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N400 and Automatic Semantic Processing Abnormalities in Patients With Schizophrenia
Daniel H. Mathalon, PhD, MD;
William O. Faustman, PhD;
Judith M. Ford, PhD
Arch Gen Psychiatry. 2002;59:641-648.
ABSTRACT
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Background One factor hypothesized to underlie thinking disturbance in patients
with schizophrenia is abnormal or disinhibited automatic spreading activation
of semantic networks, which can be assessed using the N400 event-related potential.
N400 is a negative-going component elicited at about 400 milliseconds following
semantic stimuli that are not primed by the preceding context. Semantic priming
refers to facilitated semantic processing gained through preexposure to semantic
context, which can happen automatically or strategically. Using N400, inferences
can be drawn regarding the extent to which a given context primes a word.
Methods During a picture-word matching task, N400s to primed (exact match) and
unprimed (remotely related) words were recorded from 18 healthy control subjects
and 18 patients with schizophrenia performing a picture-word matching task.
A short interval (325 milliseconds) between picture and word onset (stimulus-onset
asynchrony) was used to optimize the role of automatic spreading semantic
activation and to minimize the role of attention, expectancy, preparation,
and working memory.
Results Despite behavioral evidence of normal semantic priming, patients generated
an abnormally small N400 (ie, less negative) to unprimed words. The N400 to
primed words was neither larger nor smaller in patients than in controls,
suggesting normal use of context.
Conclusions A reduced N400 to unprimed words in patients with schizophrenia suggests
that there was inappropriate priming of words by remotely related semantic
contexts. This is consistent with an overly broad automatic spread of activation
through semantic networks in patients with schizophrenia.
INTRODUCTION
ABNORMAL or disinhibited spread of activation through semantic networks
is posited as an explanation for some of the positive symptoms of schizophrenia.1 Such overactivity might result in loose, irrelevant,
or bizarre associations,2 and be reflected
in abnormal use of local context to link words and concepts. The semantic
networks linking words and concepts can be assessed in studies of semantic
priming.
Semantic priming refers to the tendency to respond more quickly to a
target stimulus when it is preceded by a semantically related than unrelated
prime. Collins and Loftus3 suggested that priming
occurs through spreading activation of semantic networks. For example, people
respond more quickly to the target word "lime" when preceded by the prime
"lemon" than when preceded by the more distantly related prime "pear" or the
unrelated prime "truck."4 Seeing lemon selectively
activates other related concepts (citrus fruits first and then other fruits)
and may inhibit unrelated concepts. Many investigators1
have used semantic priming paradigms to study semantic networks in patients
with schizophrenia.
At short (about 300 milliseconds) intervals between the onsets of prime
and target stimuli (stimulus-onset asynchrony [SOA]), the mechanism for priming
is primarily automatic activation of semantic networks, involving minimal
attentional processing5-6 but
nevertheless involving semantic context, because meaning is primed. At longer
SOAs, these automatic processes are still present but are supplemented by
controlled and strategic processes such as expectancy and preparation.7-8 Priming under long SOAs, relative to
short SOAs, is also more dependent on working memory.
Using short SOAs, some investigators,9
but not others,5-6 have observed
larger reaction time (RT) priming effects in patients with schizophrenia than
in control subjects, a phenomenon known as hyperpriming. Hyperpriming is generally
interpreted as reflecting overactivation of appropriate semantic networks,
such that a primed target is processed faster than normal. Some short SOA
studies10-11 have found hyperpriming
to be associated with more severe thought disorder in schizophrenic patients,
but others have not. For example, one study12
found priming to be more related to medication dose than thought disorder.
In another study,13 patients with mild thought
disorder showed normal priming, but patients with more severe thought disorder
showed the reverse—responding more slowly to primed than unprimed words.
