Neural basis of semantic priming in schizophrenia during a lexical decision task: A magneto-encephalography study

Schizophrenia Research 130 (2011) 114–122

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Neural basis of semantic priming in schizophrenia during a lexical decision task: A magneto-encephalography study Damien Vistoli ⁎, Christine Passerieux, Bérengère Houze, Marie-Christine Hardy-Baylé, Eric Brunet-Gouet EA 4047, Université de Versailles Saint-Quentin, Service de Psychiatrie Adulte, Centre Hospitalier de Versailles, Fondation FondaMental, 177 route de Versailles, 78150 Le Chesnay, France

a r t i c l e

i n f o

Article history: Received 28 May 2010 Received in revised form 19 May 2011 Accepted 22 May 2011 Available online 17 June 2011 Keywords: Semantic priming Schizophrenia MEG N400 Semantic network Minimum norm localization

a b s t r a c t Numerous behavioral and electrophysiological studies have provided evidence of abnormal semantic processing in schizophrenia. However, the neural basis of these deficits is poorly understood. We investigated magnetic cortical responses elicited by a word-pair lexical decision task in 20 patients with schizophrenia and 12 healthy control subjects. The task involved presentation of a prime word (200 ms), followed by a blank (250 ms), and then a target stimulus (1200 ms); the subject had to decide whether the target was a real word or not. During this task, bilateral temporal and left prefrontal activations were observed in both groups. However, in contrast to controls, patients with schizophrenia did not show increased activation in the left temporal and anterior cingulate cortices between 200 and 450 ms in response to semantic incongruity. These results suggested that schizophrenia was associated with a functional disturbance in some semantic regions that gave rise to the N400 component. Moreover, a significant modulation in the right temporal cortex was observed in patients, but not in controls. This suggested the existence of alternative processes in patients because both groups showed similar behavioral priming. Finally, we elucidated some functional abnormalities in the semantic network during prime word processing in patients, indicated by prolonged activation compared to healthy controls. Thus, in addition to context integration impairment, abnormal activations during the prime word provided new evidence of context processing deficits in schizophrenia. © 2011 Elsevier B.V. All rights reserved.

1. Introduction From the first recognition of schizophrenia as a clinical category (Bleuler, 1911/1950; Kraepelin, 1919), language abnormalities were identified as a core component. Language impairments include anything from single word processing to sentence and discourse comprehension (for reviews, see DeLisi, 2001; Covington et al., 2005). Some studies have suggested that language disorders in schizophrenia might partly stem from a context processing deficit (Gray et al., 1991; Hemsley et al., 1993). For example, Cohen and Servan-Schreiber (1992) showed that patients with schizophrenia had difficulties in selective attention and language comprehension tasks that arose from a deficit in “internal representation of context”. Moreover, Cohen et al. (1999) reported a significant association between this type of deficit and disorganization. Consistent with those results, Hardy-Bayle et al. (2003) suggested that a deficit in meaning integration based on contextual information underlies communication disorders in schizophrenia. To investigate putative abnormalities in contextual integration within the domain of language, most authors use semantic priming paradigms. The semantic priming effect, identified in healthy subjects by Meyer and Schvaneveldt (1971), refers to a facilitated processing of

⁎ Corresponding author. Tel.: + 33 1 39 63 90 11; fax: + 33 1 39 63 90 80. E-mail address: [email protected] (D. Vistoli). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.05.021

words preceded by semantically related words by comparison with those preceded by semantically unrelated words. Several paradigms test this effect, including pronunciation or semantic judgment tasks, but the most common is the lexical decision task (LDT). The LDT presents participants with two letter-strings stimuli (i.e., two sequences of letters) respectively referred to as “primes” and “targets”. These two letter-strings may or may not be semantically related, and the participant decides whether the target belongs to the lexicon. This paradigm allows measures of semantic processes based on subject behavior. By recording EEG signals during presentation of word-pairs, Bentin et al. (1985) brought to light event-related potential (ERP) correlates of semantic priming; this was called the N400 effect, due to the increased amplitude of the ERP from 200 to 600 ms post target stimulus (peak at approximately 400 ms) in response to contextually incongruous stimuli. From the vast literature on the N400, it is now well accepted that this component reflects both lexicon activation and contextual integration (Kutas and Federmeier, 2000). Investigations of behavioral semantic priming in schizophrenia have led to apparent contradictory results: some studies reported normal priming effects (Ober et al., 1995; Barch et al., 1996), but others found reduced (Aloia et al., 1998; Besche et al., 1997; Kuperberg et al., 1998; Ober et al., 1997; Passerieux et al., 1997) or enhanced effects (Spitzer et al., 1993, 1994; Moritz et al., 2001, 2002). Several reviews have suggested that these discrepancies might be due to different experimental parameters used in different studies (Minzenberg et al., 2002;

