Abnormal inhibitory processes in semantic networks in

schizophrenia.

M. Niznikiewicz (1,2) , M. Singh Mittal (1, 2) , PG Nestor (1,2,3), RW. McCarley (1, 2) .

1. Boston VA Medical Center, 2. Harvard Medical School.

3. University of Massachusetts, Boston.

The research presented in this paper has been supported by RO1MH 63360 (MAN), R03 MH 078036 (MAN) and RO1 MH 48799 (RWM)

Abstract.

Abnormal language in schizophrenia has been regarded as a hallmark of this disorder.

Language abnormalities include loose and unusual associations, tangentiality, and

inability to maintain a topic. Recent theories of language dysfunction have invoked

working memory abnormalities, as well as abnormal processes within semantic memory

in schizophrenia. Two views, often construed as opposing, have been offered to

account for language peculiarities in schizophrenia: one holds that initial processes of

activation are abnormal while the other holds that late processes of context utilization

might be disturbed. We suggest that these views may be complementary rather than

mutually exclusive. Given the relative paucity of data on the early processes within

semantic networks, we present new evidence using ERP short SOA paradigm that these

processes are abnormal in schizophrenia. Furthermore, reduced N400 in the unrelated

condition found in this study suggests that the abnormality was related to inefficient early

inhibitory processes.

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Introduction.

Abnormal language function in schizophrenia has long been regarded as a

hallmark of this disorder, dating back to the writings of Kraepelin (1919) and Bleuler

(1911/50). Language dysfunction in schizophrenia is believed to be an important

component of schizophrenia psychopathology and a contributing factor to formal thought

disorder (e.g., Mitchell & Crow, 2005). The features commonly found in schizophrenia

language include poverty of speech, derailment, loose associations, loss of goal,

perseveration, distractibility, tangentiality, and an inability to adhere to a topic (e.g.,

Docherty et al., 2004). Existing research has highlighted attentional and working memory

impairments as factors contributing to language abnormalities in schizophrenia (e.g.,

Cohen et al., 1999), as well as operations within semantic memory and their interactions

with working memory. A number of studies, including those from our laboratory, support

this line of theorizing (e.g., Niznikiewicz et al., 2004a, Niznikiewicz et al., 2004b,

Salisbury et al., 2002; Mathalon et al., 2002).

The studies that explored semantic memory dysfunction in schizophrenia

focused almost exclusively on processes that operate within semantic memory.

Relatively recent memory models assume that memory is organized as a network

(irrespective of how such a network might be instantiated in the brain) and that concepts

close in meaning are activated proportionally to semantic and temporal distance from a

word that has been activated (Neely, 1991; Hutchison, 2003). According to this model, if

a person thinks/speaks/hears a word ‘dog’, concepts such as ‘cat’, ‘bone’ or ‘leash’ will

also be activated proportionally to how close in meaning they are to the word ‘dog’.

However, words such as ‘sky’ and ‘leaf’ will not be activated as they do not share any

semantic features with the word ‘dog’. Thus, both activation of related items and

inhibition of the unrelated items are taking place in the healthy functioning semantic

system in the initial stages of word processing. It is often conceptualized that the initial

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stages of a word analysis are dominated by processes of activation that last about 400-

500 ms after the stimulus onset and that processes of inhibition are getting more

dominant with the temporal distance from the onset of the stimulus (Neely, 1991). It is

believed that after the first 400-500 ms processes of fitting the word into the context

either via post-lexical matching strategy or via expectancy generation (Neely, 1991)

come into play and that these are primarily inhibitory processes that narrow a set of word

candidates that would fit a given word context. In behavioral research, one of the most

common paradigms to probe processes in semantic memory is a word pair priming

paradigm where the task is either lexical decision (deciding if a target is a word or non-

word) or pronunciation (where the target word is read aloud). It is believed that when

two words are presented sequentially, the first word activates its semantic neighbors

such that if the next presented word is related to its ‘prime’ it will take less time to either

make a decision about its lexical status or to pronounce it and this saving in time is

called priming (e.g., Hutchison, 2003). It is further believed that designs using a short

temporal distance between prime and target (stimulus onset asynchrony or SOA), i.e.,

SOA under 400-500 ms, probe primarily early processes of activation and inhibition,

while designs using longer SOA over 500 ms probe processes of context use and

contextually driven inhibition (e.g., Hutchison, 2003).