At longer SOAs, automatic processes that promote priming and that may contribute
to hyperpriming in patients may be offset by controlled processing deficits,
resulting in a failure to observe priming effects in patients with schizophrenia.6
Scalp-recorded event-related potentials (ERPs) provide a more direct
measure of the neural mechanisms underlying semantic priming than behavioral
measures. The N400 ERP is a negative-voltage component occurring at about
400 milliseconds following semantic targets that are not primed by the preceding
context, with primed targets eliciting a relatively positive voltage. N400
was first identified in experiments in which subjects read sentences that
ended with a word that did not make sense in the context.14
Since then, N400 has been elicited by unprimed words in different tasks: reading
sentences silently while trying to make sense of them,15
reading or listening to sentences in preparation for answering questions about
them,16-18 making
overt yes/no decisions about whether a word matches the previous context,19-23
and performing a task unrelated to the priming manipulation, such as indicating
whether an object is real.24 Thus, N400 is
elicited by a stimulus that is incongruous with (ie, unprimed by) its semantic
context. When the unprimed stimulus is infrequent or a target, it may also
elicit a P300, a prolonged positive component usually occurring 300 milliseconds
after the stimulus, potentially contaminating the measurement of N400.
N400 protocols have been used to study semantic processing in patients
with schizophrenia with varied results. Because ERPs can be recorded without
any overt behavioral response, some studies of N400 in patients with schizophrenia
have used passive paradigms. Although these studies25-27
have not shown group differences in N400, studies with active task requirements
have reported abnormally large28-29
and small25, 30 N400s to unprimed
stimuli and abnormally large N400s to primed stimuli28-32
in patients with schizophrenia.
A primed stimulus should not elicit an N400, but should be associated
with a relatively positive voltage deflection at the N400 latency. Furthermore,
an abnormally positive voltage at this latency following a primed stimulus
is the ERP analogue of hyperpriming, suggesting abnormally facilitated activation
of the associated semantic network. An abnormally negative voltage at this
latency (ie, abnormal elicitation of an N400) following a primed stimulus
suggests that the stimulus does not fit into the semantic context, as understood
by the subject, possibly because of inefficient or deficient use of context,
but perhaps also because of poor working memory of the context.33
An unprimed stimulus should elicit an N400. An abnormally negative voltage
at the N400 latency following an unprimed stimulus suggests heightened incongruity,
perhaps resulting from an overly narrow or constrained semantic network. Furthermore,
an abnormally positive voltage (or reduced negativity) at this latency following
an unprimed stimulus suggests an overly inclusive semantic network that allows
integration of an inappropriately wide range of stimuli into the preceding
context. Expected normal priming effects on N400 and the implications of the
various possible abnormalities are summarized in Table 1.
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Table 1. N400 Amplitudes During Semantic Priming: Possible Findings
and Interpretations
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Although short SOAs allow the study of automatic spread of activation
uninfluenced by controlled and strategic processes, all ERP studies of semantic
processing in patients with schizophrenia have used only long SOAs. In this
study, a short SOA was used, not only to emphasize automatic processing but
also to reduce the working memory burden associated with the long SOAs characteristic
of sentence-reading paradigms and some word-word and picture-picture paradigms.
In addition, while most N400 schizophrenia studies have compared semantically
primed stimuli with highly unrelated unprimed stimuli, the semantic slippage
present in schizophrenia may be more evident over relatively short semantic
distances. One example of this is the facilitated indirect priming effect
(eg, lemon soursweet) exhibited by patients with schizophrenia
relative to controls.34 Accordingly, subtler
semantic discriminations were used herein than have been typically used to
manipulate priming. Specifically, word stimuli and the pictures priming them
were always drawn from the same semantic category, resulting in partial priming
of the "unprimed" words at the superordinate category level (eg, the word
"duck" following a picture of a swan) relative to strong priming of the words
semantically matched to the preceding picture (eg, the word "swan" following
a picture of a swan).
Hypotheses were tested regarding the nature of semantic networks in
patients with schizophrenia: (1) Automatically activated semantic networks
in schizophrenic patients are overly inclusive, accepting related but not
identical unprimed words as primed, resulting in a smaller than normal N400
to unprimed words. (2) Schizophrenic patients are deficient in their use of
semantic context, responding to primed words as if they were unprimed, generating
larger than normal N400s to primed words. (3) Alternatively, schizophrenic
patients are overly efficient in their use of context, resulting in hyperpriming
and smaller than normal N400s to primed words. The relationship of priming
abnormalities to positive symptoms of schizophrenia was also explored.