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Lecardeur et al., 2006; Kuperberg et al., 2010). Despite the heterogeneity of experimental conditions and populations, both Lecardeur et al. (2006) and Minzenberg et al. (2002) concluded that a reduction of the semantic priming effect in schizophrenia was the most robust result reported. This conclusion was consistent with several ERP investigations, which showed a reduced N400 effect in patients with schizophrenia (Sitnikova et al., 2002; Hokama et al., 2003; Kostova et al., 2003, 2005; Kiang et al., 2008). Again, several works failed to find this result, but the majority of ERP investigations in schizophrenia reported an abnormal N400 modulation (Kumar and Debruille, 2004), which suggested disorders in underlying neurocognitive mechanisms. Advances in neuroimaging techniques have allowed researchers to investigate brain regions that participate in the N400 effect. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies of brain activity during an LDT have implicated a left fronto-temporal network in the N400 component (Van Petten and Luka, 2006). Those investigations demonstrated that the left middle temporal gyrus (MTG), temporal pole (TP), inferior frontal cortex, and anterior cingulate cortex (ACC) showed enhanced activation in response to semantic incongruity (Kotz et al., 2002; Matsumoto et al., 2005; Wible et al., 2006; Copland et al., 2007) and thus, had contributed to the N400 effect. Interestingly, some studies showed similar effects in right MTG (Kotz et al., 2002; Friederici et al., 2003; Wible et al., 2006). Moreover, intracortical/subdural recordings indicated that a region in the anterior medial temporal lobe (AMTL) was associated with the N400 component (McCarthy et al., 1995; Nobre and McCarthy, 1995). Despite the wealth of electrophysiological data on abnormal semantic priming in schizophrenia, surprisingly few studies have investigated the corresponding neural basis. Han and collaborators (2007) found with fMRI that patients with schizophrenia, compared to healthy controls, failed to show increased activation in temporal and frontal areas in response to semantic incongruity in a LDT. They suggested that schizophrenia was associated with a functional disturbance in semantic network activation. Kuperberg et al. (2007) also used fMRI with a LDT and found a global over-activation in the fronto-temporal network in response to semantic relationships. They suggested that this result reflected an “abnormal increase or prolongation” in processes that underlie semantic priming in schizophrenia (i.e., abnormal controlled semantic matching, and automatic spreading of activation within the semantic memory). In contrast, Kuperberg and collaborators (2008) used a different paradigm (a sentential sensicality judgment task) and found that patients with schizophrenia showed normal modulation (given the semantic relatedness between a word and its preceding sentential context) in the temporal and inferior prefrontal blood oxygenation level dependent (BOLD) responses. However, those patients showed an abnormally reduced activation of the dorsolateral prefrontal cortex during incongruous words processing. The authors concluded that the “memory-based mechanisms” (i.e., “activating, retrieving, and matching stored semantic information”) were preserved in schizophrenia, but the integration of semantic and syntactic information was impaired (Kuperberg et al., 2008). To summarize, although all these studies used fMRI, the lack of data and the heterogeneity of paradigms and psycholinguistic parameters (for example, the duration between prime and target presentation) made it difficult to draw conclusions about the nature of functional abnormalities associated with semantic priming in schizophrenia. Several authors have successfully used magneto-encephalography (MEG) to investigate semantic processing in healthy subjects (Halgren et al., 2002; Marinkovic et al., 2003; Lin et al., 2006; Maess et al., 2006; Ihara et al., 2007). They reported increased activation detected within the N400 time-window in the left fronto-temporal network in response to semantic incongruity. That suggested that temporal and frontal activity gave rise to the N400 component. However, to our knowledge, only one MEG study was conducted in patients with schizophrenia. Froud et al. (2010) found that, during an LDT, four of six schizophrenic patients exhibited a magnetic field

