Copy Number Variants and Schizophrenia Risk
Large rare DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia, autism and mental retardation. As these conditions are associated with reduced fecundity, these pathogenic CNVs are likely to be depleted from the population by selection, and must be replenished by new de novo events. Rees et al. (pages 1109–1114) show that the 10 most robustly implicated loci for these disorders undergo strong selection and have high mutation rates. The rarest CNVs had the highest selection coefficients and odds ratios to develop schizophrenia.
Certain CNVs, relatively rare mutations that influence the number of gene copies in the genome, are known risk factors for schizophrenia and related disorders. Melhem et al. (pages 1115–1121) report on risk CNVs found in Palauan subjects ascertained for psychotic disorders, comparing them to those seen in other samples, typically of European ancestry. Risk CNVs were similar across ancestries. In Palau, few risk CNVs have existed for many generations, consistent with the variants diminishing reproductive success.
Neural and Cognitive Dysfunction in Schizophrenia
Positive symptoms of schizophrenia can reflect an inability to distinguish internal thoughts from external reality. Capturing these symptoms in animals has been elusive. Here, McDannald et al. (pages 1122–1126) demonstrate that adult rats given neonatal ventral hippocampal lesions, an animal model of schizophrenia, have difficulty distinguishing an internal representation of reward from a real reward. This finding may provide a basis for using animals to explore the neural dysfunction associated with positive symptoms of schizophrenia.
To examine the neural substrates of altered self-reference in schizophrenia, Menon et al. (pages 1127–1133) presented schizophrenia patients with delusions of reference and healthy controls with ambiguous statements while undergoing magnetic resonance imaging (MRI). Patients endorsed many more of the generic statements than did controls and showed slower reaction times in classifying stimuli as not being specifically about them. Patients also showed reduced differentiation in the functional MRI response to self-relevant and non-self-relevant stimuli in parts of the medial prefrontal cortex, insula and striatal regions.
Schizophrenia is associated with reduced functional connectivity between regions of the cerebral cortex. In this study, Hinkley et al. (pages 1134–1142) examined imaginary coherence of spontaneous magnetoencephalography recordings and found specific regions of reduced alpha (8-12 Hz) functional connectivity in patients with schizophrenia, compared to healthy controls. Functional connectivity in frontal and temporal cortex correlated with patient symptoms, suggesting that this may be an important treatment target in schizophrenia.
Catani et al. (pages 1143–1150) used a novel diffusion imaging approach to perform virtual dissections of language pathways in schizophrenia patients and healthy controls. They report bilaterally reduced fractional anisotropy in the arcuate fasciculi of patients, relative to controls. In patients, more extensive bilateral damage was associated with a greater vulnerability to auditory verbal hallucinations. These findings suggest a selective vulnerability of specific anatomical connections to Wernicke's territory, an area normally involved in auditory comprehension.
Zandbelt et al. (pages 1151–1158) used functional MRI to investigate two forms of inhibitory control in patients with schizophrenia and unaffected siblings of patients. They showed that patients and siblings were impaired in proactive inhibition (anticipation of stopping), whereas reactive inhibition (outright stopping) was unaffected. Reduced proactive inhibition was associated with cortico-striatal dysfunction and poor working memory.
Using functional MRI, Anticevic et al. (pages 1159–1168) examined the effects of various types of distraction, including aversive and nonemotional distraction, on cognition in patients with schizophrenia. They found that patients were more susceptible to distraction, regardless of interference type, compared to controls. Furthermore, patients showed abnormalities in regions involved in resisting distraction, suggesting a general interference-filtering deficit in schizophrenia.
Successful social functioning requires a theory of mind (ToM), i.e., the capacity to understand how another person's perspective influences one's thoughts, feelings, and behavior. Individuals with schizophrenia have behavioral deficits in ToM skills, yet little is known about the underlying neural mechanisms. Here, Hooker et al. (pages 1169–1178) show that among schizophrenia participants, reduction in gray matter volume in the ventromedial prefrontal cortex is strongly related to ToM skills. These findings identify a neural structure that could be a potential target for treatment.
Paliperidone Clinical Trial in Adolescents
Paliperidone extended-release (ER) is approved for schizophrenia treatment in adults. In this double-blind, randomized, placebo-controlled study, Singh et al. (pages 1179–1187) evaluated once-daily paliperidone ER for treatment of schizophrenia in adolescents. After six weeks, 3, 6 and 12 mg of paliperidone ER, by actual dose strengths rather than weight-based dosing, significantly improved symptoms of schizophrenia in adolescents. No new safety concerns were reported.
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© 2011 Published by Elsevier Inc. All rights reserved.
