Dominance of Objects over Context in a Mediotemporal Lobe Model of Schizophrenia

Background: A large body of evidence suggests impaired context processing in schizophrenia. Here we propose that this impairment arises from defective integration of mediotemporal ‘what ’ and ‘where ’ routes, carrying object and spatial information to the hippocampus. Methodology and Findings: We have previously shown, in a mediotemporal lobe (MTL) model, that the abnormal connectivity between MTL regions observed in schizophrenia can explain the episodic memory deficits associated with the disorder. Here we show that the same neuropathology leads to several context processing deficits observed in patients with schizophrenia: 1) failure to choose subordinate stimuli over dominant ones when the former fit the context, 2) decreased contextual constraints in memory retrieval, as reflected in increased false alarm rates and 3) impaired retrieval of contextual information in source monitoring. Model analyses show that these deficits occur because the ‘schizophrenic MTL ’ forms fragmented episodic representations, in which objects are overrepresented at the expense of spatial contextual information. Conclusions and Significance: These findings highlight the importance of MTL neuropathology in schizophrenia, demonstrating that it may underlie a broad spectrum of deficits, including context processing and memory impairments. It is argued that these processing deficits may contribute to central schizophrenia symptoms such as contextuall

The acute mania of King George III: A computational linguistic analysis.

We used a computational linguistic approach, exploiting machine learning techniques, to examine the letters written by King George III during mentally healthy and apparently mentally ill periods of his life. The aims of the study were: first, to establish the existence of alterations in the King's written language at the onset of his first manic episode; and secondly to identify salient sources of variation contributing to the changes. Effects on language were sought in two control conditions (politically stressful vs. politically tranquil periods and seasonal variation). We found clear differences in the letter corpus, across a range of different features, in association with the onset of mental derangement, which were driven by a combination of linguistic and information theory features that appeared to be specific to the contrast between acute mania and mental stability. The paucity of existing data relevant to changes in written language in the presence of acute mania suggests that lexical, syntactic and stylometric descriptions of written discourse produced by a cohort of patients with a diagnosis of acute mania will be necessary to support the diagnosis independently and to look for other periods of mental illness of the course of the King's life, and in other historically significant figures with similarly large archives of handwritten documents

Synaptic Dysbindin-1 Reductions in Schizophrenia Occur in an Isoform-Specific Manner Indicating Their Subsynaptic Location

Background: An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific. Methodology/Principal Findings: Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171). Conclusions/Significance: Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory

Wegner on Hallucinations, Inconsistency, and the Illusion of Free Will. Some Critical Remarks

Wegner's argument on the illusory nature of conscious will, as developed in The Illusion of Conscious Will (2002) and other publications, has had major impact. Based on empirical data, he develops a theory of apparent mental causation in order to explain the occurrence of the illusion of conscious will. Part of the evidence for his argument is derived from a specific interpretation of the phenomenon of auditory verbal hallucinations as they may occur in schizophrenia. The aim of this paper is to evaluate the validity of the evidence on auditory verbal hallucinations as employed by Wegner. I conclude that auditory hallucinations do not provide solid evidence for Wegner's theory. Moreover, the phenomena in schizophrenia provide, in fact, an argument against part of Wegner's theory of apparent mental causation. © 2010 The Author(s)

Automated computerized analysis of speech in psychiatric disorders

PURPOSE OF REVIEW: Disturbances in communication are a hallmark of severe mental illnesses. Recent technological advances have paved the way for objectifying communication using automated computerized linguistic and acoustic analysis. We review recent studies applying various computer-based assessments to the natural language produced by adult patients with severe mental illness. RECENT FINDINGS: Automated computerized methods afford tools with which it is possible to objectively evaluate patients in a reliable, valid and efficient manner that complements human ratings. Crucially, these measures correlate with important clinical measures. The clinical relevance of these novel metrics has been demonstrated by showing their relationship to functional outcome measures, their in vivo link to classic ‘language’ regions in the brain, and, in the case of linguistic analysis, their relationship to candidate genes for severe mental illness. SUMMARY: Computer based assessments of natural language afford a framework with which to measure communication disturbances in adults with SMI. Emerging evidence suggests that they can be reliable and valid, and overcome many practical limitations of more traditional assessment methods. The advancement of these technologies offers unprecedented potential for measuring and understanding some of the most crippling symptoms of some of the most debilitating illnesses known to humankind

What do we really know about blunted vocal affect and alogia? A meta-analysis of objective assessments

Deficits in nonverbal vocal expression (e.g., blunted vocal affect, alogia) are a hallmark of schizophrenia and are a focus of the Research Domain Criteria initiative from the National Institute of Mental Health. Results from studies using symptom rating scales suggest these deficits are profound; on the order of four to six standard deviations. To complement this endeavor, we conducted a meta-analysis of studies employing objective analysis of natural speech in patients with schizophrenia and nonpsychiatric controls. Thirteen studies, collectively including 480 patients with schizophrenia and 326 nonpsychiatric controls, were identified. There was considerable variability across studies in which aspects of vocal communication were examined and in the magnitudes of deficit. Overall, speech production (reflecting alogia) was impaired at a large effects size level (d = −.80; k = 13), whereas speech variability (reflecting blunted affect) was much more modest (d = −.36; k = 2). Regarding the former, this was largely driven by measures of pause behavior, as opposed to other aspects of speech (e.g., number of words/utterances). On the other hand, ratings of negative symptoms across these studies suggested profound group differences (d = 3.54; k = 4). These data suggest that only certain aspects of vocal expression are affected in schizophrenia, and highlight major discrepancies between symptom rating and objective-based measures. The discussion centers on advancing objective analysis for understanding vocal expression in schizophrenia and for identifying and defining more homogenous patient subsets for study