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reversal (compared to healthy controls) in the left hemisphere at around 350 ms post-stimulus. However, the neural origin of this observation remained unclear, because Froud et al. did not perform a source localization analysis. In the present work, to elucidate abnormal cortical activation during LDT in schizophrenia, we recorded MEG signals in patients with schizophrenia and in healthy controls while they performed a validated LDT (Kostova et al., 2003, 2005). We used minimum norm algorithms to localize electric activities and extract corresponding time-courses. To our knowledge, this was the first study on semantic processes in schizophrenia to use MEG associated with localization algorithms to characterize brain networks at both temporal and anatomic levels. Based on the existing literature, we hypothesized healthy subjects to show increased activations for semantically unrelated pairs in bilateral middle temporal gyri (MTG), left temporal poles (TP), left anterior medial temporal lobe (AMTL), left inferior prefrontal regions as well as the anterior cingulate cortex (ACC) between 200 and 600 ms (the N400 time-window). In schizophrenic patients, abnormal (reduced) modulation of this network was expected during the same time-interval. In addition, correlations between functional abnormalities and clinical patterns have been tested in the present study. With a similar LDT, Kostova et al. (2005) demonstrated that formal thought disorders were negatively correlated to the N400 effect. Based on that result, we hypothesized that disorganization symptoms would be positively correlated to abnormal modulation in the brain regions that underlie the N400 component. Furthermore, we investigated whether brain responses were correlated to behavioral measures (priming effect) or the age at illness onset. Finally, to improve our understanding of the semantic priming phenomenon, we explored functional differences in prime word processing between controls and patients with schizophrenia, and tested whether these differences influenced modulation of brain activity in response to the target words. 2. Materials and methods 2.1. Subjects This study included 12 healthy subjects and 20 patients diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). The patients had been taking antipsychotic medication (Table 1). Interviews by trained experimenters revealed that healthy participants were free of psychiatric illness and antipsychotic medication. Subjects were right-handed according to the Edinburgh handedness inventory, native French speakers, and had no neurological illnesses. Participants were free of substance abuse and medical co-morbidities and had normal or corrected visual acuity. All participants provided informed consent. The study was approved by the local Ethical Committee (CCP Versailles, France). Patients' symptoms were assessed with the positive and negative syndrome scale (PANSS, Kay et al., 1987), which provided positive, negative, and general scores. We assigned PANSS items to the six “factors” (Positive, Negative, Anxiety/Depression, Disorganization, Excitation, and Withdrawal) defined on the basis of a factor analysis conducted by Van den Oord et al. (2006). Table 1 shows the items pertaining to each factor. 2.2. Task Three recording sessions were performed. Each session consisted of 170 or 160 trials, for a total of 500 trials. Stimuli were different across the three sessions. The order of sessions was counterbalanced between subjects. During each trial, two letter-string stimuli (i.e., sequences of letters forming words or pseudo-words) were consecutively displayed on a screen. The prime (the first letter-string) was a known word and appeared for 200 ms (Fig. 1). After a 250 ms interval, the target (the second letter-string), which was either a word or a pseudo-word,

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Table 1 Characteristics of patients with schizophrenia and healthy subjects. When possible, the two groups are statistically compared. Patients (SD); [range]

Healthy subjects

Comparison

Females/Males Age (years) Duration of illness (years)

5/15 4/8 n.s (p= 0.7a) 37.6 (9.9) [23 50] 26.5 (4.9) [21 40] p b .05b 13.2 (6.9) –

PANSSc Positive Negative General

15.0 (5.8) 18.9 (4.6) 40.1 (7.3)

PANSS Six factors solution (items) Positive (P1,P5,P6,G9) 10.4 (4.5) Negative (N1,N3,N6,G7) 10.4 (4.0) Anxiety/depression 11.3 (2.5) (G1,G2,G3,G6) Disorganization 12.7 (4.1) (P2,N5,G10,G11,G13) Withdrawal (N2,N4,G16) 8.7 (2.7) Excitation (P7,G8,G14) 4.8 (2.2) Medication Chlorpromazine equivalents (mg) 1st generation/2nd generation/both Mood stabilizers Antidepressants Benzodiazepines a b c

– – –

– – – – – –

450 (321)

–

6/10/4

–

7 9 4

– – –

distribution was chosen for two main reasons. First, we used existing material that had been validated in participants with and without schizophrenia by Kostova and collaborators (2003, Kostova and collaborators 2005). The authors had originally developed this LTD to test controlled contextual integration process that is thought to be encouraged by the use of 50% or more of PW (Neely et al., 1989, Neely, 1991). Second, our aim was to localize the brain network involved in the N400 effect; therefore, we were interested in the comparison between RW and UW pairs. We chose a 20% RW and 30% UW distribution in order to use 10% of the UW pairs for defining the regions of interest (ROIs). Indeed, among the 30% of UW pairs, 10% (called filler pairs) were not included in subsequent statistical analyses and were exclusively used for ROI selection. This procedure avoided the non-independence error inherent in statistical comparisons performed on the same trials used in ROI definitions. Thus, we compared an equal number of RW and UW trials (20% of the whole material each). This approach is suitable for non circular analyses (Kriegeskorte et al., 2009). The words included in the RW and UW trials were compared for psycholinguistic characteristics based on two French lexical databases, the Brulex (Content et al., 1990) and the Lexique2 (New et al., 2010). We ensured that the RWs and UWs were not statistically different in the number of letters, number of homographs, and the frequency used in books. 2.3. MEG recording

P-value based on the Fisher exact test. P-value based on the t-test. Positive and negative syndrome scale.

appeared for 1200 ms, followed by a 350 ms blank screen. Thus, the onsets of the prime and target were separated by an interval of 450 ms (stimulus onset asynchrony, SOA) and the total duration of each trial was 2000 ms. During each trial, the subjects decided whether the target was a real word or a pseudo-word and responded on a two-button pad as fast and accurately as possible. There were two experimental conditions of interest: 1) related-word pairs (RW), where the target was a real word, semantically related to the prime, and 2) unrelated-word pairs (UW), where the target was a real word, but not semantically related to the prime. In addition, the material included pseudo-word pairs (PW), where the target did not belong to the lexicon. The RW condition was presented for 20% of the trials, the UW condition for 30% and the PW condition for 50%. This uneven

