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.     

An event-related brain potential study of direct and indirect semantic priming in schizophrenia

OBJECTIVE: Following a meaningful prime stimulus, schizophrenia patients have been hypothesized to exhibit impaired neurophysiological activation of related concepts in general, and/or supranormal activation of weakly related concepts in particular, within semantic memory. The former abnormality may occur at longer intervals, and the latter at shorter intervals, after the prime. The authors tested these hypotheses using the N400 event-related brain potential as a probe of activation of concepts in semantic memory. METHOD: Event-related potentials were recorded in 16 schizophrenia patients and 16 normal comparison subjects who viewed prime words, each followed by a target that was a directly (strongly) related word, indirectly (weakly) related word, unrelated word, or nonword, in a lexical-decision task. Equal numbers of each target type were presented 300 and 750 msec after the prime. RESULTS: In the comparison subjects, N400 amplitude was largest (most negative) following unrelated targets, intermediate after indirectly related targets, and smallest after directly related targets. In contrast, patients' N400 amplitudes did not differ between these target types, reflecting larger amplitudes following both directly and indirectly related targets in patients than in comparison subjects; these findings held regardless of prime-to-target stimulus-onset asynchrony. Within patients, at the longer asynchrony, larger N400 amplitudes after directly and indirectly related targets correlated with positive psychotic symptoms. CONCLUSIONS: The results suggest hypoactivation of strongly and weakly related concepts following a meaningful stimulus, regardless of interval, in schizophrenia. An N400 index of this hypoactivation correlated with severity of delusions, suggesting a role for abnormal semantic processing in their pathogenesis.     

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.     

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.     

Test–retest reliability and stability of N400 effects in a word-pair semantic priming paradigm

ObjectiveElicited by any meaningful stimulus, the N400 event-related potential (ERP) component is reduced when the stimulus is related to a preceding one. This N400 semantic priming effect has been used to probe abnormal semantic relationship processing in clinical disorders, and suggested as a possible biomarker for treatment studies. Validating N400 semantic priming effects as a clinical biomarker requires characterizing their test–retest reliability.MethodsWe assessed test–retest reliability of N400 semantic priming in 16 healthy adults who viewed the same related and unrelated prime-target word pairs in two sessions one week apart.ResultsAs expected, N400 amplitudes were smaller for related versus unrelated targets across sessions. N400 priming effects (amplitude differences between unrelated and related targets) were highly correlated across sessions (r = 0.85, P < 0.0001), but smaller in the second session due to larger N400s to related targets.ConclusionsN400 priming effects have high reliability over a one-week interval. They may decrease with repeat testing, possibly because of motivational changes.SignificanceUse of N400 priming effects in treatment studies should account for possible magnitude decreases with repeat testing. Further research is needed to delineate N400 priming effects’ test–retest reliability and stability in different age and clinical groups, and with different stimulus types.     

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.     

The underlying mechanisms of semantic memory loss in Alzheimer's disease and semantic dementia

Patients with Alzheimer's disease (AD) and patients with semantic dementia (SD) both exhibit deficits on explicit tasks of semantic memory such as picture naming and category fluency. These deficits have been attributed to a degradation of the stored semantic network. An alternative explanation attributes the semantic deficit in AD to an impaired ability to consciously retrieve items from the semantic network. The present study used an implicit lexical-decision priming task to examine the integrity of the underlying semantic network in AD and SD patients matched for degree of impairment on explicit semantic memory tasks. The AD (n=11) and SD (n=11) patient groups were matched for age, education, level of dementia and impairment on four explicit semantic memory tasks. Healthy elderly participants (n=22) were matched for age and education. Semantic priming effects were evaluated for three types of semantic relationships (attributes, category coordinates, and category superordinates) and compared to lexical associative priming. Healthy controls showed significant priming across all conditions. In contrast, AD patients showed normal superordinate priming, and significant (although somewhat reduced) coordinate priming, but no attribute priming. SD patients showed no priming effect for any semantic relationship. All groups showed significant associative priming. The results indicate that SD patients do indeed have substantial degradation of semantic memory, while AD patients have a partially intact network, accounting for priming in superordinate and coordinate conditions. These findings suggest that AD patients' impairment on explicit semantic tasks is the product of deficient explicit retrieval in combination with a partially degraded semantic network.     

Association of schizotypy with semantic processing differences: an event-related brain potential study

Disorganized speech in both schizophrenia and schizotypy has been hypothesized to result from abnormalities in how concepts activate one another in semantic memory. To study whether schizotypy is associated with differences in how categories activate their exemplars, we examined the N400 component of the event-related brain potential (ERP) elicited during a category-verification task. ERPs were recorded in young adults from the general population while they viewed category definitions each followed by a target that was either a high-typicality exemplar, low-typicality exemplar, or non-exemplar; participants' task was to indicate whether or not the target belonged to the category. Schizotypy was assessed via the Schizotypal Personality Questionnaire (SPQ). Overall, N400 amplitude was largest for non-exemplars, smallest for high-typicality exemplars, and intermediate for low-typicality exemplars. SPQ score was associated with decreased N400 amplitude to non-exemplars, and increased amplitude to both types of exemplars. SPQ score was negatively correlated with the N400 amplitude difference between non-exemplars and both low- and high-typicality exemplars, but was not correlated with the amplitude difference between low- and high-typicality exemplars. N400 amplitude differences between non-exemplars and both types of exemplars were correlated with the SPQ Interpersonal factor, but not the Disorganized factor. The results are consistent with an association of schizotypy with decreased use of context to activate related items and inhibit unrelated items.     

