Electrophysiological evidence for primary semantic memory functional organization deficits in schizophrenia

N400, an event-related brain potential (ERP) waveform elicited by meaningful stimuli, is normally reduced by stimulus repetition (N400 repetition priming), and relatedness between the eliciting stimulus and preceding ones (relatedness priming). Schizophrenia patients' N400 relatedness priming deficits suggest impairment in using meaningful prime stimuli to facilitate processing of related concepts in semantic memory. To examine whether this deficiency arises from difficulty activating the prime concept per se, as indexed by reduced N400 repetition priming; or from impaired functional connections among concepts in semantic memory, as reflected by reduced relatedness priming but normal repetition priming; we recorded ERPs from 16 schizophrenia patients and 16 controls who viewed prime words each followed at 300- or 750-ms stimulus-onset asynchrony (SOA) by an unrelated, related or repeated target word, or a nonword, in a lexical-decision task. In both groups, N400s were largest (most negative) for unrelated, intermediate for related, and smallest for repeated targets. Schizophrenia patients exhibited subnormal N400 relatedness priming at the 300-ms SOA, but normal repetition priming at both SOAs, suggesting that their impairment in using prime words to activate related concepts results from abnormal functional connections among concepts within semantic memory, rather than inability to activate the prime concept itself.     

Depth-of-processing effects on semantic activation deficits in schizophrenia: an electrophysiological investigation

N400, an event-related brain potential (ERP) waveform elicited by meaningful stimuli, is normally reduced (made less negative) by relatedness between the eliciting stimulus and preceding ones (N400 semantic priming). Schizophrenia patients' N400 semantic priming deficits suggest impairment in using meaningful context to activate related concepts in semantic memory. We aimed to examine the degree to which this impairment can be ameliorated by task instructions that more explicitly require processing of stimulus meaning. We recorded ERPs from 16 schizophrenia patients and 16 controls who viewed prime words each followed at 750-ms stimulus-onset asynchrony by an unrelated or related target word, or a nonword, in a non-semantic task (indicating whether a letter occurred in the target) compared to an explicit semantic task (judging prime-target relatedness). Consistent with previous work, controls exhibited greater N400 semantic priming (larger amplitude reductions for related versus unrelated targets) in the semantic task than in the orthographic task. Schizophrenia patients showed this same pattern, although their N400 semantic priming effects were smaller than controls' across tasks. Nevertheless, patients' priming effects increased as much as did controls' from the orthographic to the semantic task. Thus, connections among related concepts in schizophrenia patients' semantic memory appear grossly intact, such that, given a meaningful stimulus, they can make use of explicit cues to activate related concepts at a neurophysiological level, although their ability to do so remains less than normal. These data provide support for further research on semantic-cueing strategies for cognitive remediation of verbal memory in schizophrenia.     

Unimpaired automatic processing of verbal information in the course of clinical depression

In this study automatic processing of verbal information was investigated in 22 clinically depressed inpatients and 22 healthy controls in a longitudinal design. A semantic priming task with word pronunciation was administered twice, about 7 weeks apart. Following brief presentations of prime words, subjects had to read target words aloud as quickly as possible. Prime words were directly related, indirectly related, or unrelated to the target words. Stimulus onset asynchrony (SOA) of prime and target was 250 ms. In the course of inpatient treatment, patients recovered significantly. Semantic priming occurred in both study groups for the directly and indirectly related conditions across both testing times. As expected, directly related primes resulted in stronger priming than indirectly related primes. Patients and controls did not differ in semantic priming at either time or relatedness condition. Size of priming was not associated with depression severity, anxiety level, intelligence, medication, or clinical features. We conclude that depression is not characterized by dysfunctional automatic processing of verbal information.     

N400 and automatic semantic processing abnormalities in patients with schizophrenia

BACKGROUND: One factor hypothesized to underlie thinking disturbance in patients with schizophrenia is abnormal or disinhibited automatic spreading activation of semantic networks, which can be assessed using the N400 event-related potential. N400 is a negative-going component elicited at about 400 milliseconds following semantic stimuli that are not primed by the preceding context. Semantic priming refers to facilitated semantic processing gained through preexposure to semantic context, which can happen automatically or strategically. Using N400, inferences can be drawn regarding the extent to which a given context primes a word. METHODS: During a picture-word matching task, N400s to primed (exact match) and unprimed (remotely related) words were recorded from 18 healthy control subjects and 18 patients with schizophrenia performing a picture-word matching task. A short interval (325 milliseconds) between picture and word onset (stimulus-onset asynchrony) was used to optimize the role of automatic spreading semantic activation and to minimize the role of attention, expectancy, preparation, and working memory. RESULTS: Despite behavioral evidence of normal semantic priming, patients generated an abnormally small N400 (ie, less negative) to unprimed words. The N400 to primed words was neither larger nor smaller in patients than in controls, suggesting normal use of context. CONCLUSIONS: A reduced N400 to unprimed words in patients with schizophrenia suggests that there was inappropriate priming of words by remotely related semantic contexts. This is consistent with an overly broad automatic spread of activation through semantic networks in patients with schizophrenia.     