Event-related magnetic responses were recorded at the MEG Center, Hôpital de la Pitié-Salpêtrière, with a CTF Omega 151 apparatus (CTF Inc., Vancouver). This device allowed simultaneous recording of 151 MEG channels that covered the whole head. Signals were digitized at a 1250 Hz sampling rate with a 200 Hz low-pass filter. Electric potentials generated by eye movements were recorded with four electrodes placed around the right eye. Heart activity was recorded with two electrodes placed around the collar bone and the lower abdomen. Each subjects' referential was defined with three magnetic coils attached to the nasion and the preauricular points. The locations of these coils were checked before each session to measure the subject's head position relative to the magnetometer. 2.4. Data analysis Magnetic artifacts induced by heart activity were corrected on each channel with linear regression. Signals recorded during eye blinks were removed from the analysis. Evoked magnetic signals were filtered with a

Lexical decision

…

SOA = 450 ms

200 ms 250 ms prime stimulus

1200 ms 350 ms target stimulus

t

Fig. 1. Design of a single trial of the lexical decision task. The prime stimulus (first word) was followed by a 250 ms interval before the target stimulus (second word) was presented to the subject. The subject then decided whether the target word was a real word (Lexical decision). SOA: stimulus onset asynchrony.

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0.4–35 Hz band-pass filter. Magnetic potentials evoked by prime and target words were extracted separately. For both prime and target words, the time origin was set to stimulus onset, and the baseline corresponded to the preceding 100 ms (i.e., primes and targets had separate baselines). Source localization was performed with a linear minimum norm algorithm implemented in BrainStorm (http://neuroimage.usc.edu/ brainstorm). White and gray matter segmentation was performed on the Montreal Neurological Institute (MNI) standard brain. The white/gray matter interface was decimated to 15,000 sources evenly distributed on this surface; i.e., at each node of the cortical tessellation. Source orientation was constrained to be perpendicular to the interface. This cortical surface served as the solution space for the estimated current generators. Source estimation was performed with a spherical head model with homogenous conductivity. Source localization was transformed to each subject's head coordinate system based on the positions of the three coils. A cortically constrained L2 minimum norm algorithm (Dale and Sereno, 1993; Hämäläinen et al., 1993) was used, as described by Baillet et al. (2001), to estimate the respective contributions of sources to the recorded evoked magnetic signals (inverse problem) at each time step. Time-series expressed in amperes-meter (A·m) were computed on raw data. This procedure was performed for each group. We reported results between the 0 and 600 ms timewindow for target stimuli and between the 0 and 450 ms interval for prime words.

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100–400 ms time window) and then removed that influence (Table 2). Besides, in both controls and patients, each time a significant amplitude modulation was found, we tested whether age was significantly correlated (Spearman correlation coefficients) with the UW vs. RW differences (for target stimuli) or with the averaged amplitude during the prime words (RW+UW+PW). Findings of significant correlation was indicated in Table 2. We also focused on ROIs that exhibited a group × condition interaction and more specifically on the time intervals in which this interaction was found. For each group, we computed nonparametric Spearman correlations (.001 threshold) between the amplitude modulation observed in response to the target stimulus (UW minus RW) and behavior (priming effect) or various psychiatric variables (age at illness onset; PANSS positive, negative, and general subscores; and the six PANSS factors: Positive, Negative, Anxiety/Depression, Disorganization, Excitation, and Withdrawal). In periods where patients and controls differed significantly, we also tested correlations between these variables and the mean amplitudes of the prime words. Finally, for each group and ROI, we tested whether the mean levels of activation in response to the prime word in the 100–400 ms time window were correlated to the amplitude modulations (UW minus RW) measured for each 25 ms epoch during target word processing (Spearman correlations, .001 threshold).

3. Results 2.5. Statistical analysis 3.1. Behavioral results An ROI was defined as a set of 20 contiguous sources selected as the local maxima of normalized activations (normalization with respect to the variance of the ROI's 100 ms baseline) from a minimum norm reconstruction of “filler” pairs. ROIs were defined in controls and then in patients with schizophrenia. A visual inspection and coordinate verification ensured that the ROIs of both groups were identical, or could be considered identical, based on MEG spatial resolution and spatial filtering caused by the minimum norm algorithm. Empirically, the sources of each ROI were selected based on a criterion of activation amplitude (z-score ≥ 4.2). Subsequently, we performed statistical analyses on raw signals that satisfied this activation criterion. We used non-parametric methods (permutation tests), because they did not require assumptions on the data distribution. For target stimuli, visual inspection of the time courses showed that activations in all the ROIs occurred preferentially within the 200– 500 ms time interval. For comparisons between RW and UW within each group, this interval was analyzed with paired-permutation tests in 25-ms epochs; 100,000 permutations for each test allowed high confidence for estimating p-values around the .001 threshold. To control for type-I errors in multiple comparisons, we adopted a ROI approach that considerably reduced the number of comparisons compared to a whole-brain signal analysis. In addition, we used a .001 alpha threshold correction, which is more stringent than the Bonferroni correction, for the 12 comparisons that corresponded to the twelve 25-ms epochs. For the regions investigated with an a priori hypothesis (confirmatory analysis) we also reported results with a .05 threshold. Between-group comparisons (patients vs. controls) were performed on averaged RW+ UW conditions (unpaired permutation tests with 100,000 permutations) during the same time-window. Interactions between the group (patients and controls) and the condition (RW and UW) were also tested (unpaired permutation tests). For prime words, permutation tests (unpaired test with 100 000 permutations) were computed on the averaged data of RW, UW, and PW in each group between the 50 and 450 ms time interval. To control for a possible age bias, all group and condition comparisons were conducted a second time on raw reconstructed data, after adjustments for age. For each ROI, we performed a linear estimation of the unspecific influence of age on evoked signals (averaged signals in the