Most of the research on semantic dysfunction in schizophrenia has been

dominated by two hypotheses, often described as opposing: 1) over-activation in

semantic networks 2) dysfunction in late, controlled processes. The hypothesis of over-

activation in semantic networks holds that in schizophrenia initial activation propagates

too far and leaves a person with too many word choices thus producing characteristic

schizophrenic utterances. Thus, in behavioral priming studies using short SOAs, faster

RTs to related words in patients relative to normal control subjects are treated as

evidence for over-activation in semantic networks (e.g, Frith 1979; Spitzer et al., 1993;

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Manschreck et al., 1988; Maher et al., 1996; Henik et al., 1995; Kwapil et al., 1990;

Moritz et al., 2003; Maher et al., 2005; Peled et al., 2005; Quelen et al., 2005; Gouzoulis-

Mayfrank et al., 2005). In schizotypal personality disorder (SPD), increased automatic

priming was found in individuals with high schizotypy scores (Moritz et al., 1999;

Pizzagalli et al., 2001). Schizotypal individuals also show reduced negative priming,

which has been interpreted as evidence of reduced inhibition, (Beech and Claridge,

1987; Beech et al., 1989; Claridge et al., 1992; Peters et al., 1994; Williams, 1995;

Ferraro and Okerlund, 1996; Moritz and Mass, 1997).

The hypothesis of dysfunction in late processes of context use suggests that the

inability to inhibit word choices by using context to guide the word selection process

efficiently produces disturbances in language in schizophrenia (e.g., Vinogradov et al.,

1992; Chapin et al., 1989; Blum and Freides, 1995; Passerieux et al., 1997; Barch et al.,

1996; Cohen et al., 1999; Titone et al., 2000). In SPD, neuropsychological evidence of

subtle, but significant, impairment in working memory was found in high schizotypy

individuals (Tallent and Gooding, 1999; Gooding et al., 1999; Lenzenweger and Kortife,

1994; Park and McTigue, 1997). Thus, remarkably, both these hypotheses predict

similar outcomes, i.e., features of language characteristic for schizophrenia sufferers

such as loose associations, bizarre associations and inability to adhere to a topic, but

they propose very different mechanisms to account for language abnormalities.

We believe that these hypotheses are not mutually exclusive and that both types

of impairment operate in schizophrenia. In fact, the synergistic impact of these two

impairment types might result in a particularly dysfunctional semantic system where both

the initial processes of activation and inhibition, and later processes of context use and

inhibition are abnormal. Some of the difficulties in constructing a detailed description of

just how the processes within semantic system break down stem from the fact that many

studies rely on behavioral data such as reaction times and errors rates. These, by

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definition, reflect all processes that occurred before a button press, including response

slowing which is related to the disease process but not to semantic dysfunction.

The exception are event related potential (ERP) studies that provide indices of

cognitive processes as they happen in real time and thus can better assess both

condition and group membership driven differences. ERP studies have significantly

enriched our knowledge of cognitive processes in the brain, including our understanding

of language processes. The ERP component most widely (but not exclusively) used to

probe semantic processes is the N400, a negative, or negative going, component that

has been recorded in several different paradigms and that is believed to reflect an ease

of connecting two semantic concepts (e.g., Holcomb and Neville, 1990). The N400 has

been used successfully as an index of priming, i.e., of the processes that operate within

semantic memory. The N400 is less negative to items that are semantically related to

preceding context and more negative to unrelated items. The N400 has been recorded

at both long and short SOAs (e.g., Hill et al., 2002; Hill and Weisbrod, 2005), with

masked and unmasked primes (e.g., Misra and Holcomb, 2003; Kiefer, 2002), for

ambiguous words (Chwilla and Kolk, 2003), across visual and auditory presentations

(Holcomb et al., 2005) and even for nonwords (Deacon et al., 2004) suggesting that

N400 is also sensitive to lexical processes. In schizophrenia research, the N400 has

been used as a useful tool in examining language dysfunction. Given its sensitivity to

the ease of forming semantic connections between items, one can formulate specific

predictions regarding semantic processes in schizophrenia. If it is easier for

schizophrenia patients to make a semantic connection between items, the N400

amplitude should be reduced in the patient group relative to normal comparison

subjects. Conversely, if it is more difficult to make such a connection, N400 amplitude

should be more negative in the patient group. One should note that these somewhat

mechanistic predictions are independent of theoretically motivated hypotheses. Thus,