PARTICIPANTS AND METHODS
PARTICIPANTS
Eighteen healthy adults and 18 patients with schizophrenia (with 17
men in each group) participated and gave written informed consent after the
procedures were fully described. Demographic data appear in Table 2.
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Table 2. Demographic Data*
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Controls were recruited by newspaper advertisements and word of mouth,
screened by telephone using the psychiatric screening questions from the Structured
Clinical Interview for DSM-IV,36
and excluded for any significant history of Axis I psychiatric illness. Patients
were recruited from community mental health centers and inpatient and outpatient
services of the VA Palo Alto Health Care System. All patients met DSM-IV37 criteria for schizophrenia
(6 paranoid, 1 disorganized, 11 undifferentiated patient subtypes), based
on a diagnosis from the Structured Clinical Interview for DSM-IV conducted by a trained research assistant, a psychiatrist (D.H.M.),
or a clinical psychologist (W.O.F.) (n = 15) or an inpatient medical record
review performed by a clinical psychologist (W.O.F.) (n = 3). All patients
were taking stable doses of medication. Six patients were taking typical antipsychotic
medications (haloperidol [n = 3], fluphenazine [n = 2], or thiothixene [n
= 1]), and 12 patients were taking atypical antipsychotic medications (clozapine
[n = 2], olanzapine [n = 9], or risperidone [n = 1]). Prospective patient
and control participants were excluded for a history of significant head injury
(loss of consciousness for  30 minutes or neurological sequelae) or neurological
or other medical illnesses compromising the central nervous system. Although
some patients had a history of alcohol (n = 1) or drug (n = 1) abuse or dependence
(n = 2), all but 1 (who abused alcohol) were in full remission.
Patient symptoms were assessed by 2 trained raters (a psychiatrist [D.H.M.],
a clinical psychologist [W.O.F.], or a clinical neuroscientist [J.M.F.]) administering
the 18-item Brief Psychiatric Rating Scale (BPRS)38
conducted on the same day (n = 9), within 2 days (n = 5), within 1 week (n
= 2), or within 3 weeks (n = 1) of ERP testing. The mean of the 2 ratings
was used for analysis. Brief Psychiatric Rating Scale ratings from 1 patient
were not available. Three BPRS items, reflecting positive symptom dimensions,
were examined: (1) conceptual disorganization (CD), (2) hallucinatory behavior
(HB), and (3) unusual thought content (UTC). Because symptom ratings were
based on the mean of 2 raters, the intraclass reliability coefficients were
adjusted using the Spearman-Brown Prophecy formula.39
Interrater intraclass reliability coefficients were reasonably high (CD, 0.83;
HB, 0.92; and UTC, 0.74).
TASK
A picture-word verification task, described in more detail elsewhere,40 was used. The pictures consisted of 102 line drawings,
selected for nameability from a set of 12041
based on pilot testing in young adults. Pictures were classified into 10 natural
categories (clothing, animal, bird, appliance, tool, vehicle, vegetable, fruit,
toy, and musical instrument). The full set of pictures was presented in each
block, which was repeated 4 times. Pictures were paired with different words
in the different blocks, and the order of the pictures was varied across blocks.
There was a 2- to 3-minute rest period between blocks. Two patients were tested
with fewer than 4 blocks because of scheduling constraints.
Each picture was presented for 250 milliseconds, followed 75 milliseconds
later by a word that either matched (50%) or did not match (50%) the picture.
Between picture onset and word onset, 325 milliseconds elapsed. The word remained
on the screen until a button was pressed, and the next trial was initiated
1250 milliseconds later. No feedback was given to signal performance accuracy.
All picture-word pairs were from the same category. For example, a picture
of a camel was followed twice by the word "camel" (matches), once by "cow"
and once by "fox" (nonmatches). Participants held a 7.6- x 12.7- x
1.3-cm response box on their laps and pressed buttons with right and left
thumbs to denote if the word matched the picture. Eleven patients and 11 control
subjects pressed the right button to matches and the left button to nonmatches;
the remaining did the opposite. Practice with different stimuli was given
before ERP recording. Data from this study are also presented in a separate
report42 analyzing response-locked ERP data
for effects of response accuracy.