In the control group, mean reaction times were 621 ms (SD = 66 ms) in the RW and 640 ms (SD = 62 ms) in the UW conditions. In the patients, mean reaction times were 760 ms (SD = 101 ms) and 788 ms (SD = 105 ms) in RW and UW conditions, respectively. We performed a repeated-measures ANOVA analysis with group (inter) and condition (intra) as factors; this revealed significant effects of group (F[1;30] =

Table 2 Condition and group effects on semantic network activations. (A) Regions of interest (ROIs) and (B) their 3-D Talairach coordinates (Talairach and Tournoux, 1988). (C) Effect of condition (UW vs. RW) on each ROI activation in response to target word stimuli in controls and patients with schizophrenia. (D) Effect of group (Controls vs. Patients) on each ROI activation in response to the prime word. (A) ROIs

(B) Talairach coordinates (mm) x

Y

z

Regions with a priori hypotheses MTG L − 63 − 10 −7 MTG R 53 − 34 2 TP L − 45 20 − 20 ACC L −9 39 24 OPFC L − 28 30 − 11

(C) Semantic relatedness effect on response to target stimulus

(D) Group differences in responses to prime word

Controls

Patients

(UW + RW + PW)

ns UW N RW * ns RW N UW * ns

PNC PNC PNC PNC –

RW N UW ns ns ns ns ns ns

ns – – – ns – –

(p b .05) UW N RW * ns UW N RW * UW N RW * ns

Regions without a priori hypotheses (p b .001) Occ L − 1 − 99 − 2 ns Occ R 8 − 96 5 ns OccT L − 44 − 82 − 2 ns OccT R 47 − 71 − 7 ns pMTG L − 60 − 44 − 5 UW N RW sMTL L − 47 8 − 3 ns sMTL R 39 − 19 2 ns

a

* : significant group × condition interactions (p b .05), a : significant positive correlation between signal amplitude (300–400 ms) and age in controls (ρ = .64; p b .05), ns : not significant, –: not tested. Occ: Occipital cortex, OccT: Occipito-temporal cortex, MTG: middle temporal gyrus, pMTG: posterior part of the middle temporal gyrus, sMTL: superior part of the medial temporal lobe, TP: temporal pole, ACC: anterior cingulate cortex, OPFC: orbital part of the prefrontal cortex, L: Left, R: Right, P: patients (n = 20), C: controls (n = 12), UW: unrelated words, RW: related words, PW: pseudo-words.

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17.75; p b 5.10− 4) and condition (F[1;30] = 33.88; p b 5.10− 6), but no group× condition interaction (F[1;30] = 1.78; p = .19). Patients had a slower reaction time than controls, but both groups responded faster to RW compared to UW.

age when this variable was introduced as a covariate. A positive correlation between age and the signal amplitude was observed in controls in left ACC (Spearman correlation, ρ = .64; p b .05). 3.5. Correlations