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given theoretical considerations outlined above, one can articulate the following

predictions: at short SOAs, reduced, or less negative N400 in the patient group suggests

1) too strong or too broad initial activation within the semantic network 2) ineffective

inhibition of unrelated items; and conversely, larger, or more negative N400 would

suggest 1) too narrow range of activation of related items 2) too strong inhibition that

might affect both related and unrelated items. At long SOAs, reduced N400 would

suggest overly efficient processes of context integration and contextually guided

inhibition, while more negative N400 would suggest that these processes are not

sufficiently efficient.

To date, most ERP studies exploring language processes in schizophrenia have

used either long SOA or sentence paradigms that tap into the processes of context use

of contextually guided inhibition. These studies provide rather convincing evidence that

indeed, late processes of context use are abnormal (e.g., Adams et al., 1993; Nestor et

al., 1997; Niznikiewicz et al., 1997; Koyama et al., 1991; Grillon et al., 1991; Hokama et

al., 2003; Salisbury et al., 2002; Sitnikova et al., 2002; Ruchsow et al., 2003; Iakimova et

al., 2005; Kostova et al., 2003; Kiang et al., 2008). Additional variables that may

influence the results are the length of illness (Maher et al., 1996) and the degree of

thought disorder (Aloia et al., 1998; Gouzoulis-Mayfrank et al., 2003). The association

between N400 amplitude and severity of thought disorder was also reported (Kostova et

al., 2005). The ERP studies suggest that integrative processes at long SOAs are intact

in SPD (Niznikiewicz et al., 2002) but they become compromised with increased memory

load (Niznikiewicz et al., 2004b). Also, Kiang and Kutas (2005), in a long SOA semantic

category priming study in a college population, found reduced N400 to category

exemplars and increased N400 amplitude to exemplars to be correlated with the

Schizotypal Personality Questionnaire (SPQ), an index of schizotypy, concluding that

decreased use of context characterized schizophrenia spectrum individuals. No

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published studies of context processing in patients with first-episode schizophrenia

(FES) exist.

There are many fewer ERP studies exploring initial processes within semantic

networks. For example, Condray et al., (2003) reported reduced N400 effect in the

patient group and a group difference between medicated patients and normal controls.

Mathalon et al (2002) found reduced N400 amplitude to words from the same category,

and Kreher el al. (2007) found increased priming effect to indirectly related primes (e.g.,

lion-stripes) in thought disordered patients but not in non-thought disordered individuals

or normal comparison subjects. Kiang et al., (2008), who also used an indirect priming

paradigm, found increased N400 amplitude to both directly and indirectly related primes

at both the short and long SOAs. No published studies of priming at short SOAs have

been reported in FES. The only published ERP study of DSM-IV defined SPD

individuals that used a short SOA word-pair paradigm reported group differences in the

related but not in the unrelated condition (Niznikiewicz et al., 2002).

In the face of a limited ERP evidence of abnormal early processes within

semantic networks, we sought to gather evidence on electrophysiological indices of early

priming processes using a short SOA paradigm in chronic schizophrenia patients and

normal comparison individuals. Our hypothesis was that if such processes are

abnormal, N400 amplitude will be reduced in the patient group. More specifically, we

hypothesized that if dysfunction in the early processes is primarily characterized by too

strong or too broad activation within semantic networks, the group difference will be

observed in the related condition. If the early dysfunction is primarily characterized by

inefficient inhibition of items as a function of semantic distance, then group differences

will be observed in the unrelated condition. If both initial activation gradient and inhibition

are abnormal, then group differences will be observed in both related and unrelated

conditions.

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Methods:

Subjects: Twenty chronic male schizophrenia patients and 20 normal male

comparison subjects have been tested in the short SOA word pair priming, lexical

decision paradigm. All subjects were right handed based on Edinburgh handedness

scale with English as their first language, and had normal or corrected vision. The

additional exclusion criteria for both groups were: illegal drug or alcohol dependence

within the last 5 years and drug abuse within the last year; neurological disease, and

electroconvulsive therapy (ECT). In addition, normal comparison subjects could not

carry a DSM-IV- AXIS I diagnosis in themselves or first degree relatives. The diagnosis

of schizophrenia was based on chart reviews and a SCID interview. Normal comparison

subjects were screened for participation with non-patient SCID interview.

