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Brian C. Woolfrey
University of Minnesota
ERP Evidence of abnormal 2
Abstract
comprehension in schizophrenic individuals with positive thought disorder (TD) have revealed
abnormal patterns of semantic processing at a local level of text comprehension. More recent
studies using ERP methods to study on-line processing of single sentences provide preliminary
evidence that TD patients may also fail to use context properly during discourse to integrate
semantic information into a coherent idea. We propose to explore the latter idea in more detail
using a global context manipulation paradigm introduced by St. George (1994). Specifically, we
hypothesize that TD subjects will show an abnormally small global N400 attenuation effect for
all words in titled paragraphs vs. untitled paragraphs when a context-setting title is required for
paragraph coherence. If the results support the hypothesis, it would support the idea that both
local semantic abnormalities and global context modulation difficulties are key components in
Schizophrenia is a severe and often debilitating brain disorder that affects nearly 1% of
the US population (NIMH). Although a variety of distinct subtypes of schizophrenia exist, many
of them involve either disorganized speech patterns or positive thought disturbances such as
delusions, auditory hallucinations and paranoia. Because of this, researchers have long
speculated that the etiology of certain types of schizophrenia may have something to do with
appear to support this model. Specifically, researchers have capitalized on the classic lexical
decision paradigm to show reduced semantic priming effects in schizophrenic patients with
thought disorder. In this paradigm a prime word is presented a moment before a target word, and
the participant's task is to choose whether the target word is a real word or a nonsense word.
Current cognitive theory suggests that the prime word automatically activates semantically
related concepts though a process known as "spreading activation", and that this activation
facilitates neural communication between activated "nodes" in long-term memory (LTM) and
working memory (WM) such that they require less bottom-up processing to access in the
immediate future. Consistent with this idea, normal subjects typically make faster decisions
when a target word is immediately preceded by a prime word that is strongly related in terms of
meaning (Wentura, 2007). This semantic priming process, however, seems to be disrupted in
and colleagues (1988), semantic priming effects were shown to be significantly smaller in TD
patients than in healthy control subjects. Subsequent priming studies using strongly-relate word
ERP Evidence of abnormal 4
pairs have corroborated these findings, supporting the notion that certain types of schizophrenia
Interestingly, a completely different effect has been found for word pairs that are weakly
related in terms of meaning. Rather than showing a lack of a priming effect, TD patients have
actually been found to show a stronger than normal priming effect (Wentura, 2007). This
word pairs has been interpreted by many to suggest that abnormalities in semantic processing
may involve deficient inhibition mechanisms that result in diffuse, unfocused and uncontrolled
semantic activation. Many have even speculated that this may be an etiological factor in the
Further support for this inhibition dysfunction model of thought disorder comes from
studies involving sentence reading. Using a lexical decision task after the auditory presentation
of a sentence, Titone (2000) found that schizophrenic patients failed to properly inhibit the
dominant meanings of certain critical words when immediate sentence context moderately
favored their subordinate meaning. For example, after hearing a sentence about an animal "pen"
(the subordinate meaning of pen for someone who does not live on a farm), schizophrenia
patients showed lexical decision priming effects to pictures of both animal enclosures and
objects related to the dominant meaning of "pen" (e.g. "paper" or "pencil"). Normal subjects, in
contrast, properly inhibited the dominant meaning of pen and only showed a priming effect to
animal enclosures. These results were interpreted to suggest that inhibitory deficits may lead to
the failure of proper context integration in schizophrenics. Further evidence of this came from
Kuperberg and colleagues (2006), who showed that schizophrenic subjects were relatively
insensitive to verbs that violated the context of a sentence when those verbs were semantically
ERP Evidence of abnormal 5
associated with any of the preceding words. Healthy control subjects, in contrast, were sensitive
to all verb violations. This lends strong support to the idea that schizophrenia patients may not be
Additional evidence for the semantic dysfunction model of schizophrenia comes from
occurs around 400ms after the onset of a target word (Kostova 2005). In cognitive neuroscience
literature the amplitude of the N400 component has been established as a fairly reliable measure
words typically produce a larger N400 wave than semantically primed words (Kutas & Hillyard,
1980). The size of the N400 attenuation response to primed words, then, is thought to provide a
decision reaction times. The main advantage of using this measure of priming over lexical
decision tasks is that it allows researchers to capture rapid on-line processing of information at
any point in a discourse without interruption or decay of effect due to delay in measurement
(Ditman, 2007).
Using this N400 paradigm as a measure of semantic activation, Grillon (1991) found a
reduced priming effect in a subgroup of schizophrenics during a word pair priming task. This
lack of N400 effect is analogous to lexical decision measures of strongly related word pair
priming, and has been replicated many times. Like the lexical decision findings, the N400 effect
has also been linked to the severity of positive thought disorder symptoms (Kostova, 2005).