3.2. ROIs evoked by target word presentation For both the RW and UW, strong activations were observed in bilateral occipital and left occipito-temporal regions, with peak amplitudes at 110–120 ms in both controls and patients. For both groups, the left MTG, left posterior MTG (pMTG), and the superior part of the left medial temporal lobe (sMTL) were activated slightly later, with peak amplitudes at approximately 280 ms. At about 300 ms, maximal activations occurred in the left TP, left orbital part of the inferior prefrontal cortex (OPFC), right sMTL, and right MTG. Finally, activation occurred in the ACC bilaterally, with a peak at approximately 390 ms. Between-group comparisons of the averaged RW + UW amplitudes in each ROI revealed that patients with schizophrenia exhibited significant hyperactivations compared to controls in the bilateral MGT, right sMTL, and left TP. Note, however, that the latter region was not different from controls when results were adjusted for age. No significant group effect was observed in the bilateral ACC, left OPFC, pMTG, or sMTL. 3.3. Modulations of activation in response to semantic relatedness between prime and target words In all temporal and frontal ROIs that constituted the network previously defined, we investigated amplitude differences between RW and UW within each group. In healthy participants, activation amplitudes were significantly reduced in RW compared to UW in the left MTG, TP, ACC, and pMTG. However, patients with schizophrenia did not show UW vs. RW modulations in the left MTG, TP, or pMTG (Table 2). More detailed comparisons (between groups and conditions) revealed that the absence of effect in the left MTG of patients was due to an increased activation in response to RW compared to that observed in controls. Interestingly, in contrast to controls, patients showed significantly stronger activation in UW compared to RW in right MTG during a short time-interval. Furthermore, patients exhibited an inverse profile compared to controls; i.e., RW led to a stronger activation than UW in the left ACC and left occipital area. Significant group×condition interactions were found in bilateral MTG, left TP, and left ACC. Neither group showed modulations in the left OPFC. A second analysis of the data after adjustment for age and an analysis of correlations between age and amplitude modulations revealed that these results were not influenced by age. Fig. 2 illustrates some regions and time-courses for both groups. To compare these results with future studies, the estimated mean amplitudes in each ROI with an effect are shown in Table 3 (supplementary data). 3.4. Patterns of activation in response to prime word presentation ROIs that exhibited a significant modulation during the target stimulus (Table 2) were analyzed for potential group differences in their averaged amplitudes in response to prime words (RW + UW+ PW). We observed statistically different activations in patients relative to controls in several regions. Compared to healthy participants, patients exhibited significantly stronger recruitment of bilateral MTG, the left TP, and the ACC (Table 2 and Fig. 3). These findings were not influenced by

In control subjects, for each ROI, nonparametric Spearman correlation analyses were conducted to test whether behavioral variables (semantic priming) influenced the amplitude modulation (UW minus RW) observed during the target stimulus or the amplitude level recorded in response to the prime word. In the patient group, additional variables were tested, including PANSS scores and factors and age at illness onset. No significant correlations were found in either population. We also performed correlation analyses between amplitudes in response to prime words and UW vs. RW modulations during target words. Here again, no significant correlation was observed in either group. 4. Discussion We explored brain activations during a visual word-pair LDT. As expected, healthy subjects responded to semantic incongruity with enhanced activation in left temporal regions. Although semantic priming in patients was not significantly different from that in controls, they showed aberrant activation modulation relative to experimental conditions within the semantic network. This behavior/brain dissociation was consistent with that found in previous studies with fMRI (Kuperberg et al., 2007) or MEG (Froud et al., 2010). In agreement with our working hypotheses, schizophrenic patients exhibited an abnormal brain response in the left temporal cortex. However, in contrast to healthy subjects, semantic incongruity resulted in enhanced activation in the right temporal regions. Interestingly, schizophrenic patients presented inverse modulation (RW N UW) in the left ACC compared to controls. Finally, this study revealed abnormal recruitment of the semantic network during prime word processing in patients with schizophrenia. Patients and controls showed similar patterns of global cortical activation evoked by target words, regardless of the semantic relatedness to the prime word. Early bilateral occipital and left occipito-temporal regions were followed by activations in bilateral MTG and the left TP within 200 to 400 ms. Then, prefrontal areas were activated. These findings corroborated previous fMRI and MEG data that demonstrated that semantic processing involved the left MTG, TP, OPFC (for reviews, see Marinkovic et al., 2004 and Vigneau et al., 2006), and right temporal cortex (Friederici et al., 2003; Wible et al., 2006). Subcortical electro-stimulation studies have also demonstrated the participation of temporal and orbitofrontal regions to a “ventral semantic stream” (Duffau et al., 2005; Mandonnet et al., 2007). In the present study, patients showed significant activations in all these regions. This demonstrated that MEG coupled with minimum norm localization was successfully applied to the investigation of the anatomy of the schizophrenic semantic network. Interestingly, patients displayed increased magnetic signals in several regions involved in semantic processes, including bilateral MTG. Of note, these results were consistent with neuroimaging studies that used fMRI (Kubicki et al., 2003; Ragland et al., 2004). However these findings should be interpreted with caution, because the group differences were found during short time intervals that did not match the intervals with signals modulated by the condition. Of note, when RW and UW were averaged, patients did not

Fig. 2. Reconstruction of cortical activation and time-course in semantic regions of interest during target stimuli presentation. (Left) Cortical surfaces showed magnetic activations at 265 ms (left hemisphere, top panel), 300 ms (right hemisphere, middle panel), and 370 ms (medial view, bottom panel) after target presentation in the unrelated word (UW) condition in healthy controls. Color scale: arbitrary units (z values). (Right) Time courses of (A) left middle temporal gyrus, (B) left temporal pole, (C) right middle temporal gyrus, and (D) left anterior cingulate cortex for control subjects (upper panels) and patients with schizophrenia (lower panels) in related word (RW; black) and unrelated words (UW; red) conditions. Significant differences between UW and RW were observed during times marked with an orange horizontal bar (p b .05) or a red bar (p b .001). Black-bordered rectangles represent significant group × condition interactions. Horizontal axis units: seconds (−.1 to .6 s). The time origin corresponds to target word presentation. Vertical axis units: pA.m.