One schizophrenia subject and 3 normal comparison subjects have been

excluded due to the low number of correct responses (over 50% errors). The statistical

results are reported for the subjects that have been retained for the analyses. The two

groups did not differ in age, or parental SES, but given the burden of the disease, they

differed in SES (p < 0.003), education (p <0.02) and general IQ (p <0.02) (see Table 1).

All patients were medicated (see Table 1 for antipsychotic CPZ medication levels); 17

patients were on atypical antipsychotic drugs, 1 was on a typical neuroleptic and 1 was

both on typical and atypical antipsychotic medication. Fifteen patients carried a

diagnosis of paranoid schizophrenia, 2 were schizoaffective and 2 were undifferentiated.

Stimuli: One hundred sixty stimuli were presented in a word pair priming paradigm with

40 word-pairs presented in the related condition (25%), 40 presented in unrelated

condition (25%), 40 in a nonword condition where the target word was not a real word

but followed English phonetic rules (25%), and 40 words presented in a non-word

condition where target words were random letter strings (25%). All primes were real

words. The task was lexical decision and the use of left and right hands to indicate

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whether the target word was a word or non-word was counterbalanced across subjects.

The target words were all nouns and adjectives and were one or two syllable long (1.2

syllables for related words and 1.3 syllables for unrelated words, no significant difference

between the two word types). Using the Kucera norms, the average frequency of targets

was 93.03 for related condition and 58.2 for unrelated condition (not significantly

different). Concreteness for related words was 545.3 and for unrelated targets 534.7

(not significantly different). The words were placed in the middle of a computer screen

one word at a time, subtended 4.5 visual angle, with the subjects seated 70 cm from the

screen, white on black background. The prime stayed on the screen for 150 ms, and the

interval between the offset of the prime to the onset of the target (ISI) was 50 ms. The

target stayed on the screen until the response was made.

ERP Procedure:

EEG was recorded with 64 active silver-silver chloride electrodes, using a

Neuroscience electrode cap, with the left earlobe used as a reference for all sites, and

referenced off-line to average ears. EEG was recorded with Neuroscan SYNAMP

amplifiers and software with a bandpass of DC to 100 Hz, at the sampling rate of 256

points. Vertical and horizontal eye movements were monitored with additional

electrodes placed over the right and left canthi and over the left supra- and infra-orbital

areas. EEG was continuously recorded and digitized for storage. The continuous EEG

recording was epoched off line, with 100 ms baseline before the onset of the prime and

for 1000 ms after the onset of the target. The EEG activity to the prime was included in

the baseline to minimize the influence of the prime on the EEG recorded to the target.

Single trials were corrected for eye movements using the Gratton and Coles algorithm,

and single trials exceeding +/- 75 microvolts at any of the electrode sites were excluded

from the analysis. Individual averages were constructed to related and unrelated word

targets. On average, there were 34.4 (range: 18-40; SD: 7.3) for normal comparison and

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34.8 (range: 19-40; SD: 5.8) for schizophrenia subjects single trials included in each

individual average in the related condition and 34 (range: 19-40; SD: 7.3) single trials for

normal comparison and 33.9 (range:18-40; SD: 6.6) for schizophrenia patients included

in individual waveforms in the unrelated condition (no significant group differences).

The single averages were filtered off line with the high pass filter at 16 Hz. The N400

amplitude was measured both as the most negative data point and as the mean area

within the 420-530 ms latency window in normal comparison subjects and within the

l490-600 ms latency window in schizophrenia patients, post-stimulus; and the N400

latency was measured within the same interval. The latency windows were selected

based on inspection of individual averages and grand averages for each condition in

each subjects group with a goal of including 95% of individual N400 peaks within the

selected measuring windows. In addition, care was taken for the remaining 5% of N400

peaks not to fall more than 10 ms outside the chosen measuring windows.

Statistical Analyses:

Behavioral analyses: The differences in the demographics were assessed with

one-way ANOVA. The priming effects were assessed with an ANOVA with RTs to

correctly identified related and unrelated items as within subjects factors and group as a

between subject factor. The error rates and the number of correct responses were

assessed with independent t-tests and with one sample paired t-tests.