ELECTROPHYSIOLOGICAL RECORDING PROCEDURES
Electroencephalogram data recorded from 9 central sites (F3, Fz, F4,
C3, Cz, C4, P3, Pz, and P4) are reported herein. Vertical electro-oculogram
(EOG) data were recorded from electrodes placed above and below the right
eye and horizontal EOG data were recorded from electrodes placed at the outer
canthus of each eye. Electroencephalogram and EOG data were acquired every
5 milliseconds, and were bandpass filtered between 0.1 and 30 Hz. Single trials
exceeding ±100 µV were rejected (for controls, mean number of
rejected trials was 14.2, representing 2.9% of their trials; for patients,
mean number of rejected trials was 14.7, representing 3.6% of their trials).
Remaining trials were corrected for the effects of eye blinks and eye movements
based on correlations of the vertical and horizontal EOGs with the electroencephalogram
recorded at each electrode site.43 Event-related
potential averages were high pass filtered to minimize activity below 1 Hz,
removing the influence of the late positive component from the N400.
For each subject, N400 was identified in the ERP to unprimed words as
the most negative peak between 300 and 500 milliseconds following the word
onset at Pz, where N400 was largest. The latency of this peak was then applied
to primed and unprimed waveforms at all 9 leads, and the average amplitudes
at this latency (±30 milliseconds), relative to a pre-picture baseline
of 100 milliseconds, were taken as the N400 measures. While in most situations
a preword baseline might be reasonable for assessing ERP activity associated
with word processing, there was only 325 milliseconds between picture and
word onset during which there was considerable ERP activity associated with
picture processing. Thus, a pre-picture baseline minimized the influence of
any differential activity associated with picture processing in the 2 groups.
BEHAVIORAL RESPONSE DATA
Trials with RTs exceeding 5 seconds were excluded from the analysis
of behavioral data. Median RTs were assessed to minimize the effect of outliers.
Errors of commission were tallied; there were no errors of omission because
word trials did not terminate until a response was made. Only correct trials
contributed to N400 measurements.
STATISTICAL ANALYSIS
N400 amplitudes were analyzed using repeated-measures analyses of variance
to assess effects of group (controls or patients), priming (primed or unprimed),
and anterior-posterior (frontal, central, or parietal) and lateral (left,
central, or right) sites of scalp electrode locations. Reaction times were
analyzed in a 2-way group by priming repeated-measures analysis of variance.
Greenhouse-Geisser corrections were used for repeated measures factors with
3 or more levels. Post hoc analyses used Newman-Keuls tests for between-group
comparisons and paired t tests for within-group comparisons.
To examine whether positive symptoms of schizophrenia were related to
priming abnormalities, N400 amplitudes at Pz to primed and unprimed words
and the RT difference between unprimed and primed words were correlated with
the BPRS items CD, HB, and UTC using Pearson product-moment correlations.
RESULTS
REACTION TIME
Median RTs are graphed in Figure 1.
A 2-way group by priming analysis of variance revealed a main effect for group
(F1,34 = 6.59, P = .02), in which schizophrenic
patients had longer RTs than did controls, and a main effect for priming (F1,34 = 51.93, P<.001), in which RTs to unprimed
words were longer than to primed words, but no interaction (F1,34
= 1.43, P = .24). Although patients responded more
slowly, they showed an equivalent behavioral priming effect to controls.
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Figure 1. Median (±SEM) reaction
times (RTs) (A) and N400 amplitudes (B) to primed and unprimed words are shown
for healthy control subjects (n = 18) and patients with schizophrenia (n =
18). N400 amplitudes are collapsed across all 9 electrode sites and are plotted
with negative going up to facilitate conceptual comparison with RT plots.
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N400 AMPLITUDE AND LATENCY
Mean N400 amplitudes are illustrated in Figure 1,
and grand average ERPs are shown in Figure 2.