D. Vistoli et al. / Schizophrenia Research 130 (2011) 114–122

A : RW RW vs UW

: UW

RW vs UW RW & UW

B t=265 ms RW vs UW

RW vs UW RW & UW

C

RW vs UW

t=300 ms RW vs UW RW & UW

D

RW vs UW

t=370 ms RW vs UW RW & UW

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Fig. 3. Time courses of left temporal areas activations in response to prime word presentation. Time courses of the left temporal pole (TP) and middle temporal gyrus (MTG) in healthy controls (blue) and patients with schizophrenia (red). Significant differences between controls and patients were observed during times marked with an orange horizontal bar (p b .05). Horizontal axis units: seconds (−.1 to .45 s). Time origin corresponds to prime word presentation. Vertical axis units: pA.m.

exhibit abnormal global activation in frontal areas, like the left OPFC and ACC. Taken together, the present findings provided direct electrical evidence for the existence of functional abnormalities within the semantic network in schizophrenia. 4.1. Abnormal modulations in response to semantic relatedness in schizophrenic patients As hypothesized, the left temporal areas of healthy subjects, including the MTG and TP, exhibited significantly increased amplitudes in response to UW compared to RW. This corroborated results from previous neuroimaging (Kotz et al., 2002; Copland et al., 2003; Rissman et al., 2003; Matsumoto et al., 2005) and MEG investigations (Halgren et al., 2002; Marinkovic et al., 2003; Maess et al., 2006; Ihara et al., 2007). This result suggested that these regions gave rise to the N400 component. A semantic relatedness effect was also observed in the left ACC from 370 to 450 ms. This result was consistent with results from previous fMRI (Mummery et al., 1999; Rossell et al., 2001; Gold et al., 2006) and EEG studies (Silva-Pereyra et al., 2003). According to those studies, the ACC is involved in attentional processes during semantic priming but its automatic or controlled nature remains a subject of debate. Our SOA of 450 ms was likely to engage both automatic and controlled processes; thus, our results cannot clarify this issue. Although we observed right temporal area recruitment in healthy controls, we did not find any significant amplitude modulation regarding experimental conditions in these regions. This result was consistent with results from several fMRI (Copland et al., 2003; Matsumoto et al., 2005) and MEG (Ihara et al., 2007) studies that used visual material in healthy subjects. One interpretation of these converging observations is the possible effect of presentation modality on the hemispheric distribution of the modulations, as previously shown by Marinkovic and colleagues (2003) with a repetition priming paradigm. Finally, we found that the activation modulation in each ROI was not significantly correlated with behavioral priming. This result emphasized a dissociation between behavioral and brain measurements. Compared to healthy controls, schizophrenic patients showed a complex pattern of modulations. First, we demonstrated that schizophrenic patients did not modulate the aforementioned frontotemporal network as healthy subjects do. Indeed, semantic incongru-

ity did not lead to enhanced left temporal and frontal activations. This was consistent with an fMRI investigation by Han and collaborators (2007), who reported reduced left fronto-temporal modulation regarding the degree of “word connectivity”. Moreover, the absence of effect in the left MTG of patients compared to controls was explained by an abnormally increased activation in response to RW. Similarly, Kuperberg and collaborators (2007) reported that patients with schizophrenia exhibited inappropriate hyperactivation in the left temporal cortex in response to semantically related words. The authors suggested that this reflected associative hyperactivity in schizophrenia. In addition, we found that patients exhibited an aberrant modulation in the left occipital cortex (220–300 ms). In this region, unrelated words evoked weaker activity than related words. A similar inverse pattern was found in the ACC (245–320 ms), although the averaged RW + UW activation was normal. These unexpected inverse patterns of activations will require replication and further exploration. Interestingly, patients exhibited a modulation (UW N RW) in the right MTG that was not observed in healthy controls. A recent metaanalysis of neuroimaging studies in healthy subjects reported a strikingly limited involvement of the right hemisphere during semantic processing (Vigneau et al., 2010). This reduced contribution of the right hemisphere was interpreted as the consequence of an inhibitory influence of left areas on their right homolog. Based on the results of the present study, one can hypothesize that patients with schizophrenia exhibit exaggerated right hemisphere involvement due to an absent inhibitory influence of the left hemisphere. To test this hypothesis, future MEG studies should investigate inter-hemispheric functional relations. Beyond this neurofunctional interpretation, modulation in the right hemisphere may be related to its specialization in explicit, effortful integrative processes. Indeed, using word-pair stimuli associated with visual hemi-field stimuli presentation in recent ERP studies, Kandhadai and Federmeier (2010a, b), investigated the implication of the right hemisphere in semantic processes in healthy participants. By contrasting implicit and explicit task demands, the authors showed that the right hemisphere was responsible for strategic aspects of semantic processing in the explicit condition. According to Kandhadai and Federmeier (2010b), the right hemisphere might be involved “in effortful semantic processing mechanisms when these are actively called upon by the task demands”. This phenomenon was observed in the 500–900 ms time-window. In the present study, we used an implicit task (LDT); however, we speculate that patients had engaged in effortful