N400 amplitude: The N400 amplitude has been evaluated with an ANOVA with

condition (related and unrelated) and electrode (Fz, Cz, Pz, Oz) as within-subjects

variables and group (NC and SZ) as a between-subjects variable. We have chosen

midline electrodes only as these were the sites where both the condition and group

separation was maximal and also because we did not make predictions regarding

laterality of the effects (none were observed in the inspection of the grand averages

across conditions and groups. The overall ANOVA was followed by within-subjects

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ANOVAs with the same number of electrodes (4) and two conditions, as well as two

ANOVAs comparing groups in the related and unrelated conditions using the same

electrode chain (4 electrodes).

N400 latency. Given a lack of latency differences across sites, N400 latency was

assessed at Pz using an ANOVA model.

Exploratory Correlational analyses. In exploratory analyses, we analyzed the

relationship between N400 amplitude and latency and clinical symptoms using Pearson

product correlations (two-tailed) in order to assess the possible commonalities between

processes involved in N400 generation and those related to schizophrenia

symptomatology. We correlated N400 amplitude at midline (Fz, Cz, and Pz) in related

and unrelated conditions with Positive and Negative Syndrome Scale (PANNS; Kay,

Opler, Fiszbein, 1986) SANS (Andreasen, 1981) and SAPS (Andreasen, 1984) scores

(both total scores and subscales of these tests). We also assessed the relationship

between antipsychotic medication levels (CPZ equivalents), age of illness onset and

illness duration and dependent variables (N400 amplitude and latency). Bonferroni

correction was used to adjust for multiple correlations.

Results:

Behavioral data: Behavioral priming was observed in the normal comparison

group (p <.01); (560.15 (35.9) ms for related and 702.07 (28.3) ms for unrelated targets)

but not in the schizophrenia group; (790.2 (33.9) ms for related and 787.5 (28.3) ms for

unrelated targets). In the ANOVA analysis, there was a main effect of condition (F (1,34) =

6.94 p < 0.01), the group by condition interaction (F (1,34) = 7.49) and a main effect of

group (F (1,34) = 18.15 p < 0001). Longer RTs were observed in the unrelated (744.76

(20.58) ms than related condition (675.17 (24.7) ms and in the patient (788.84 (25.4) ms

relative to comparison subject group (631.1 (26.8) ms. The error rates did not differ

significantly between groups for related condition (.64 for NC and 1.78 for SZ) or for

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unrelated condition (1.26 for NC and 2.31 for SZ). In within-group comparisons, more

errors were made in the unrelated condition by the normal controls (p < 0.016) and, at a

trend level, by the schizophrenia patients (p < 0.098).

N400 amplitude:

In the overall ANOVA, there was a main effect of condition (F (1, 34) = 7.85. p <

0.008) and a significant interaction between group and condition (F (1, 34) = 4.28 p <

0.046) but not the main group effect (F (1,34) = 2.21 p < 0.15). Less negative N400

amplitude was observed in the schizophrenia group. When related and unrelated

conditions were examined separately, the two groups differed in the unrelated condition

(F (1, 36) = 5.12; p < 0.03) with a less negative N400 amplitude found in the schizophrenia

group, but they did not differ significantly in the related condition (F (1,37) = 0.35 p < 0.56)

(see Figure 2 and Tables 2 and 3) When the effect of relatedness (priming) was

analyzed separately within each group, the normal comparison subjects showed a

priming effect (significantly reduced N400 amplitude to related targets) (F(1,16) = 13.552 p

< 0.002) while the schizophrenia subjects did not (F (1, 18) = 0.25 p < 0.626) (see Figure

1 and Tables 2 and 3).

N400 latency.

In the overall ANOVA, there was a main effect of group at Pz (F(1, 34) = 46.44 p <

0.0001) but there was not a main effect of condition or an interaction between condition

and group. Longer N400 latency was found in the patient group relative to the

comparison subjects. In the related condition, in the comparison subjects, the N400

latency peaked at 466.82 (38.35) ms and in the patient group at 533.68 (44.14) ms

latency. In the unrelated condition, in the comparison subjects, the N400 latency peaked

at 465.65 (42.35) ms and in the patient group, the N400 peaked at 536.74 (39.22) ms.

