1. Is the Anterior Splenium an Intermediate Phenotype across the Psychosis Dimension ?
AN. Francis PhD 2, IT. Mathew1 BA N. Tandon1 BS B. Clementz3, PhD GD. Pearlson MD4 JA. Sweeney5,PhD CA. Tamminga5 MD, & MS. Keshavan MD1
1 Beth Israel Deaconness Medical Center, Harvard University, Boston MA 2. Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, VA Boston Medical Center, Boston 3. Department of Psychology & Neuroscience, BioImaging Research Center, University of Georgia, Athens, Georgia 4. Olin Neuropsychiatry Research Center, Institute of Living, Hartford CT, and Yale University School of Medicine, New Haven, Connecticut 5. UT Southwestern Medical Center, Dallas Texas
Bipolar Schizophrenia Network on Intermediate Phenotypes
Abstract
Methods
Background: The corpus callosum (CC) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. It remains unclear whether CC alterations are related to the underlying familial diathesis for psychotic disorders. We examined corpus callosum (CC) and, its sub region volumes, and their relationship to cognition and in subjects with schizophrenia (SZ), psychotic bipolar disorder (PBD), schizoaffective disorder their first degree relatives and in healthy controls.
Methods: We present findings from morphometric and neurocognitive analyses of 1501 subjects [SZ (n=230); PBD (n=192); SZA (n=145); SZ relatives n=195; PBD relatives n=175; and SZA relatives (n= 112) and Controls (340). MPRAGE T1 scans across 6 sites were obtained using 3.T magnets. Image processing was done using FreeSurfer 5.1. Sub-regions of the CC were measured using the Witelson’s classification. Neurcognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS).
Results: The posterior and anterior splenium (splenia) were significantly reduced across the groups. SZ, PBD and SZA probands showed significant reductions while relatives showed reductions of intermediate severity in the splenia. The splenia volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age related decrease in the volume of the anterior splenium. The anterior splenium in PBD showed greater correlation with psychotic symptomatology as shown by the PANSS. All five sub regions showed significantly high familiality.
Conclusions: The splenia volume was reduced across the psychosis dimension. However, this volume reduction impacts cognition in the groups differentially.
Corpus Callosum Divisions
Participants: Subjects were recruited from 5 different sites across the US, and consisted of racially diverse Schizophrenia probands, Schizoaffective probands, BiPolar probands their relatives, and healthy controls. The subjects were diagnosed as per DSM-IV criteria on diagnostic interviews (Structured Clinical Interview - SCID) conducted by trained clinicians and a “best estimate” consensus diagnosis.
Image acquisition High resolution isotropic T1-weighted MPRAGE scans (TR=6.7 msec, TE= 3.1 msec, 80 flip angle, 256x240 matrix size, total scan duration=10:52.6 minutes, 170 sagittal slices, 1mm slice thickness, 1x1x1.2 mm3 voxel resolution) were obtained following the Alzheimer’s Disease Neuroimaging Initiative (ADNI) protocol. All images underwent rigorous data quality control. Brains were processed using FreeSurfer v5.1 (Desikan et al, 2006). After image processing, brains were checked for remaining dura or sinus that could interfere with accurate segmentation.
Fig 1: Anterior Splenium across the AGE spectrum
Results
We used multivariate analyses to examine the effect of diagnosis, effects of familial SZ, BD and schizoaffective –risk on CC volume in comparison with a matched healthy control group. In addition to total CC volume, each callosal subregional volume was used as a dependent variable, with study group and gender as categorical predictors, and age, site and intra cranial volume (ICV) as covariates. We ran Spearman rho correlations between regions that showed significant differences between the groups and measures of symptom severity such as the PANSS since the data was not normally distributed. We also performed partial correlations between significantly altered CC volumes and measures of cognition within the BACS inventory. Age was used as a categorical variable to examine interactions with DX, sex and site.
The posterior and anterior splenium (splenia) were significantly reduced across the groups. SZ, PBD and SZA probands showed significant reductions while relatives showed reductions of intermediate severity in the splenia. The splenia volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age related decrease in the volume of the anterior splenium. The anterior splenium in PBD showed greater correlation with psychotic symptomatology as shown by the PANSS. All five sub regions showed significantly high familiality.
Introduction
The corpus callosum (CC) is the main white matter tract connecting the two cerebral hemispheres, and consists of approximately million fibers in humans (Aboitiz et al., 1992a; Aboitiz et al., 1992b). The CC communicates perceptual, cognitive, mnemonic, learned, and volitional information between the two brain hemispheres (Bogen et al., 1965) and plays a pivotal role in integration of information. The fiber connections between corresponding hemispheric regions are topographically arranged across the callosum (de Lacoste et al., 1985).
We examined Corpus Callosum (CC) volume, its sub regions and neurocognitive function in subjects with Schizophrenia (SZ), psychotic bipolar disorder (BP) their relatives and in healthy controls. We used a Witelson’s type classification for subdividing the CC. We present findings from morphometric and neurocognitive analyses of 1501 subjects [SZ (n=230); PBD (n=192); SZA (n=145); SZ relatives n=195; PBD relatives n=175; and SZA relatives (n= 112) and Controls (340).
Fig 2: Anterior Splenium against Duration of Illness
Discussion
Although anterior splenium volume reduction may be a common feature between SZ, BP, SZA and their relatives, the impact on cognitive function is different. The anterior splenium fulfills the 5 criteria for classification as an endophenotype across the Psychosis spectrum. These finding represents a potentially important clue to a further understanding of the pathogenetic differences between the three major psychoses.
Select References
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Francis AN, Bhojraj TS, Kulkarni S, Prasad KM, Eack SM, Montrose DM, Keshavan MS. Abnormalities of the Corpus Callosum in Non Psychotic high-risk offspring of Schizophrenia patients. Psychiatry Research – Neuroimaging Volume 191, Issue 1, Pages January (6):
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