A 4-way group by priming by lateral site by
anterior-posterior site analysis of variance revealed a main effect of priming
(F1,34 = 44.80, Greenhouse-Geisser P<.001),
in which unprimed words elicited a larger (ie, more negative) N400 than primed
words. In addition, there was a priming by group interaction (F1,34
= 4.00, P = .05). The interaction was parsed in 2
ways: by assessing priming effects within each group separately and by assessing
group effects within primed and unprimed words separately. The effects of
priming were significant for controls (t17
= 6.49, P<.001) and patients (t17 = 3.16, P = .006). The effects
of group were significant for unprimed (F1,34 = 6.25, P = .02, Newman-Keuls P<.05) but not for
primed (F1,34 = 0.32, P = .57, Newman-Keuls P>.05) words, with patients showing a smaller N400 than
controls to unprimed words but no tendency to show inappropriately large or
small N400s to primed words. N400 latency at Pz was not affected by group
(F1,34 = 0.32, P = .58).
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Figure 2. Event-related potentials associated
with primed and unprimed picture-word pairs recorded from healthy control
subjects (n = 18) (A) and patients with schizophrenia (n = 18) (B). Picture
onset is shown with a vertical line at -325 milliseconds and word onset
by a vertical line at 0 milliseconds. VEOG indicates vertical electro-oculogram;
HEOG, horizontal electro-oculogram.
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CLINICAL CORRELATIONS
None of the BPRS positive symptoms examined was correlated significantly
with N400 amplitude to primed (CD: r = 0.12, P = .64; HB: r = -0.38, P = .14; and UTC: r = -0.20, P = .44) or unprimed (CD: r =
0.24, P = .36; HB: r = 0.29, P = .26; and UTC: r = -0.10, P = .80) words. The RT priming effect (RT for unprimed
words - RT for primed words) was not significantly related to CD (r = -0.01, P = .96) or UTC
(r = 0.05, P = .86), but
did show a significant negative correlation with HB (r
= -0.56, P = .02), indicating that patients
with more severe hallucinations showed a smaller RT priming effect.
COMMENT
In this report, we present neurophysiological evidence of abnormally
broad automatic spread of semantic activation in patients with schizophrenia,
but normal automatic use of semantic context. N400 is a neurophysiological
index of semantic priming; in healthy subjects, unprimed words elicit a large
N400 and primed words elicit no N400. As such, inferences can be drawn regarding
the extent to which a given context primes a word. In our paradigm, when the
word "duck" followed a picture of a swan, it was relatively unprimed, and
when the word "swan" followed a picture of a swan, it was completely primed.
In both groups, unprimed words elicited larger N400s than primed words—the
neurophysiological signature of priming. However, patients with schizophrenia
generated smaller N400s to unprimed words than did controls, suggesting that
these words were abnormally primed by the relatively incongruous picture context.
This abnormally small N400 to unprimed words suggests insensitivity to subtle
incongruities in language, perhaps due to an overly broad or facilitated spread
of activation through a loosely structured semantic network. The N400 to primed
words was normal in patients; it was neither abnormally large nor abnormally
small. That is, when presented with the pictorially congruous context, patients
used it effectively, priming neither too little nor too much (ie, hyperprime).
However, because the unprimed picture-word pairs were moderately related (swan-duck),
belonging to the same superordinate category, abnormally small N400s to these
pairs could be construed as evidence of hyperpriming. That is, schizophrenic
patients showed more priming than did controls when pictures primed words
at the superordinate categorical level. Hyperpriming over this span of semantic
space occurred in the patients despite the absence of hyperpriming when the
picture prime exactly matched the subsequent word.
To our knowledge, this is the first neurophysiological study of semantic
priming in patients with schizophrenia to use a short SOA, allowing only automatic
spreading activation of semantic networks. Longer SOAs allow both automatic
and controlled semantic processing, but in unknown proportions,8
possibly contributing to inconsistencies in the literature on the effects
of schizophrenia on N400 semantic priming. In addition, perhaps because of
the short SOA, this is the first report, to our knowledge, showing no slowing
of N400 in patients with schizophrenia. This equivalence of N400 latency in
the 2 groups reinforces the notion that the paradigm used in this study tapped
into semantic processes that were unaffected by attention, strategy, and motivation.
Bobes et al30 reported abnormally small
N400s to unprimed pairs but abnormally large N400s to primed pairs in patients
with schizophrenia, using picture-picture pairs presented with long SOAs.
Comparison of the Bobes et al study with ours is complicated by their use
of a long SOA and by our exclusive use of within-category picture-word pairs.