Exploratory correlational analyses with clinical measures. In the patient group,

N400 amplitude at Cz in the related condition was significantly correlated with PANSS

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score (r =0.48, p < .021), total SANS (r = 0.44, p< .04); alogia (r = 62 p < .002) and

attention (r = 46 p < .03); in the unrelated condition Cz was correlated with avolition

(r=.51 p < .02). For all these correlations, more positive N400 (i.e., more impaired) was

associated with more impairment on a clinical scale. No significant correlations were

found in the patient group for the N400 latency. No significant correlations were found

with CPZ medication equivalents, age of onset or years of illness duration. None of the

significant correlations survived Bonferroni correction.

Discussion.

In this study we examined semantic processes using ERP indices of priming in a

short SOA (200 ms) paradigm and a relatively low number of related primes (25%). This

design is believed to engage primarily early automatic semantic processes. Given the

functional role of the N400, it has been hypothesized that the N400 amplitude will be

reduced in the schizophrenia group. This effect has been observed only in the unrelated

condition suggesting that in this study the processes that were statistically different

between the two groups were processes of inhibition and not primarily the processes of

activation (in spite of the visual impression of the N400 reduction in the grand averages

to the related targets). This is one of the first studies to demonstrate an abnormality in

the early semantic processes using a direct priming paradigm and documenting

statistical differences both in within and between group comparisons: a reliable priming

effect was found in the normal comparison group while no priming effect was found in

the schizophrenia group in addition to the already mentioned group effect in the

unrelated condition. Importantly, the N400 amplitude was found significantly reduced in

the patient group in the unrelated condition which would suggest abnormal processes of

inhibition and not the processes of activation. These results are in line with Lecardeur et

al (2007) study who, using behavioral priming paradigm at both short (250 ms) and

relatively long (500 ms) SOAs, sought to distinguish between facilitation and inhibition as

14

contributing factors to hyper-priming observed in several earlier studies. Unlike in the

current study, neutral, in addition to related and unrelated, items were used allowing for

the computation of facilitation and inhibition effects. At short SOA (identical to the one

used in the current study) no significant inhibition effect was found in normal comparison

subjects while a significant inhibition effect was found in the schizophrenia group.

Based on the behavioral measures, the schizophrenia patients did not show

priming (paralleling the N400 results) while the normal comparison subjects did. In a

fairly recent paper, Mitzenberg and colleagues (2002) reviewed results of existing

behavioral priming studies in schizophrenia. There was a consistent finding of hypo-

priming in schizophrenia at long SOAs while results from short SOA designs were more

variable with some studies reporting hyper-priming, others reporting normal priming or a

lack of priming effects in schizophrenia individuals. The authors suggested that the lack

of priming effects, like the one observed in the current study, may be due to abnormal,

post-lexical, controlled mechanisms. We think that this explanation is possible as the

distinction between automatic and controlled processes is not categorical but rather is a

matter of the dominance of one type of processes over others. However, we would like

to point out that entertaining a possibility of the influence of controlled processes on RT

data does not mean that we believe that the same mechanisms contributed to the lack of

N400 priming effects. In fact, the N400 and the behavioral data provide two different

temporal windows of analysis of cognitive mechanisms underlying priming with the N400

capturing temporally earlier events by about 200 ms.

Finally, the characteristics of the schizophrenia sample should be considered.

The subjects in this study were somewhat older than those used in the previous studies.

Also, fifteen out of twenty schizophrenia subjects were paranoid type suggesting the

absence of disorganized thinking at the time of clinical evaluation. These subject

features may have additionally contributed to the results observed in this study.

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Overall, these results complement in interesting ways available evidence on early

semantic processes in schizophrenia. First, this study used the shortest SOA of all

reported ERP studies, which by itself may be an important variable in probing processes

within semantic networks. Also, the study used a relatively low ratio of related primes

(25%) further assuring that captured processes will be early automatic processes within

semantic networks (Neely, 1991). The results of the study are closest to the results of

Condray et al. (2003) who reported group differences between normal comparison and

chronic medicated schizophrenia patients at the short SOA (350 ms) to directly related

primes. The results are somewhat different from Kiang et al (2008) who used directly

and indirectly related primes at 300 and 750 ms SOA and found group differences to

both directly and indirectly related targets but not to unrelated targets irrespective of the

SOA. Interestingly, the authors concluded that the affected processes were the

processes of context use at both SOA. While we do not propose context involvement,

we do propose ineffective mechanisms of inhibition related to suppressing unrelated

items. In a way, these two proposals are related, as the use of context does imply the

use of inhibition.