Some studies have also found a stronger than normal N400 effect in response to weakly-related
words (Kreher, 2007, as cited in Ditman, 2007), although others have only found changes in
ERP Evidence of abnormal 6
latency measures (Kiang, 2008). Further study on this issue may be required to clarify this
relationship. If the effect is indeed stronger than normal as Kreher suggests, this would be in line
with behavioral findings of hyperactivation of weakly related concepts, and thus lend further
Other studies have used the N400 paradigm to examine the on-line dynamics of semantic
activation during whole-sentence discourse. These studies have yielded several interesting
results. First, Adams (1993) found that schizophrenic patients showed significantly smaller N400
sentences. This provides general support for the idea that schizophrenia is associated with a
deficiency in the context integration. More interestingly, Sitnikova (2002) found N400 evidence
of failure to override the dominant meaning of a homonym in a sentence where context suggests
that the subordinate meaning is more appropriate. All participants in this study were given a two-
clause sentences with the first clause ending in a homograph (word with multiple meanings). The
second clause of the sentence always started with a target word that was semantically related to
the dominant meaning of the homograph and were either congruent or incongruent with prior
sentence context. The average evoked N400 component was then analyzed for each group and
target word, and it was found to discriminate between congruent and incongruent target words in
the control group but not schizophrenic group. Consistent with behavioral findings described
earlier, this suggests that abnormal sentence processing in schizophrenia may be related to a
These word-pair and single-sentence studies have provided valuable insights into the
local mechanisms of semantic and contextual processing in thought disorder patients. A fuller
and more fruitful understanding of thought disorder, however, can only be achieved if these basic
ERP Evidence of abnormal 7
problems are found to be related to the more global, controlled level of everyday discourse where
psychological intervention is actually possible. With this in mind, Ditman (2007) conduced an
ERP investigation into the global build up meaning in schizophrenia patients. Specifically, he
examined how the N400 is modulated while schizophrenics integrate critical words into
preceding discourse context. To do this he used a 3-sentence discourse scenario design in which
all sentences were internally coherent but the last sentence varied in terms of its causal
relatedness to the preceding sentences. In the control group, the amplitude of the N400 response
to critical words in the final sentence decreased when the sentences were more causally related.
In subjects with high severity of thought disorder symptoms, however, this effect was
significantly reduced. Based on these results it was concluded that TD patients have difficulties
integrating both context cues and semantic information across sentences to build up global
discourse coherence.
introduced by St. George (1994) that has been shown to be sensitive to global semantic
expectancy in whole paragraphs. This paradigm capitalizes on the unique strengths of N400
during extended discourse. Essentially, it involves recording ERP responses to specially designed
paragraphs that are presented one word at a time. These paragraphs, which were taken from
several well-known studies on the effects of context on comprehension, are perfectly coherent in
terms of grammar and structure but require the presence of a context-setting title to be coherent
in terms of meaning. Without context, they seem to be just a series of vague, disconnected
propositions. In normal subjects it was shown that the average N400 peak values for every word
in the untitled paragraphs, across all electrodes, were significantly greater than in the titled
ERP Evidence of abnormal 8
paragraphs (St. George, 1994). According to the authors, this reflects the modulation of semantic
processing and integration by contextual cues. Because this process may be dysfunctional in TD
patients, I hypothesize that schizophrenic patients will show a less pronounced N400 effect for
Method
Participants
For this study I propose to recruit 20 (10 male) schizophrenia patients with clinically diagnosed
positive thought disorder from the inpatient psychiatric ward at a local hospital. All will receive
an appropriate monetary compensation for their time. Patients with neurological disorders or
EEG abnormalities as detected in the routine examination will be excluded. No change will be
made to patient's current course of medication, and all clinical patients will complete a Positive
and Negative Syndrome Scale at the onset of the study (Kay, Fiszbein, & Opler, 1987, as Cited in
Wagner, 2006). Additionally, 20 (10 male) healthy controls will be recruited and matched for age
and level of education. All participants must be native English speakers and have normal or
Apparatus
As in the St. George study (1994), five Ag/AgCl electrodes will be placed on the scalps of
participants. Three electrodes will be located along the midline at Fz, Cz and Pz according to the
international 10-20 system (Harner & Sannit, 1974, as cited in St. George, 1994). One of the
electrodes will be placed approximately over Wernike's area in the left hemisphere (lateral to the
vertex by 30% of interaural distance and posterior by 12.5% of the nasion-inion distance), and
the other will be placed symmetrically on the right hemisphere as a comparison. A linked
ERP Evidence of abnormal 9
mastoid reference will be used and the ground site will be placed on the forehead. Additionally, a
vertical electro-oculogram (EOG) electrode will be used to detect and discard trials with ocular
artifacts.
controlled laboratory room. All words will be presented on 36-point red font against a solid gray
centimeters from the participants' eyes (as ensured by a chin-rest). ERPs will be recorded for
every word in each paragraph starting 50ms before each word is presented. All fluorescent lights
will be turned off to reduce 60hz noise, and all electrode impedances will be kept below 5Ω.
