A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia
Introduction
Structural brain abnormalities have consistently been shown to be present in people with schizophrenia (reviewed in (Shenton et al., 2001, Glahn et al., in press)) and the illness has also been shown to be highly heritable (reviewed in McGue and Gottesman, 1991, DeLisi, 1997). The illness rarely is detected prior to late adolescence or early adulthood when the incidence peaks. Several theories have been proposed for this delayed onset, but one intriguing possibility is that of Feinberg (Feinberg, 1982), who suggested that the programmed axonal pruning process and the normal formation of new synaptic connections that normally takes place during adolescence has been disturbed.
Feinberg based his hypothesis on EEG studies of adolescents, but until recently, there has not been anatomical support for this theory. Recently it has been possible to study white matter abnormalities in schizophrenia with MRI using Diffusion Tensor Imaging (DTI). DTI measures the Brownian motion or free diffusion of water through tissue. When applied to neural tissue, DTI assesses the degree to which water diffusion is constrained by barriers such as myelin sheaths, membranes or neuronal fiber tracts. Diffusion in white matter is anisotropic meaning that, in a given white matter voxel, axial diffusion (parallel to the principal fiber direction) is much greater than radial diffusion (perpendicular to the principal fiber direction). Fractional anisotropy (FA) is the most frequently used measure obtained from DTI and is a normalized variable derived from the 3 eigenvalues of the diffusion tensor. FA is a measure of the degree of diffusion anisotropy within a voxel and varies from 0 (corresponding to completely isotropic diffusion) to 1 (corresponding to free diffusion in one direction only). Thus, FA is a measure of white matter microstructure that may reflect fiber organization, fiber directional coherence, and/or fiber integrity (Beaulieu, 2002). White matter abnormalities with axonal disorganization might therefore be expected to decrease FA.
Abnormalities in white matter integrity in schizophrenia, particularly in the frontal lobe and its connections (e.g., the uncinate fasciculus (Kubicki et al., 2002)) have been reported in several diffusion tensor imaging studies (reviewed in Kubicki et al., 2007, Kanaan et al., 2005). Some of these abnormalities appear to be present in patients experiencing a first episode of schizophrenia (Szeszko et al., 2005, Szeszko et al., 2008), as well as in patients with early onset schizophrenia (Kumra et al., 2005). These data suggest that at least some of the DTI findings in schizophrenia are not likely to be medication effects, and that they are present at an early stage in the illness.
If the abnormal white matter integrity seen in schizophrenia is due to deviations in brain development, people who are at high risk for schizophrenia might be expected to have reduced FA or overall reduced white matter integrity that may be detectable before any symptoms of illness are present, and this might represent a biologic vulnerability for later illness. Although it is clear that schizophrenia may arise from environmental or gene–environment interactions, having a first-degree relative with schizophrenia is the strongest known risk factor for schizophrenia (reviewed in Gottesman, 1991). For this reason, in the present study we evaluated a group of genetically at high risk young adults. Individuals in the age range of highest risk for schizophrenia (DeLisi, 1992) from families in which at least one other first-degree relative was previously diagnosed with schizophrenia were scanned using DTI in parallel with adults with schizophrenia from these families, as well as age-appropriate low-risk comparison participants. Because little is known about the regional distribution of FA abnormalities in those at high risk, we performed exploratory voxelwise analyses.
Section snippets
Participants
Families were recruited in which at least one available individual had a diagnosis of schizophrenia and one or more other siblings who were in the peak age range of risk for schizophrenia (defined as age 12–30 years) were also available. Recruitment was done by placing advertisements in newspapers and newsletters distributed by multiple chapters of The National Alliance for The Mentally Ill (NAMI). In addition, families who previously participated in other genetic studies on schizophrenia (
Overall ANOVA results
Groups differed in WM FA in the left subgenual anterior cingulate and inferior frontal gyri, as well as in right deep cingulate WM and middle/superior frontal gyrus, left middle and superior temporal gyri, in left cingulate gyrus and posterior cingulate WM, in the angular gyri, left inferior longitudinal fasciculus (ILF) and lingual gyrus. Subcortically, we found group differences in left insular, thalamic and pericaudate WM, as well as bilateral perilentiform WM, right posterior limb of the
Discussion
The primary finding of this study is that people who are at genetic high risk for schizophrenia can be shown by DTI to have abnormal white matter integrity (as measured by FA) relative to a control group. The regions found to have abnormal FA in genetic high risk individuals may be implicated as possible foci of vulnerability for later development of schizophrenia, whereas the more widespread regional changes in those with schizophrenia may indicate a progressive pathology that continues after
Role of funding source
Funding for this study was provided by NIMH grants MH71720 (LED), an unrestricted educational grant from Eli Lilly and MH64783 (MJH); NIMH, and Eli Lilly had no further role in the study design; in the collection, analysis and interpretation of data; in writing of the report; and in the decision to submit the paper for publication.