Neural evidence for faster and further automatic spreading activation in schizophrenic thought disorder

It has been proposed that the loose associations characteristic of thought disorder in schizophrenia result from an abnormal increase in the automatic spread of activation through semantic memory. We tested this hypothesis by examining the time course of neural semantic priming using event-related potentials (ERPs). ERPs were recorded to target words that were directly related, indirectly related, and unrelated to their preceding primes, while thought-disordered (TD) and non-TD schizophrenia patients and healthy controls performed an implicit semantic categorization task under experimental conditions that encouraged automatic processing. By 300-400 milliseconds after target word onset, TD patients showed increased indirect semantic priming relative to non-TD patients and healthy controls, while the degree of direct semantic priming was increased in only the most severely TD patients. By 400-500 milliseconds after target word onset, both direct and indirect semantic priming were generally equivalent across the 3 groups. These findings demonstrate for the first time at a neural level that, under automatic conditions, activation across the semantic network spreads further within a shorter period of time in specific association with positive thought disorder in schizophrenia.     

Electrophysiological insights into conceptual disorganization in schizophrenia

Disorganized speech, or thought disorder, in schizophrenia may reflect abnormal processing of meaningful concepts. To examine whether schizophrenia involves abnormalities in how a meaningful context influences processing of concepts strongly, weakly, or not related to it, we used the N400, an event-related brain potential (ERP) index of semantic relatedness. ERPs were recorded from schizophrenia patients (n=18) and normal controls (n=18) while they viewed category definitions (e.g., a type of fruit), each followed by a target word that was either a high-typicality category exemplar (apple), low-typicality exemplar (cherry), or non-exemplar (clamp). Participants' task was to indicate via button-press whether or not the target belonged to the category. In both patients and controls, N400 amplitude was largest (most negative) for non-exemplars, intermediate for low-typicality exemplars, and smallest (least negative) for high-typicality exemplars. Compared to controls, patients showed a trend toward reduced N400 amplitude differences between non-exemplars and low-typicality exemplars. Most importantly, within patients, reduced N400 amplitude differences between high- and low-typicality exemplars were correlated with psychotic symptoms. This association of an N400 index of semantic processing with psychotic symptoms suggests that psychosis in schizophrenia may be associated with greater similarity in how concepts strongly and weakly meaningfully related to their context are processed.     

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

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.     

Reversing the N400: event-related potentials of a negative semantic priming effect

We investigated electrophysiological correlates of the access to semantic representations. Participants had to make word/nonword decisions to target words. A first word (i.e. the prime) preceded the target. The prime was either semantically related or unrelated to the target. Using a special masking technique we were able to present the prime rather long (approximately 140 ms) while preventing participants from consciously processing the prime. In line with former studies, participants showed a reversed priming effect: they reacted faster to unrelated compared with related targets. Interestingly, the N400 mimicked the behavioral effect: we observed more negative-going waveforms to related relative to unrelated targets. The result indicates that the N400 can reflect temporarily reduced access to semantic representations.     

Cross-modal semantic priming in schizophrenia.

Work on implicit memory in normal subjects has demonstrated the influence of stimulus modality on the retrieval of semantic information. The present study examined the effects of auditory and visual semantic priming on the recognition of visual words using a lexical decision task. Performance was studied in a group of 20 patients with DSM-IV schizophrenia and 26 normal volunteers of similar age and sex. There were two versions of the task: ipsimodal, in which the word or nonword visual target followed 400 ms after the onset of a visual word prime which may or may not be semantically related to the target; and cross-modal, in which the visual target followed 400 ms after the onset of an auditory word prime. Both groups showed significant priming in both modality conditions, although the schizophrenia patients exhibited significantly greater priming in the cross-modal condition. Priming effects in the ipsimodal condition did not differ substantially between patients and controls. The priming effects in the two conditions correlated with each other in the schizophrenia patients only. The results suggest that priming may occur through amodal semantic representations. In schizophrenia, there appears to be increased cross-modal connectivity (reduced modality modularity and informational encapsulation) between lexical representations that could result in impaired language, particularly speech, processing.     