The same four paragraphs that were used in St. George's (1994) study will be used in the
present study. As described earlier, these paragraphs were specially designed so that each
sentence is locally coherent, but a context-setting title is required to establish global coherence.
An example of this is the paragraph entitled Making and Flying a Kite. The first few sentences of
the body of the paragraph are as follows: "A newspaper is better than a magazine. A seashore is a
better place than the street. At first it is better to run than to walk. You may have to try several
times….". Clearly the propositions in this paragraph seem meaningless and unconnected without
context. Other paragraph titles include The Procedure for Washing Clothes, Space Trip To the
Procedure
As in the St. George (1994) study, each participant will be run individually. After filling
out consent forms, the procedure will be explained in detail so there is no confusion.
Additionally, to ensure attention is being paid to the whole paragraph and not the individual
ERP Evidence of abnormal 10
pieces, participants will be told that there will be a recall task regarding the meaning of the
ensure they understand the task. The four stimuli paragraphs will be then presented to
counterbalanced such that all subjects will see the same four paragraphs in one of four different
orders. Half of the participants will be randomly assigned to receive the titles of the paragraphs
before they are presented, and the other half will not be provided with titles. After all four
Data Analysis
Ocular artifacts will be corrected for before the data is analyzed using Gratton, Coles, and
Donchin's (1983) eye movement correction paradigm (as cited in St. George, 1994). Also, a
14HZ low-pass filter will be applied to the data and the resulting ERP waveforms will be
averaged across all words in all paragraphs for each participant across all electrodes. N400
waveforms will be quantified by taking the mean amplitude within the 300ms to 500ms time
window. These raw N400 mean values will then be entered into a 2 (clinical status: TD and no
TD) X 2 (title manipulation: title and no title) between-subjects analysis of variance for statistical
analysis.
Results
First, analysis of variance should show a main effect for title manipulation such that participants
who were presented with titled paragraphs have smaller N400 waves than those who were
presented with untitled paragraphs F(1,39) = X, p < .05. There should also be a main effect of
ERP Evidence of abnormal 11
clinical status such that TD patients elicit a greater N400 wave overall than non TD patients,
F(1,39) = X, P < .05. Further analysis should reveal an interaction between TD and title such that
the effect of title is significantly weaker in TD patients (See Figure 1). Moreover, there should be
no N400 difference between TD and non TD groups in the non-titled condition because there is
no context to process differently. If this pattern is found, it would lend support to the idea that
healthy individuals. An alternative to these results may be that TD and NTD subjects react the
same way to the title manipulation. If so, this would suggest that the modulation of semantic
Discussion
In this study changes in N400 waves were measured during the processing of whole
paragraphs to test the hypothesis that, at a global coherence level (linking multiple propositions
patients with thought disorder than in healthy controls. This paradigm was proposed because it is
able to capture neural correlates of real-time on-line semantic processing that would be
impossible to measure with behavioral methods. If the results support my hypothesis, it would be
First, an important confound would exist in the form of anti-psychotic medication. Since it would
be unethical to instruct schizophrenic patients cease their regular medication for this study, we
can not be sure whether changes in N400 patters are due to schizophrenia itself or due to the
ERP Evidence of abnormal 12
effects of psychoactive medication. Also, the EEG apparatus proposed in this study is a simple
one with only 5 electrodes and no differentiation between electrodes in the final analysis. Effects
of context manipulations may be stronger if a more complex electrode montage is used and the
final statistical analysis employs weighted principle components rather than a grand average.
Future studies may also benefit form a more graduated categorization of TD and TD symptoms.
If a lack of N400 effect could be shown to be correlated with severity of TD symptoms this
Despite these few weaknesses, this study would be an important step in exploring the
neurophysiological correlates of global semantic processing and context use in positive thought
disorder. Better knowledge of these language comprehension processes may eventually lead to
development of clinical applications that capitalize on new behavioral approaches to better the
schizophrenia markers like abnormal modulation of the N400 wave may eventually provide an
wise to investigate these and other potentially useful applied clinical applications.
ERP Evidence of abnormal 13
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Figure Caption
Figure 1. Hypothetical results showing an interaction between thought disorder (TD and NTD)
and paragraph condition (titled and untitled) on the mean of evoked N400 waves.
Figure 1
TD
N400 Mean
NTD