The schizophrenia syndrome is clinically characterized by abnormal constructions of meaning during comprehension (delusions), perception (hallucinations), action (disorganized and non-goal-directed behavior) and language production (thought disorder). This article provides an overview of recent studies from our laboratory that have used event-related potentials and functional magnetic resonance imaging to elucidate abnormalities in temporal and spatial patterns of neural activity as meaning is built from language and real-world visual events in schizophrenia. Our findings support the hypothesis that automatic activity across semantic memory spreads further within a shorter period of time in thought-disordered patients, relative to non-thought-disordered patients and healthy controls. Neuroanatomically, increased activity to semantic associates is reflected by inappropriate recruitment of temporal cortices. In building meaning within sentences, the fine balance between semantic memory-based mechanisms and semantic-syntactic integration (dictating "who does what to whom") is disrupted, such that comprehension is driven primarily by semantic memory-based processes. Neuroanatomically, this imbalance is reflected by preserved (and sometimes increased) activity within temporal and inferior prefrontal cortices, but abnormal modulation of dorsolateral prefrontal and parietal cortices. In building meaning across sentences (discourse), patients fail to immediately construct coherence links, but may show inappropriate recruitment of temporal and inferior prefrontal cortices to incoherent discourse, again reflecting inappropriate semantic memory-based processing (abnormal inferencing). Finally, these abnormalities may generalize to real-world visual event comprehension, where patients show reduced neural activity in determining relationships around goal-directed actions, and comprehension is again dominated by semantic memory-based mechanisms.
In 1980, the N400 event-related potential was described in association with semantic anomalies within sentences. When, in 1992, a second waveform, the P600, was reported in association with syntactic anomalies and ambiguities, the story appeared to be complete: the brain respected a distinction between semantic and syntactic representation and processes. Subsequent studies showed that the P600 to syntactic anomalies and ambiguities was modulated by lexical and discourse factors. Most surprisingly, more than a decade after the P600 was first described, a series of studies reported that semantic verb-argument violations, in the absence of any violations or ambiguities of syntax can evoke robust P600 effects and no N400 effects. These observations have raised fundamental questions about the relationship between semantic and syntactic processing in the brain. This paper provides a comprehensive review of the recent studies that have demonstrated P600s to semantic violations in light of several proposed triggers: semantic-thematic attraction, semantic associative relationships, animacy and semantic-thematic violations, plausibility, task, and context. I then discuss these findings in relation to a unifying theory that attempts to bring some of these factors together and to link the P600 produced by semantic verb-argument violations with the P600 evoked by unambiguous syntactic violations and syntactic ambiguities. I suggest that normal language comprehension proceeds along at least two competing neural processing streams: a semantic memory-based mechanism, and a combinatorial mechanism (or mechanisms) that assigns structure to a sentence primarily on the basis of morphosyntactic rules, but also on the basis of certain semantic-thematic constraints. I suggest that conflicts between the different representations that are output by these distinct but interactive streams lead to a continued combinatorial analysis that is reflected by the P600 effect. I discuss some of the implications of this non-syntactocentric, dynamic model of language processing for understanding individual differences, language processing disorders and the neuroanatomical circuitry engaged during language comprehension. Finally, I suggest that that these two processing streams may generalize beyond the language system to real-world visual event comprehension.
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.
Auditory verbal hallucinations are a common and distressing symptom experienced by patients with schizophrenia. They can be understood as arising from an impairment in reality monitoring-the process by which internally and externally generated events are distinguished. This impairment might arise through primary abnormalities in the reality-monitoring mechanism or through secondary mechanisms (abnormalities in the perceptual characteristics of internally generated events or in the perception of externally generated events). This article examines evidence for and against an association between abnormalities in reality monitoring and auditory verbal hallucinations in schizophrenia. A comprehensive review of the psychological literature suggests that there is little evidence for an association between auditory verbal hallucinations and secondary mechanisms leading to abnormalities in reality monitoring. There is some evidence suggesting that hallucinators show a primary reality-monitoring abnormality that is most apparent when patients are required to distinguish self from other in real time. To draw firmer conclusions, however, it is imperative that future studies select patient populations precisely, match control groups, and use consistent criteria for defining hallucinators.
Schizophrenia is often associated with cognitive deficits, particularly within the domains of memory and language. Specific cognitive deficits have recently been linked to psychotic phenomena, including verbal hallucinations and disorganized speech. Impairments of working and semantic memory are primarily due to dysfunction of the frontal cortex, temporal cortex, and hippocampus. Cognitive skills in schizophrenia predict social functioning and may serve as outcome measures in the development of effective treatment strategies.
