Papers

BACKGROUND: Schizophrenia is characterized by small reductions in cortical gray matter volume, particularly in the temporal and prefrontal cortices. The question of whether cortical thickness is reduced in schizophrenia has not been addressed using magnetic resonance imaging (MRI) techniques. Our objectives were to test the hypothesis that cortical thinning in patients with schizophrenia (relative to control subjects) is greater in temporal and prefrontal regions of interest (ROIs) than in control ROIs (superior parietal, calcarine, postcentral, central, and precentral cortices), and to obtain an unbiased estimate of the distribution of cortical thinning in patients (relative to controls) by constructing mean and statistical cortical thickness difference maps. METHODS: Participants included 33 right-handed outpatients receiving medication and meeting DSM-IV criteria for schizophrenia and 32 healthy volunteers, matched on age and parental socioeconomic status. After high-resolution MRI scans, models of the gray-white and pial surfaces were generated for each individual’s cortex, and the distance between these 2 surfaces was used to compute cortical thickness. A surface-based averaging technique that aligned the main cortical folds across individuals allowed between-group comparisons of thickness within ROIs, and at multiple, uniformly sampled loci across the cortical ribbon. RESULTS: Relative to controls, patients showed greater cortical thinning in temporal-prefrontal ROIs than in control ROIs, as revealed by a significant (P<.009) interaction between group and region type. Cortical thickness difference maps revealed significant (at P<.05, corrected) thinning within the orbitofrontal cortices bilaterally; the inferior frontal, inferior temporal, and occipitotemporal cortices on the left; and within the medial temporal and medial frontal cortices on the right. Superior parietal and primary somatosensory and motor cortices were relatively spared, even at subthreshold significance levels. CONCLUSIONS: Patients with chronic schizophrenia showed widespread cortical thinning that particularly affected the prefrontal and temporal cortices. This thinning might reflect underlying neuropathological abnormalities in cortical structure.

The aim of this study was to determine whether or not the brain distinguishes between two types of conceptual relationships between noun-phrases (NPs) and verbs during online processing of simple, unambiguous English sentences. A total of 15 participants read and made plausibility judgments on sentences that were presented word-by-word. Event-related potentials elicited by critical verbs were measured. In all cases, the critical verb assigned a thematic role of ’agent’ to its subject NP. In non-violated sentences (e.g. "For breakfast the boys would only eat em leader"), the preceding NP was animate ("boys") and was a likely agent for a given verb ("eat") given its preceding context ("For breakfast"). In both types of conceptually violated sentences, the NPs were unlikely agents for the verbs given their preceding contexts. In ’thematic role animacy violations’ (e.g. "For breakfast the eggs would only eat em leader"), the NP was inanimate ("eggs") and was therefore more likely to occupy the role of ’theme’ than ’agent’, i.e. eggs, being inanimate, cannot eat but they can be eaten. In ’non-thematic role pragmatic violations’ (e.g. "For breakfast the boys would only bury em leader"), the thematic role of agent assigned by the verb ("bury") to its preceding NP ("boys") is inherently acceptable (boys can bury), but the sentence is still pragmatically incongruous given the preceding context ("At breakfast"). As expected, the non-thematic role pragmatic violations elicited a significant N400 effect. The thematic role animacy violations elicited a smaller N400 effect that only approached significance across all participants. The thematic role animacy violations, however, elicited a significant P600 effect-an ERP component that is most commonly associated with processing syntactic information during language comprehension. We discuss the possibility that the P600 was elicited by the thematic role animacy violations (but not by the non-thematic role pragmatic violations) because, in the former but not the latter, there was an online attempt to structurally repair and make sense of the sentences by reassigning the thematic role of the NP that preceded the critical verb from ’agent’ to ’theme’. Our findings suggest a qualitative neural distinction in processing these two types of conceptual anomalies within simple, unambiguous sentences.

The aim of this study was to gain further insights into how the brain distinguishes between meaning and syntax during language comprehension. Participants read and made plausibility judgments on sentences that were plausible, morphosyntactically anomalous, or pragmatically anomalous. In an event-related potential (ERP) experiment, morphosyntactic and pragmatic violations elicited significant P600 and N400 effects, respectively, replicating previous ERP studies that have established qualitative differences in processing conceptually and syntactic anomalies. Our main focus was a functional magnetic resonance imaging (fMRI) study in which the same subjects read the same sentences presented in the same pseudorandomized sequence while performing the same task as in the ERP experiment. Rapid-presentation event-related fMRI methods allowed us to estimate the hemodynamic response at successive temporal windows as the sentences unfolded word by word, without assumptions about the shape of the underlying response function. Relative to nonviolated sentences, the pragmatic anomalies were associated with an increased hemodynamic response in left temporal and inferior frontal regions and a decreased response in the right medial parietal cortex. Relative to nonviolated sentences, the morphosyntactic anomalies were associated with an increased response in bilateral medial and lateral parietal regions and a decreased response in left temporal and inferior frontal regions. Thus, overlapping neural networks were modulated in opposite directions to the two types of anomaly. These fMRI findings document both qualitative and quantitative differences in how the brain distinguishes between these two types of anomalies. This suggests that morphosyntactic and pragmatic information can be processed in different ways but by the same neural systems.

Schizophrenia is, at once, a biological disease, a neuropsychological disorder and a dysfunction of social interactions. This presents clinicians with a series of problems with regards to therapy. In the first section of this article, some of the clinical challenges that face those attempting to develop new drugs, are summarised. Several potential pharmacological therapeutic targets that have been, and are continuing to be used, in the development of new antipsychotic drugs, are then considered. This is followed by an outline of the pharmacological and clinical profiles of some of the newer generation antipsychotics, as well as investigational drugs in the pipeline for schizophrenia. Finally, the implications of the introduction of these new drugs for the management of schizophrenia, are discussed.

Deficits in language comprehension in schizophrenia were examined using event-related potentials (ERPs). Schizophrenic and healthy participants read sentences in which the first clause ended with a homograph, and the second clause started with a target word that was semantically related to the homograph’s dominant meaning (e.g., 1. Diving was forbidden from the bridge because the river had rocks in it. or 2. The guests played bridge because the river had rocks in it.). Processing of the targets (e.g., “river”) was expected to be primarily influenced by the preceding overall sentence context (congruent in 1; incongruent in 2) in healthy participants, but to be inappropriately affected by the dominant meaning of homographs (e.g., the “structure” meaning of “bridge”) in sentences like 2 in schizophrenic patients. The N400 ERP component that is known to be sensitive to contextual effects during language processing confirmed these predictions. This showed that language abnormalities in schizophrenia may be related to deficient processing of context-irrelevant semantic representations of words from the discourse.

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.

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