Disturbed frontal gyrification within families affected with schizophrenia

Department of Psychiatry and Psychotherapy, University of Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Germany.
Journal of Psychiatric Research (Impact Factor: 3.96). 11/2007; 41(10):805-13. DOI: 10.1016/j.jpsychires.2006.07.018
Source: PubMed


Recently, in a post-mortem and a subsequent structural MR study, a significantly increased gyrification index (GI) was demonstrated in the frontal lobe in individuals with schizophrenia. To examine whether frontal lobe hypergyria is region-specific and whether this might be a suitable endophenotype in the search for the genetic basis of schizophrenia, the frontal as well as parieto-occipital GI were determined in MRI scans of families affected with schizophrenia.
In the MRI scans of 48 subjects suffering from schizophrenia, in 82 of their first-degree relatives and in 41 control subjects, the GI was determined in three sections anterior to the genu of the corpus callosum and three sections posterior to the splenium, thus allowing for a selective determination of this measure in the frontal as well as the parietal lobe. Outer and inner contours constituting the GI was determined in each section by manual tracing. Statistical analysis was performed using MANOVA with factors diagnostic group and intervening factors from preliminary analyses.
The frontal, but not parieto-occipital GI was significantly higher in schizophrenic patients as well as unaffected relatives compared with control subjects (right: 7%, F=13.24, df=3, 155, p<0.0005, left: 6%, F=8.92, df=3, 155, p<0.0005). There was no overall difference between affected and unaffected family members. On the left side however, there was a significant interaction between diagnostic group and genetic loading (F=4.68, df=2, 101, p=0.01): significantly higher GI was found in affected compared with unaffected family members only in uniaffected and not multiaffected families.
These results support our primary finding of hypergyria in the frontal lobe in schizophrenic patients. Compared to the parietal lobe, hypergyria seems to affect the frontal lobe selectively and serves as a suitable neurodevelopmental, possibly even an endophenotypic marker.

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    • "Such structural effects on cortical folding might then relate to functional pathologies of connectivity [White and Hilgetag, 2011]. Also, recent findings suggest a genetic impact on (frontal) gyrification in families affected with schizophrenia [Falkai et al., 2007]. However, schizophrenia can manifest at different stages of brain development (late childhood, adolescence, or adulthood), and it also shows considerable heterogeneity of clinical phenotype, disease course, as well as genetic load in different patients. "
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    ABSTRACT: Schizophrenia is assumed to be a neurodevelopmental disorder, which might involve disturbed development of the cerebral cortex, especially in frontal and medial temporal areas. Based on a novel spherical harmonics approach to measuring complexity of cortical folding, we applied a measure based on fractal dimension (FD) to investigate the heterogeneity of regional cortical surface abnormalities across subgroups of schizophrenia defined by symptom profiles. A sample of 87 patients with DSM-IV schizophrenia was divided into three subgroups (based on symptom profiles) with predominantly negative (n = 31), disorganized (n = 23), and paranoid (n = 33) symptoms and each compared to 108 matched healthy controls. While global FD measures were reduced in the right hemisphere of the negative and paranoid subgroups, regional analysis revealed marked heterogeneity of regional FD alterations. The negative subgroup showed most prominent reductions in left anterior cingulate, superior frontal, frontopolar, as well as right superior frontal and superior parietal cortices. The disorganized subgroup showed reductions in bilateral ventrolateral/orbitofrontal cortices, and several increases in the left hemisphere, including inferior parietal, middle temporal, and midcingulate areas. The paranoid subgroup showed only few changes, including decreases in the right superior parietal and left fusiform region, and increase in the left posterior cingulate cortex. Our findings suggest regional heterogeneity of cortical folding complexity, which might be related to biological subgroups of schizophrenia with differing degrees of altered cortical developmental pathology. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
    Human Brain Mapping 04/2014; 35(4). DOI:10.1002/hbm.22283 · 5.97 Impact Factor
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    • "In patients, fetal hypoxia has been related to increased ventricular size and reduced cortical gray matter (McNeil et al., 2000; Cannon et al., 2002b; Falkai et al., 2003), but results are not consistent (Haukvik et al., 2009). Assessment of the two-dimensional gyrification index (GI) revealed no relationship between obstetric complications and cortical folding (Falkai et al., 2007), but after application of a three-dimensional local GI calculation cortical gyrification has been observed to be reduced in the Broca's area in patients and healthy controls with obstetric complication (Haukvik et al., 2012). Since early stages of gyrification take place during gestational week 16 with a rapid increase in the third trimester (Armstrong et al., 1995), this possibly reflects neurodevelopmental disturbances. "
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    ABSTRACT: During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders.
    Frontiers in Neuroscience 02/2014; 8(8):19. DOI:10.3389/fnins.2014.00019 · 3.66 Impact Factor
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    • ", Narr et al. [2004], Harris et al. [2004], Falkai et al. [2007] and Sallet et al. [2003] MRI gyrification Indices Mean increase in gyrification in right prefrontal region in males. Narr et al [2004] found significant increases in cortical folding in the right superior frontal cortex [Harris et al., 2004], in male but not female patients [Narr et al., 2004]; bilateral increase in SCHZ [Falkai et al., 2007] decrease on left [Sallet et al., 2003]. "
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    ABSTRACT: Sex differences in psychosis and their interaction with laterality (systematic departures from 50:50 left-right symmetry across the antero-posterior neural axis) are reviewed in the context of the X-Y gene hypothesis. Aspects of laterality (handedness/cerebral asymmetry/the torque) predict (1) verbal and non-verbal ability in childhood and across adult life and (2) anatomical, physiological, and linguistic variation relating to psychosis. Neuropsychological and MRI evidence from individuals with sex chromosome aneuploidies indicates that laterality is associated with an X-Y homologous gene pair. Within each mammalian species the complement of such X-Y gene pairs reflects their potential to account for taxon-specific sexual dimorphisms. As a consequence of the mechanism of meiotic suppression of unpaired chromosomes such X-Y gene pairs generate epigenetic variation around a species defining motif that is carried to the zygote with potential to initiate embryonic gene expression in XX or XY format. The Protocadherin11XY (PCDH11XY) gene pair in Xq21.3/Yp11.2 in probable coordination with a gene or genes within PAR2 (the second pseudo-autosomal region) is the prime candidate in relation to cerebral asymmetry and psychosis in Homo sapiens. The lately-described pattern of sequence variation associated with psychosis on the autosomes may reflect a component of the human genome's adjustment to selective pressures generated by the sexually dimorphic mate recognition system. © 2013 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by John Wiley and Sons, Ltd.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2013; 162(8). DOI:10.1002/ajmg.b.32202 · 3.42 Impact Factor
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William G Honer