An MRI study of temporal lobe abnormalities and negative symptoms in chronic schizophrenia

Anderson, Jane; Wible, Cynthia G.; McCarley, Robert W.; Jakab, Marianna; Kasai, Kiyoto; Shenton, Martha E.

doi:10.1016/s0920-9964(01)00372-3

Cited by 100 publications

(70 citation statements)

References 55 publications

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“…Investigation of the functional correlates of FA in the uncinate fasciculus revealed significant inverse correlations with negative symptoms, including alogia and affective flattening. Our results thus converge with prior studies reporting an association between temporal gray (Anderson et al, 2002) and white (Sigmundsson et al, 2001) matter volumetric deficits and negative symptoms in patients with schizophrenia. Moreover, lower FA in this region correlated significantly with worse memory functioning.…”

Section: Discussionsupporting

confidence: 91%

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

Szeszko

Robinson

Ashtari

et al. 2007

Neuropsychopharmacol

225

184

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The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (po0.001, cluster size X100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure-function relations in schizophrenia and constraining neurobiological models of the disorder.

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Section: Discussionsupporting

confidence: 91%

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

Szeszko

Robinson

Ashtari

et al. 2007

Neuropsychopharmacol

225

184

View full text Add to dashboard Cite

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“…Neuroimaging studies report reductions in amygdalar volumes in schizophrenic patients (Rajarethinam et al, 2001, Anderson et al, 2002. In addition, fMRI studies revealed reduced amygdalar activation in schizophrenic subjects when evaluating facial expressions for emotional salience (Gur et al, 2002, Hempel et al, 2003 and this impairment appears to be specific to patients with primary negative symptoms (Anderson et al, 2002).…”

Section: Discussionmentioning

confidence: 97%

Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin

Lee¹,

Brady²,

Shapiro³

et al. 2007

Brain Research

240

188

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Neurodevelopmental changes induced by environmental stress exposure play a significant but poorly defined role in the etiology of schizophrenia. Exposure of pregnant female rats to a series of unpredictable stresses during the final week of pregnancy generates behavioral deficits and molecular changes in the offspring similar to those observed in schizophrenic individuals. We used this rat prenatal stress preparation to investigate social withdrawal behaviors that may have relevance to the negative symptoms of schizophrenia. The cumulative time adult male offspring of stress-exposed pregnant female rats actively interacted with a weight-matched, same-sex peer was decreased approximately 76% relative to non-stress exposed control rats. Prenatal stress exposure also diminished the quality of the social interaction behavior indicative of reduced social drive. Analysis of the oxytocinergic system in the prenatally stressed male rats revealed significantly less oxytocin mRNA in the paraventricular nucleus and increased oxytocin receptor binding in the central amygdala. Moreover, oxytocin, but not vasopressin, administration into the central amygdala reversed the social incompetence of the prenatally stressed rats without increasing behavior in nonstressed control animals. In addition, cross-fostering pups from prenatally stressed mothers to nonstressed mothers failed to improve the social deficit of the prenatally stressed male offspring. Two behavioral assays designed to measure anxiety did not differentiate the prenatally stressed rats from non-stressed controls. These data indicate that prenatal stress may be an etiologically appropriate animal model for some aspects of schizophrenic social withdrawal. Furthermore, unpredictable prenatal stress exposure selectively degrades social interaction behaviors without increasing anxiety measures.

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“…29 In humans, hippocampal abnormalities have been identified as important susceptibility factors for schizophrenia. [30][31][32][33][34] Recently, extensive studies have been focusing on information-processing deficits, as manifested by sensorimotor gating, in schizophrenia and other neuropsychiatric disorders. Nevertheless, how hippocampal abnormalities contribute to information-processing deficits remains to be explicated.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Hf-1b/Sp4, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. Molecular Psychiatry ( Keywords: transcription factor; hippocampus; schizophrenia; mouse model; behavior; Cre recombinase; genetic rescue Sp1, the prototypal member of the Sp family of transcription factors, has been demonstrated to be essential for embryogenesis. 1 The reduction of its expression in heterozygous Sp1 mice causes a decreased expression of its downstream target gene, MeCP2, whose mutation is responsible for Rett syndrome, a human neurodevelopmental disorder. 2 Recently, Sp1 and other glutamine-rich transcription factors have been implicated in the pathogenesis of neurodegenerative diseases. 3,4 Sp4, also known as HF1b, is another member of the Sp1 family of transcription factors. Sp1 and Sp4 proteins have approximately 50% homology in primary structure, which consists of two glutamine-rich transcription activation domains and Cterminal three zinc-finger DNA binding domains. 5 Both proteins recognize the same DNA binding motif with similar affinity, and often functionally substitute for each other in vitro. 6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes. The generated hypomorphic Sp4 allele mice were grossly normal and displayed no increased lethality. Unexpectedly, the mutant mice displayed both vacuolization in the hippocampus and abnormal behavioral phenotypes, particularly with regard to contextual memory and sensorimotor gating deficits. Hence, these studies suggest a new molecular pathway involving the Sp4 gene that functions within the hippocampu...

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An MRI study of temporal lobe abnormalities and negative symptoms in chronic schizophrenia

Cited by 100 publications

References 55 publications

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

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