenia, 1 authors Dias et al describe a “case-control” study intended to examine whether objective physiological evidence exists for their encoding hypothesis of memory impairments in persons with schizophrenia. Based on their comparison of event-related potentials (ERPs) in 30 medicated schizophrenic subjects and 17 healthy (un-medicated) controls, they conclude that visual working memory deficits in schizophrenia may reflect impairments of sensory processing, rather than deficits in retention of memories. Their conclusions are interesting and, if validated, are potentially very important in understanding the genesis and treatment of the cognitive impairments that limit functional recovery in schizophrenia. However, the conclusions are questionable because this study clearly does not meet the basic criteria for a case-control study. In order to make a rigorous comparison that illuminates the cognitive deficits that may be particular to schizophrenia, as opposed to the impact of antipsychotic drugs, both groups would have to be similarly medicated. Alternatively -- and perhaps more tractably -- it would be useful to explore whether or not there is a dose-response relationship between prescribed antipsychotics and degree of working memory impairments in schizophrenia. Indeed, there is substantive evidence that antipsychotics can induce deficits in working memory.2,3
Although the ERP paradigm described by Dias et al may theoretically localize the pathways involved in schizophrenia-related memory impairment and distinguish them from those that may be induced by drugs, the interplay between sensory and frontal cortices as they relate to working memory are exceedingly complex and not well understood enough to lend themselves to this kind of electrophysiological parsing. In short, there is no a priori evidence to believe that medicated schizophrenics would be sufficiently similar to an un-medicated healthy people to advance such striking constructs concerning the basis for one of the more disabling “positive symptoms” of schizophrenia.
It would be appropriate and helpful if Dias et al were to include a section in their report to describe the limitations of their study, and perhaps pursue experiments that address these limitations.
1. Dias EC, Butler PD, Hoptman MJ, Javitt DC. Early Sensory Contributions to Contextual Encoding Deficits in Schizophrenia. Arch Gen Psychiatry. July 2011; 68(7): 654-664.
2. Reilly JL, Harris MSH, Keshaven MS, et al. Adverse Effects of Risperidone on Spatial Working Memory in First-Episode Schizophrenia. Arch Gen Psychiatry. Nov 2006; 63(11): 1189-1197.
3. Castner SA, Williams GV, Goldman-Rakic PS. Reversal of Antipsychotic-induced Working Memory Deficits by Short-term Dopamine DI Receptor Stimulation. Science. 17 Mar 2000; 287(5460): 2020-2022.

Conflict of Interest: Dr. Kruszewski does not have any current business or financial arrangements with any pharmaceutical company. Prior to 2001, Dr. Kruszewski participated on the speaker’s bureaus of the following companies: Pfizer, Inc., GlaxoSmithKline, Janssen (Johnson and Johnson), AstraZeneca, Wallace Labs, Watson, Sandoz, Eli Lilly, GE-Amersham Biosciences; and previously served on an Eli Lilly Northeast Advisory Panel (1998). Dr. Kruszewski has been, and continues to be, directly involved as an expert in Zyprexa and Neurontin state and federal, individual plaintiff and class action, litigation. An amicus brief was submitted to the US Supreme Court for Dr. Kruszewski in the matter concerning Levine v. Wyeth. The US Department of Justice has publicly disclosed that it has settled three qui tam actions as co-plaintiff with Dr. Kruszewski: v. Southwood Psychiatric Hospital, a subsidiary of YFCS, Austin, Texas; v. Pfizer; and v. AstraZeneca. Dr. Paczynski does not have any current business or financial arrangements with any pharmaceutical company. Prior to 2003, Dr. Paczynski participated in speaker bureau activities for Boehringer-Ingelheim and Astra-Zeneca.
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Early Sensory Contributions to Contextual Encoding Deficits in Schizophrenia
Arch Gen Psychiatry.2011;68(7):654-664.eSupplement

eSupplement -Download PDF (1954 KB). This file requires Adobe Reader®.

eAppendix. Path analysis and CNV slope analysis.

eTable 1. Slope of CNV (μV/ms).

eTable 2. Effect sizes.

eFigure 1. Activity following presentation of the Cue in task variant AY-70. The activity ispresented in two ways. The scalp voltage distributions for each component for patients(right) and controls (left) are shown plotted over the head representation; scales are inμV/step, red is positive and blue is negative. The plots show ERP waveforms recorded atthe electrode highlighted over the scalp renditions, for both patients (blue) and controls(red) and for cues A and B.

eFigure 2. Activity following presentation of the Probe in task variant AY-70. The left panelshows activity following presentation of the valid probe (X) and the right panel showsactivity following presentation of the invalid probe (Y). Conventions are the same as in

eFigure 1.

eFigure 3. Activity following presentation of the Cue in task variant BX-70. Conventionsare the same as in eFigure 1.

eFigure 4. Activity following presentation of the Probe in task variant BX-70. Conventionsare the same as in eFigure 2.

eFigure 5. Path analysis results in the AX-70 task variant. Component variables areoverlaid on a schematic brain based upon generator locations derived from sourceanalysis2, monkey intracranial recordings3 and prior fMRI studies4. Arrows reflectsignificant statistical associations as shown by path analysis, with thickness of arrowrepresenting strength of connection. CMIN/DF of the model was 1.109, and RMSEA was0.052. For statistics, P1 values were collapsed across A- and B-cues, which were notsignificantly different (p>.2).
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