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.     

Semantic activation and verbal working memory maintenance in schizophrenic thought disorder: insights from electrophysiology and lexical ambiguity.

We have examined language processing using ambiguous words (homographs like panel or toast) and rapid or slow presentation rates while recording event-related brain potentials (ERPs). Homographs allow for tracking the train of thought at points of lexical ambiguity and detecting modulation of associative threads by previous context. Rapid presentation rates stress automatic semantic activation, and slow rates stress controlled verbal working memory contextual modulation. In conjunction with reaction times and performance, ERPs allow for objective measurement of activity related to language processing from word presentation through overt behavioral response. Smaller N400 to related and unrelated items at short stimulus onset asynchronies (SOAs), the presence of a semantic bias, and large N400 to related and unrelated items at long SOAs are present in schizophrenia. We describe a model of initial semantic memory hyper-priming and subsequent decay of information in verbal working memory stores, the activation-maintenance model of schizophrenic thought disorder hypothesized to underlie the thought disorder in schizophrenia.     

An effect of priming task repetition on memory processes in an epileptic with amnesia

The purpose of this paper is to investigate memory processes in an epileptic with amnesia. Selective impairment of memory in organic amnesia has been reported in some clinical observations. They also demonstrated that organic amnesia can retain some aspects of learning experience, despite their inability to recollect them. We investigated an effect of priming task repetition on memory processes in a female with organic amnesia aged 28 (probable encephalitic patient) and eight control college students aged 20-26. In this paper, her memory processes were analyzed, using the same picture priming task, carried twelve times during the period of seven months. We used semantic priming paradigm. Three types of prime-target pair were used: identical, semantically related and unrelated. After a prime picture, a target picture appeared on the CRT display. She was asked to name each target as rapidly and accurately as possible. We analysed reaction time (RT) in naming the picture targets, error rate, and verbal reports of the priming task in the pre- and post-examination interview. In the first examination, priming effect was observed in her RT as in the controls'. This suggests that she retained some amount of semantic memory, and the structure of her semantic memory closely resembled that in the controls. Naming RT reduced and error rate decreased with repetition of the examination. This suggests that she acquired picture naming skill during early few examinations. However it was difficult for her to recognize and recollect the picture stimuli in this period. Further, she did not show any episodic memory of the examinations. There was dissociation between improved RT performance and poor verbal reports during early few examinations. When the same priming task was repeated in early few examinations, the priming effect became weaker in her RT. In the controls, on the contrary, the priming effect remained during the whole task repetition. Semantic strategy was apparently used in the controls, but not in the amnesic patient. She apparently used strategy of non-semantic association between the prime and target. In the last few examinations, her naming RT delayed and the priming effect was observed again as in the first examination. She seemed to use semantic strategy. In addition to this priming effect, she re-collected a few pictures and showed some episodic memory of the examination.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Attentional modulation of unconscious "automatic" processes: evidence from event-related potentials in a masked priming paradigm

Automatic processes are usually thought to occur independently of any cognitive resources. This traditional view has been recently challenged by showing that temporal attention to a target stimulus is a prerequisite for "automatic" response priming. The event-related potential (ERP) study reported here extends this research by pursuing a somewhat different approach. In two experiments, it was investigated whether masked semantic priming effects can be modulated by temporal attention to the prime using a cueing procedure. We hypothesized that masked priming is amplified when attention is directed to the stimulus stream in the time window of masked prime presentation, even in the absence of any prime awareness. ERPs were recorded while subjects performed a primed lexical decision task. Target words were preceded by semantically related or unrelated masked prime words, which were not consciously identified. A cue stimulus prompted subjects to direct their attention to the stimulus stream either shortly before the masked prime (short cue interval) or a long time interval before. Priming affected the amplitude of the N400 ERP component, an electrophysiological index of semantic processing. Unrelated prime-target pairs elicited a larger N400 than related pairs (N400 priming effect). Most importantly, this masked N400 priming effect was strongest when the cue interval and the stimulus onset asynchronies were short. The present results show that temporal attention to the prime is a prerequisite for obtaining masked N400 priming effects. They also demonstrate that unconscious automatic processes are susceptible to attentional modulation.     