An electrophysiological (ERP) component, the recognition potential, in the assessment of brain semantic networks in patients with schizophrenia

Abnormal activation of semantic networks may be the underlying basis for thought disorder (ThD) in patients with schizophrenia. However, whether this abnormality consists of increased or decreased activation is unclear. Previous behavioral and electrophysiological (N400) data have failed to yield consistent evidence for clarifying this hypothesis. One of the event-related potentials (ERP) components (the recognition potential, RP), presumably reflecting activation of specific semantic networks involved in ThD, has not been used to studies of schizophrenia, and may add additional information to support or refute this hypothesis. In an initial experiment, RP amplitude was reduced in schizophrenic patients, but particularly in those with ThD. In a second experiment, in addition to reduced overall RP amplitude, concrete words were shown to have higher amplitudes than abstract words in both patients and controls, supporting a relative integrity of the lexicon in ThD patients. RP reduction suggests that a fewer number of networks' elements are activated when an incoming word is processed, thus supporting hypoactivation of the semantic networks as the basis for ThD.     

Semantic activation within and across the cerebral hemispheres: what's left isn't right

This study examined differences in the spread of semantic activation within and between the cerebral hemispheres. A lateralised lexical decision task using indirect priming was presented to 58 undergraduates with primes and targets separated by 215 or 750 milliseconds (ms). Prime and target words were presented to the same or opposite visual fields and were either directly related (book-read), indirectly related (lion-[tiger]-stripes), or unrelated (cup-street). At 215 ms participants exhibited significant priming effects to directly related words in all conditions except when primes and targets were both presented to the right hemisphere (RH). In contrast, priming to indirectly related words was effective only when primes and targets were presented to opposite hemispheres. At 750 ms, significant priming occurred for directly related words in all conditions, and for indirectly related words when primes were presented to the RH. Results suggest that priming for directly and indirectly related concepts occurs unilaterally in each hemisphere before 215 ms. Both prime types activate semantic networks in the RH within 750 ms, whereas the LH processes information in a more focused manner. This suggests that activation spreads contralaterally from each hemisphere first to directly and then to indirectly related concepts, indicating the importance of incorporating contralateral priming contrasts in lexical decision tasks.     

Electrophysiological correlates of direct versus indirect semantic priming in normal volunteers.

The N400 component of event related potentials (ERP) was studied in 27 right-handed healthy subjects in a speeded lexical decision task. The semantic distance between primes (always words) and targets (50% words, 50% non-words) was systematically varied. Prime-target relations included directly related words (hen-egg), indirectly related words (lemon-sweet), and non-related words (sofa-wing). ERPs were recorded from 20 scalp electrodes positioned according to the international 10-20 system. The N400 reflected semantic distance with the most negative and latest N400 peak in the non-related condition, the least negative and earliest N400 peak in the direct condition and the peak in the indirect condition in-between. Hence, N400 priming effect in the indirect condition was obtained in the absence of strong sentential constraints and even though the mediating word was physically not present.     

Differences between noun and verb processing in a minimal phrase context: a semantic priming study using event-related brain potentials

The aim of the present study was to enforce the priming of either nouns or verbs in order to evoke word-category-specific N400 effects. In two experiments two primes which were either a verb-noun or a noun-noun pair were followed by a semantically related or unrelated target which was a noun or verb, respectively. This target always completed the word sequence to a minimal phrase comprising verb, subject, and object (VNN or NNV triplets). In experiment I subjects judged the semantic relatedness of the target to the two primes, in experiment II subjects first generated an appropriate target of the required word category and then judged the semantic relatedness between self-generated word and target. ERPs were recorded from 124 scalp electrodes. In both experiments verbs and nouns as such evoked reliably distinct ERP topographies between 300 and 800 ms. With verbs in relation to nouns the amplitudes were most often found to be more positive over central to frontal or parietal areas and more negative over occipital and temporo-parietal areas. In contrast, N400 effects proved as topographically invariant for noun and verb targets in both experiments. The results suggest that access to noun and verb representations involves topographically distinct cell assemblies while the N400 effect seems to reflect semantic evaluation and integration processes which are more abstract and independent from a particular word category.     