If the effects of priming cannot be sustained over relatively long intervals
in schizophrenic patients because of working memory deficits, the long SOA
might be responsible for their reduced sensitivity to both incongruity and
congruity in the Bobes et al study. While within-category pairs enabled us
to assess subtle abnormalities in semantic activations in the range in which
semantic slippage underlying thinking disturbance in patients with schizophrenia
may be most evident, the absence of categorically unrelated pairs (eg, swan-truck)
makes comparison with other studies difficult. Moreover, this feature distinguishes
our study from others9 that have found RT hyperpriming
in patients at short SOAs.
Reaction time and ERP measurement modalities can bring important and
somewhat independent information to bear on the question of whether schizophrenia
is associated with an abnormally broad spread of activation through semantic
networks. While the N400 data from the present study indicate abnormal spread
of semantic activation in the patients, the RT data indicate normal RT priming,
a finding that is both consistent6 and inconsistent13 with other studies using short SOAs. Compared with
RT, N400 is a relatively direct measure of neural processes associated with
priming, unaffected by response selection and execution. Moreover, the N400
index of priming does not depend on taking a difference score between 2 conditions
to draw conclusions about semantic congruity effects, a limitation of behavioral
RT measures of priming. Nevertheless, assuming some correspondence between
behavioral and neurophysiological measurements, we would have expected a smaller
RT priming effect in patients than controls based on N400 data. The dissociation
of N400 and RT effects observed herein suggests that neurophysiological indices
have relatively greater sensitivity to semantic processing abnormalities in
patients with schizophrenia.
Consistent with many,25, 28-32
but not all,44 prior ERP priming studies, the
present study did not yield any significant relationships between severity
of thought disorder and N400 measures of priming. In our case, one possible
reason for this may be that the BPRS does not provide as precise an assessment
of thought disorder as other more extensive measurements.45
Another reason is that underlying semantic processing abnormalities may reflect
traitlike aspects of schizophrenia, whereas patient symptoms can fluctuate
over the illness course in a statelike fashion and respond differentially
to antipsychotic medication. Thus, clinical state fluctuations and medication
effects would attenuate the cross-sectional relationships between semantic
priming abnormalities and symptoms. Many patients who no longer appear to
have thought disorder may still have the neurobiological circuitry allowing
loose and bizarre associations, as reflected by neurophysiological priming
abnormalities.
Reaction time indices of priming also failed to show significant correlations
with formal thought disorder, consistent with some,6
but not all,13 prior reports. However, this
study did show a significant tendency for patients with more severe hallucinations
to exhibit relatively smaller RT priming effects, suggesting that the automaticity
of semantic inexactitude in patients wtih schizophrenia may underlie other
misperceptions of reality, including auditory hallucinations.
AUTHOR INFORMATION
Submitted for publication March 26, 2001; final revision received September
6, 2001; accepted October 12, 2001.
This study was supported by grants MH40052 and MH58262 from the National
Institutes of Health, Bethesda, Md; and by the resources of the Department
of Veterans Affairs at the VA Palo Alto Health Care System, Palo Alto, Calif.
This study was presented in preliminary form at the Society for Psychophysiological
Research Conference, San Diego, Calif, October 22, 2000; and at the International
Congress of Schizophrenia Research, Whistler, British Columbia, May 1, 2001.
We thank Mark Rothrock, MD, for referring patients to our studies; Mark
Fedor, Jennifer Hoffman, Sontine Kalba, Max Gray, and Sue Whitfield for various
aspects of data acquisition and analysis; Nusha Askari for paradigm development;
Margaret Rosenbloom for work on paper preparation; and all the patients for
their participation.
Corresponding author and reprints: Daniel H. Mathalon, PhD, MD, Psychiatry
Service 116A, VA Connecticut Healthcare System, 950 Campbell Ave, West Haven,
CT 06516 (e-mail: daniel.mathalon{at}yale.edu).
From the Department of Psychiatry, VA Connecticut Healthcare System,
West Haven, and Yale University School of Medicine, New Haven (Dr Mathalon);
the Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Stanford, Calif (Drs Faustman and Ford); and VA Palo Alto
Health Care System, Palo Alto, Calif (Drs Faustman and Ford).
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