Event-related brain potentials elicited by morphological, homographic, orthographic, and semantic priming

The morphological structure of words, in terms of their stem morphemes and affixes, could influence word access and representation in lexical memory. Three experiments were carried out to explore the attributes of event-related potentials evoked by different types of priming. Morphological priming, with pairs of words related by their stem (hijo/hija [ son/ daughter]), produced a sustained attenuation (and even a tendency to positivity) of the N400 shown by unrelated words across the three experiments. Homographic priming (Experiment 1), using pairs of words with a superficially similar stem, but without morphological or semantic relation (foco/foca [floodlight/seal]), produced an initial attenuation similar to the morphological pairs, but which rapidly tended to form a delayed N400, due to the impossibility of integration. However, orthographic priming (rasa/rana [flat/frog]) in Experiment 2 does not produce attenuation of the N400 but an effect similar to that of unrelated pairs. Experiment 3 shows that synonyms advance more slowly than morphological pairs to meaning coherence, but finally produce a more positive peak around 600 msec.     

Reduced levels of specific autobiographical memories in schizophrenia

Autobiographical memory is intrinsically related to the self and personal identity. This study investigated whether both personal episodic memory and semantic memory are impaired in schizophrenia, a disease characterized by an abnormal personal identity. Personal episodic memory and personal semantic memory were investigated in 24 patients with schizophrenia and 24 normal subjects using an autobiographical fluency task and an autobiographical memory inquiry. Autobiographical memory scores and the proportion of specific memories were lower in patients with schizophrenia than in normal subjects. The deficit of personal episodic and semantic memory, as assessed by the autobiographical memory inquiry and the autobiographical fluency task, respectively, was most apparent after the onset of clinical symptoms. Schizophrenia is associated with an impairment of both personal episodic and semantic memory and with a reduction of specific autobiographical memories. Those impairments are consistent with the existence of an abnormal personal identity in patients with schizophrenia.     

Explicit semantic tasks are necessary to study semantic priming effects with high rates of repetition

ObjectiveThe purpose of the present study was to clarify in which experimental conditions the semantic processing of repeated words is preserved.MethodsWe contrasted a short (250 ms) and a long (1000 ms) stimulus onset asynchrony (SOA) in two different experiments, using a relatively low proportion of related words (30%). One group of participants performed a lexical decision task (LDT) and a second group performed an explicit semantic matching task with the same words (except for pseudowords) and the same task parameters. In both tasks, word stimuli consisted solely of two prime and two target words repeated throughout the experiment.ResultsThe effects of semantic priming on reaction time (RT) and the amplitude of the N400 ERP were absent for both the short and the long SOA in the LDT. In contrast, in the explicit semantic task, these effects were significant. In this task, the activity of N400 generators in the left superior temporal gyrus and the inferior parietal cortex significantly differentiated primed and unprimed trials but this effect did not interact with SOA.ConclusionsOur results indicate that task instruction is critical to preserve semantic processing with repeated presentations.SignificanceUsing explicit semantic designs, it may be possible to study associative or categorical relations between individual concepts.     

Verbal memory processes in schizophrenia patients and biological relatives of schizophrenia patients: intact implicit memory, impaired explicit recollection

Verbal memory deficits are arguably the most common cognitive abnormalities in biological relatives of schizophrenia patients. Because verbal memory is a complex cognitive function, it is necessary to differentiate its intact and compromised aspects in order to reveal aberrant neural systems that reflect genetic risk in relatives of schizophrenia patients. Using an experimental verbal memory task, we examined encoding, free-recall, repetition priming, and recognition of verbal material in 22 schizophrenia patients, 22 first-degree biological relatives of schizophrenia patients, and 23 nonpsychiatric control participants. Schizophrenia patients exhibited intact repetition priming, but worse size judgment task performance (encoding), recall, and recognition than the control participants. Biological relatives of schizophrenia patients exhibited intact size judgment task performance, repetition priming, and recognition, but a free-recall deficit. Although size judgment task performance at encoding was associated with recall of verbal material in schizophrenia and control groups, in the relative group encoding performance was associated with the degree of repetition priming. Findings are consistent with impaired explicit recollection of verbal material, but intact implicit verbal memory in schizophrenia patients and biological relatives of schizophrenia patients.     

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.     

Event-related potentials, lexical decision and semantic priming

ERPs were recorded during a lexical decision task in order to investigate electrophysiological concomitants of semantic priming. The stimuli were 240 words and 240 nonwords presented one per trial at a fixed intertrial interval. Subjects were required to classify each stimulus as a word or nonword by pressing one of two response buttons. ERPs were recorded from 14 scalp locations, the right suborbital ridge, and the left earlobe, all referred to a balanced non-cephalic reference. RT and error data confirmed that semantic priming occurred under the conditions employed: primed words (those preceded by a semantically related word) were identified as words faster and more accurately than were unprimed words (those preceded by semantically unrelated words or nonwords). ERPs for all stimulus types were characterized by a large positivity peaking between 550 and 650 msec, preceded by a negative-going deflection peaking at approximately 400 msec. ERPs for primed and unprimed words were shown to differ significantly, diverging 200-250 msec following stimulus onset, reaching a maximum near the peak of the negative-going deflection at 400 msec. These differences were observed at locations over both hemispheres and were maximal in the centroparietal region. Although P300 latency differences between primed and unprimed words were also obtained, the priming effect on ERPs at shorter latencies could not be explained solely by P300 latency effects. Possible relationships between these ERP concomitants of semantic priming and P300, N200, and N400 were discussed.