The results are different from Kreher et al (2007) study, who reported

comparable priming effects between patients (both thought and non-thought disordered)

and normal control subjects at 350 SOA but found group effects for the indirectly related

primes in thought disordered patients. Importantly, this effect was significant only for

300-400 ms latency window but not for the 400-500 ms latency window, underscoring

the importance of temporal factors in the comprehensive analysis of semantic

abnormalities in schizophrenia. Finally, the results are also different from Mathalon et al

(2002) who reported reduced N400 amplitude to related targets at the short SOA of 325

ms in chronic schizophrenia. Unrelated targets were not used in this experiment so it is

impossible to predict what results would be obtained.

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Overall, the ERP studies reviewed here as well as the new data presented in the

paper provide important evidence for the disturbances in the processes within semantic

networks. Moreover, this evidence relates directly to abnormal neural processes

uncontaminated by complications of behavioral responses. What emerges is strong

evidence for abnormal processes of context use in guiding a well-formed train of thought

that emanates from studies using long SOA and sentence paradigms. A growing

number of studies focusing experimentally on early semantic processes suggest that

these processes are also abnormal. Both the results of the current study, as well as the

results of Kiang at al. suggest that the early abnormality consists of ineffective inhibitory

processes. There is also indication that processes of activation propagation throughout

the network are abnormally fast (Kreher et al., 2007). It is worth noting that apparent

differences between the studies are most likely related to exact methodologies

employed. While this situation may create some interpretative difficulties, it has an

important function of forming a detailed account of the type of processes that are

affected by schizophrenia. It moves the field away from a simple dichotomy between

abnormalities in the early as opposed to late semantic processes and closer to a full

appreciation of the different ways in which the semantic system is broken in

schizophrenia. Overall, it appears that abnormal inhibitory processes at different levels

play a major role in language abnormality in schizophrenia, but that over-activation is

also a factor.

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Figure and table captions:

1. Figure 1: Grand average waveforms to related and unrelated target

words for normal control and schizophrenia subjects –within group

comparisons.

2. Figure 2: Grand average waveforms in 17 normal control and 19

schizophrenia subjects to related and unrelated target words –

between group comparisons.

3. Table 1: Demographic data for normal control and schizophrenia

subjects and clinical data for schizophrenia subjects.

4. Table 2: N400 mean amplitude to related and unrelated word

targets in 17 normal control and 19 schizophrenia subjects.

Table 1: Demographic data for schizophrenia and normal comparison individuals.

SZ NC mean SD mean SD

Age 45.9 9.5 46.4 9.5 NS Educational score*

4.7 (13.7 years)

1.12 5.4 (15.4 years)

.8 .024

Full Scale IQ

94.4 14.5 105.3 15.32 .024

SES* 3.4 1.16 2.26 1.1 .003 PSES* 2.87 1.1 3.26 1.3 NS Illness onset 16 37 - - NA Illness duration

23.41 10.64 - - NA

CPZ 439.3 294.3 - - NA

* Two factor Index of Social Position, Hollingshead, 1957 was used to calculate educational score and (P)SES. For educational score the scale is from 1 to 7 with the lowest educational level scored as 1 (less than 7th grade) and for (P)SES the scale is 1-5 with the lowest level scored as 5.

Table 2: N400 amplitude to related and unrelated word targets

Related word targets NC SZ

Electrode Mean (SD) Mean (SD) Fz -0.535 (3.847) 0.628 (3.354) Cz 1.870 (4.645) 2.634 (4.219) Pz 3.075 (4.374) 3.733 (4.636) Oz 1.588 (3.542) 1.214 (4.230)

Unrelated word targets NC (SD) SZ (SD)

Electrode Mean Mean Fz -2.200 (3.456) 0.688 (3.097) Cz -0.176 (3.791) 2.169 (3.143) Pz 1.523 (3.850) 3.214 (4.255) Oz -1.960 (6.072) 0.815 (3.431)