Contributors
Dr. DeLisi designed the study and wrote the protocol along with Drs. Hoptman, Nierenberg, Branch and Ardekani. Dr. Bertisch and Mr. Catalano managed the data and processed the imaging data. Drs. Hoptman and Nierenberg analyzed the imaging data and Dr. Hoptman wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
Drs. Hoptman, De Lisi, Nierenberg, Bertisch, Ardekani and Branch and Mr. Catalano, reported no biomedical financial interests or potential conflicts of interest.
Acknowledgements
We thank Vitria Adisetiyo, BA, for her technical assistance, Raj Sangoi RT(R)(MR) and Rhonda El-Sheikh, MS, for their assistance in scanning the participants. Portions of this data were presented at the International Congress on Schizophrenia Research, Colorado Springs, CO, March 2007. This work was partially supported by a grant to LED from NIMH (R21 MH071720) and an unrestricted educational grant from Eli Lilly and company. MJH was supported by MH64783.
References (54)
- et al.
Thresholding in correlational analyses of magnetic resonance functional neuroimaging
Magn. Reson. Imaging
(2003) The genetics of schizophrenia: past, present and future concepts
Schizophr Res.
(1997)- et al.
Early detection of schizophrenia by diffusion weighted imaging
Psychiatry Res.
(2006) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?
J. Psychiatr. Res.
(1982)- et al.
Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia
Biol. Psychiatry
(2008) - et al.
Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia
Schizophr. Res.
(2003) - et al.
Diffusion tensor imaging in schizophrenia
Biol. Psychiatry
(2005) - et al.
DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity
NeuroImage
(2005) - et al.
A review of diffusion tensor imaging studies in schizophrenia
J. Psychiatr. Res.
(2007) - et al.
White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study
J. Am. Acad. Child Adolesc. Psych.
(2005)
fMRI study of language activation in schizophrenia, schizoaffective disorder and in individuals genetically at high risk
Schizophr. Res.
An fMRI study of language processing in people at high genetic risk for schizophrenia
Schizophr. Res.
White-matter integrity predicts Stroop performance in patients with geriatric depression
Biol. Psychiatry
Parametricand non-parametric statistical analysis of DT-MRI data
J. Magn. Reson.
Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: a resting and activation SPECT study
Psychiatry Res.
Supratentorial profile of white matter microstructural integrity in recovering alcoholic menand women
Biol. Psychiatry
A hybrid approach to the skull-stripping problem in MRI
NeuroImage
A review of MRI findings in schizophrenia
Schizophr. Res.
An association between reduced interhemispheric EEG coherence in the temporal lobeand genetic risk for schizophrenia
Schizophr. Res.
Microstructural white matter abnormalities and remission of geriatric depression
Am. J. Psychiat.
A fully automatic multimodality image registration algorithm
J. Comput. Assist. Tomogr.
MRI study of white matter diffusion anisotropy in schizophrenia
NeuroReport
Disruption of white matter integrity in the inferior longitudinal fasciculus in adolescents with schizophrenia as revealed by fiber tractography
Arch. Gen. Psychiatry
The basis of anisotropic water diffusion in the nervous system — a technical review
NMR in Biomed.
Visual white matter integrity in schizophrenia
Am. J. Psychiat.
Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch. Gen. Psychiat
Am. J. Psychiat.
Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America
Arch. Gen. Psychiatry
Cited by (134)
Serum S100B protein and white matter changes in schizophrenia before and after medication
2024, Brain Research BulletinDiffusion MRI derived free-water imaging measures in patients with schizophrenia and their non-psychotic siblings
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryAnatomy and White Matter Connections of the Parahippocampal Gyrus
2021, World Neurosurgery