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explicit processes in the 400–500 ms time interval to compensate for a deficit in integrative operations that involved the left hemisphere. Interestingly, this interpretation was supported by the fact that several patients, but no controls, spontaneously referred to the existence of semantic associations in some trials after MEG recordings during a debriefing with the experimenter. However, further investigation would be required to determine the compensatory nature of abnormal cortical activities. We speculate that inducing brain interference with repetitive transcranial magnetic stimulation (rTMS) that targeted these right hemisphere areas would result in a dramatic decrease of the priming effect in patients. Our results showed that activation modulation was not significantly correlated to behavioral results or clinical variables, like age at illness onset or PANSS scores. Surprisingly, activation modulation was not correlated with the disorganization syndrome. This lack of correlation was consistent with previous neuroimaging studies (Kuperberg et al., 2007, 2008). There are two possible explanations. First, our findings suggested that disorganization symptoms were not quantitatively associated with functional abnormalities observed in any one isolated region; instead, they may be related to a complex pattern of activations that reflect both impaired and alternative processes, as hypothesized above. Second, our result emphasized the need for finer disorganization assessments with specific clinical instruments (Bazin et al., 2005). Exploration of large patient populations would be required to address these issues. 4.2. Abnormal activation profiles in response to prime word in patients with schizophrenia Prime word analyses provided additional insight into semantic process impairments in patients with schizophrenia. For each ROI, we compared the amplitudes of the averaged RW + UW + PW conditions between groups. In the bilateral MTG, left TP, and ACC, we found hyperactivation in patients compared to controls. However, note that the effect in the left ACC was supposedly due to age difference between groups as we found a positive correlation between the signal amplitude and the age in controls. Time-course observations revealed that this hyperactivation was due to a prolonged activation after 300 ms in patients. This suggested that patients experienced inappropriate semantic network activation during prime word processing. To the best of our knowledge, this report is the first to describe this dysfunction in schizophrenia. This dysfunction was not significantly correlated with behavioral or clinical measures. Moreover, we expected that this abnormal activation in response to prime words would be correlated to modulations in response to the target words. Our negative finding was surprising and should be confirmed in future studies. Nevertheless, functional abnormalities in response to prime words suggested that schizophrenia is associated with impaired context processing in addition to the classic proposition of impaired context integration, which was corroborated by abnormal modulation in response to the target word. 4.3. Limitations of the study The present study had some limitations in the design. We have shown that MEG provided good spatial/temporal resolutions for investigating schizophrenia. However, we emphasize that the results require replication for confirmation of the unexpected findings (i.e., inverse activation patterns in several left cortical areas; semantic modulations in the right temporal cortex; and functional abnormalities in response to the first word). The following improvements could strengthen the conclusions: 1) populations should be strictly matched in age; we found some marginal effects of age on brain responses and 2) clinical evaluations of disorganization should be made with specialized tools, including the Scale for the assessment of thought, language, and communication (Andreasen, 1986) and the Schizophrenia Communication Disorder Scale (Bazin et al., 2005), in order to test

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correlations between disorganization and abnormal brain responses. Moreover, an important limitation in this study was the lack of individual MRI data to constrain the source localization. Thus, although our observations of activations in the left MTG, TP, and ACC regions were consistent with previous fMRI and PET studies (Mummery et al., 1999; Kotz et al., 2002; Copland et al., 2003; Matsumoto et al., 2005; Gold et al., 2006), future work should account for inter-individual anatomical variability in order to refine the present findings. Supplementary materials related to this article can be found online at doi:10.1016/j.schres.2011.05.021. Role of funding source This work was supported by a grant of Neuropôle (DV), and an Institut National de la Santé Et de la Recherche Médicale (Contrat d'Interface, EBG).

Contributors Damien Vistoli and Eric Brunet-Gouet designed the study, wrote the protocol and managed the literature searches and analyses. Eric Brunet-Gouet and Damien Vistoli also undertook the statistical analysis and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest All authors declare that they have no conflicts of interest.

Acknowledgements We would like to thank Frédéric Bergame, Antoine Ducorps, Nathalie George, Christophe Gitton and Denis Schwartz (MEG Center, Hôpital de la Pitié-Salpêtrière) for their technical support. We are thankful to Audrey Angelard, Nadine Bazin, Catherine Bourdet, Corrine Coffinier, Armelle Volkringer (Hôpital de Versailles) and Galina Iakimova (EA 1189, Université Nice Sophia-Antipolis) for their help in patients' recruitments, evaluations and/or their comments on the manuscript. EA 4047 (Université Versailles Saint-Quentin)—Service de Psychiatrie Adulte (Centre Hospitalier de Versailles) is a member of FondaMental (mental health foundation for research and care).

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