The effects of prime visibility on ERP measures of masked priming

In two experiments, the effect of the duration (40, 80 and 120 ms) of pattern masked prime words on subsequent target word processing was measured using event-related potentials. In Experiment 1, target words were either repetitions of the prior masked prime (car-CAR) or were another unrelated word (job-CAR). In Experiment 2, primes and targets were either semantically related (cap-HAT) or were unrelated (car-HAT). Unrelated target words produced larger N400s than did repeated (Exp 1) or semantically related (Exp 2) words across the different prime durations and these N400 priming effects tended to be smaller overall for semantic than repetition priming. Moreover, there was only a modest decline in the size of N400 repetition priming at the shortest prime durations, and there was no relationship between this N400 effect and a measure of prime categorization performance. However, the size of semantic priming at the shortest durations was relatively smaller than at longer durations and was correlated with prime categorization performance. The findings are discussed in the context of the functional significance of the N400 as well as a model that argues for different mechanisms during masked repetition and semantic priming.     

Semantic activation in Parkinson's disease patients on and off levodopa

Research suggests that dopamine may exert a neuromodulatory influence on automatic spreading activation within semantic networks. In order to investigate the influence of dopamine depletion on semantic activation in Parkinson's disease (PD), nine patients with PD performed a lexical decision task when on and off levodopa medication. Eleven healthy controls matched to the PD patients in terms of sex, age and education also participated in the study. Both directly related word pairs (e.g., tiger - stripe) and indirectly related word pairs (word pairs related via a mediating word, e.g., chalk - black) were used to measure semantic activation across stimulus onset asynchronies (SOAs) of 270 msec, 520 msec and 1020 msec. Analysis of variance statistics revealed that the activation of directly related and indirectly related targets was slower for the PD group relative to the control group. Within group comparisons revealed further changes to semantic activation in PD patients off medication, with no activation of directly or indirectly related target words evident in PD patients off medication. These results further clarify the nature of dopamine's neuromodulatory influence on semantic activation, and suggest that the nature of altered semantic activation in PD may depend on the magnitude of dopamine depletion.     

Increased temporal and prefrontal activity in response to semantic associations in schizophrenia

CONTEXT: Loosening of associations has long been considered a core feature of schizophrenia, but its neural correlate remains poorly understood. OBJECTIVE: To test the hypothesis that, in comparison with healthy control subjects, patients with schizophrenia show increased neural activity within inferior prefrontal and temporal cortices in response to directly and indirectly semantically related (relative to unrelated) words. DESIGN: A functional neuroimaging study using a semantic priming paradigm. SETTING: Lindemann Mental Health Center, Boston, Mass. PARTICIPANTS: Seventeen right-handed medicated outpatients with chronic schizophrenia and 15 healthy volunteers, matched for age and parental socioeconomic status. INTERVENTIONS: Functional magnetic resonance imaging as participants viewed directly related, indirectly related, and unrelated word pairs and performed a lexical decision task. MAIN OUTCOME MEASURES: Event-related functional magnetic resonance imaging measures of blood oxygenation level-dependent activity (1) within a priori temporal and prefrontal anatomic regions of interest and (2) at all voxels across the cortex. RESULTS: Patients and controls showed no behavioral differences in priming but opposite patterns of hemodynamic modulation in response to directly related (relative to unrelated) word pairs primarily within inferior prefrontal cortices, and to indirectly related (relative to unrelated) word pairs primarily within temporal cortices. Whereas controls showed the expected decreases in activity in response to semantic relationships (hemodynamic response suppression), patients showed inappropriate increases in response to semantic relationships (hemodynamic response enhancement) in many of the same regions. Moreover, hemodynamic response enhancement within the temporal fusiform cortices to indirectly related (relative to unrelated) word pairs predicted positive thought disorder. CONCLUSION: Medicated patients with chronic schizophrenia, particularly those with positive thought disorder, show inappropriate increases in activity within inferior prefrontal and temporal cortices in response to semantic associations.     

Disturbance of semantic processing in temporal lobe epilepsy demonstrated with scalp ERPs

We investigated event-related potentials (N400, LPC and CNV) elicited in temporal lobe epilepsy (TLE) patients and control subjects from scalp electrodes, using a word-pair category matching paradigm. Each prime consisted of a Japanese noun (constructed from 2-4 characters of the Hiragana) followed by a Chinese character (Kanji) as the target, the latter representing one of five semantic categories. There were two equally probable target conditions: match or mismatch. Each target was preceded by a prime, either belonging to, or not belonging to, the same semantic category. The subjects were required to respond with a specified button press to the given target, according to the condition. We found RTs to be longer under the mismatch condition in both subject groups. The N400 amplitude was reduced in TLE subjects under both conditions, although LPC and CNV amplitudes showed no significant differences. These results suggest that scalp N400 is capable of demonstrating disturbance of semantic processing in TLE non-invasively.     

Automatic activation of the semantic network in schizophrenia: evidence from event-related brain potentials.

BACKGROUND: Language disorder associated with schizophrenia might be due to disturbances in both automatic activation and mechanisms of controlled attention. The contribution of each process to semantic memory dysfunction has not been determined for schizophrenia, and the semantic priming paradigm is well-suited for addressing this question. In the present report, event-related potentials (ERPs) elicited under conditions assumed to reveal automatic activation (short prime-target interval and low proportion of related words) are compared directly with ERPs elicited under conditions associated with controlled processing (long prime-target interval and high proportion of related words). METHODS: Visual ERPs were recorded during a lexical decision task, in which semantic relationship (associated and unassociated words), expectancy (relatedness proportions), and prime-target interval (250- and 850-msec inter-stimulus intervals [ISIs]) were varied. Diagnosis and expectancy were between-subjects factors; semantic relationship and ISI were repeated measures. The N400 priming effect (enhanced negativity to unassociated words) was compared between 34 male normal control subjects tested once and 37 male schizophrenia inpatients evaluated during their participation in a double-blind haloperidol maintenance therapy and placebo replacement protocol. RESULTS: The N400 priming effect for patients was significantly reduced during both pharmacologic phases, compared with controls. During haloperidol treatment, however, patients showed a significant N400 priming effect over the anterior scalp region and additionally under the automatic activation condition. The N400 priming effect was enhanced under the controlled processing condition for control subjects; this effect was not observed for patients. N400 amplitude elicited under the rapid presentation rate (250-msec ISI) differed between medicated patients and controls; groups did not differ for the 850-msec ISI. CONCLUSIONS: Findings suggest that automatic activation and mechanisms of controlled attention are both disrupted during semantic memory access for schizophrenia patients. Pharmacologic agents, such as haloperidol, might enhance automatic activation of the semantic network in this patient population, as indexed by the N400 component of the ERP.     

汉字单字词识别的N400

目的　探讨单词识别过程中事件相关电位N40 0成分的心理学意义。方法　在长 ( 60 0ms)与短 ( 2 0 0ms)两种刺激呈现间隔 (SOA)、3种语境 (相关、中性和无关 )条件下 ,进行词汇抉择作业 ,通过对反应时间 (RT)和事件相关电位 (ERP)的检测 ,观察目标词词汇抉择的语义启动效应 (RT效应和N40 0波幅效应 )。结果　长SOA时 ,RT实验有语义促进效应 (相关语境RT较中性语境短 )和抑制效应 (无关语境RT较中性语境长 ) ,而ERP实验只有N40 0波幅抑制效应 ;短SOA时 ,RT实验只有语义促进效应 ,而ERP实验无任何N40 0波幅效应。结论　结果表明 ,N40 0反映了词汇后水平的整合加工 ,而不反映词汇水平的词汇提取加工。     

Semantic and cross-case identity priming in patients with Parkinson's disease

Semantic and cross-case identity priming were investigated in nondemented patients with Parkinson's disease (PD) and controls using the Lexical Decision Task. Three conditions were administered that consisted of the presentation of prime and target word pairs. In the semantic priming condition the word pairs were semantically related (e.g., table-CHAIR), in the cross-case identity priming condition the word pairs consisted of the same word (e.g., noise-NOISE), and in the unrelated condition the word pairs were not related semantically (e.g., guns-DEEP). A fourth condition was also administered that consisted of the presentation of a prime word and a pronounceable nonword target (e.g., starved-FORVE). Participants were asked to indicate whether the target was a real word or a nonword. The prime and target were separated by either a short or long (250 ms or 1000 ms) stimulus onset asynchrony (SOA). Results indicated that PD patients displayed normal semantic priming (i.e., faster responding to the target in the semantic condition as compared to the unrelated condition) at both the short and long SOA. Similarly, PD patients displayed normal cross-case identity priming (i.e., faster responding to the target in the identity condition relative to the unrelated condition) at the long SOA. At the short SOA, however, PD patients displayed hyper identity priming relative to controls (134 ms vs. 50 ms). These results suggest that semantic processes are normal in nondemented PD patients but that the processes involved in accessing lexical information may be overly activated in these patients.