1 Cognitive Neuroscience Unit, Montreal Neurological Institute, McGill University, , 2 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University and , 3 Department of Maths and Statistics, McGill University, Montreal, Quebec, Canada
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Abstract |
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Introduction |
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The analysis of structural asymmetries is also of use in identifying the neuroanatomical basis of disorders with a presumed developmental etiology, such as dyslexia, autism and schizophrenia (Crow, 1990; Filipek, 1995
; Petty, 1999
; ,Sharma et al.1999
; ,Hendren et al.2000
). The underlying assumption in such studies is that abnormal brain development results in atypical structural asymmetries, which in turn are related to abnormal functional organization.
The asymmetry of the planum temporale was revealed initially by analysis of post-mortem specimens. Analysis of skulls and computed tomography brain scans revealed other asymmetries, namely the extension of the frontal lobe in the right hemisphere and the occipital lobe in the left hemisphere (LeMay, 1977; Chui and Damasio, 1980
; LeMay, 1984
). These asymmetries have become known as the frontal and occipital petalias, a term originally used to refer to the indentation made on the inner table of the skull by these extensions. These extensions could be related to a spatial displacement of the left and right hemispheres with respect to each other rather than to a difference in the amount of tissue in these regions. Similarly for the planum temporale, it has been suggested that the apparent difference in size between the left and right hemispheres is related to a shape asymmetry of the posterior Sylvian fissure (Westbury et al.1999
). Several morphometric studies using magnetic resonance imaging (MRI), have also described the presence of right frontal and left occipital petalias and the leftward asymmetry of the planum temporale (Falk et al.1991
; Steinmetz and Galaburda, 1991
). Similarly, several volumetric region-of-interest MRI studies of clinical populations have revealed abnormal asymmetries of many brain structures [for reviews see (Filipek, 1995
; ,Hendren et al.2000
)].
These morphometric studies are labor-intensive and typically focus on one or two regions-of-interest. Also, they suffer from difficulties related to defining structural anatomical boundaries; gross morphological landmarks such as cerebral sulci are variable in their presence and location. Such difficulties can result in low intra- and inter-rater reliability. There is a need, therefore, for a whole-brain imaging analysis that is both reproducible and automated. One such method, a voxel-based statistical analysis of the amounts of gray and white matter (Wright et al.1995; ,Vargha-Khadem et al.1998
; ,Paus et al.1999
; Ashburner and Friston, 2000
), is well suited for examining structural hemispheric asymmetries. This analysis of MRI brain volumes uses computer-based spatial transformations to remove differences due to brain size and automated algorithms to classify tissues. The latter removes the need for subjective identification of tissue boundaries, a potential source of error in many manual analyses.
We used voxel-based analyses to examine structural asymmetries throughout the whole brain in a population of 142 healthy adults. MRI brain volumes were acquired in each subject and processed to create maps of the difference in the amounts of gray matter between the two hemispheres. The difference images were statistically analyzed on a voxel-by-voxel basis. Although previous studies have used automated analyses of deformation fields to examine shape differences between the left and right hemispheres (Ashburner et al.1998; ,Prima et al.1998
), to our knowledge, this is the first fully automated analysis of cerebral asymmetries in regional amounts of gray matter, which also has the advantage of being unbiased with respect to focusing on specific regions-of-interest. Such an analysis provides the opportunity to discover asymmetries that have not been reported previously because of difficulties in the definition of anatomical boundaries.
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Materials and Methods |
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Each subject was scanned using MRI on a Phillips Gyroscan 1.5 T superconducting magnet system. Three sequences were used, yielding T1-weighted (3D fast field echo scan with 140160 slices, 1 mm isotropic resolution, TR = 18 ms, TE = 10 ms, flip angle = 30°), T2-weighted (2D multi-slice fast spin echo scan with 140160 2 mm slices with a 1 mm overlap, TR = 3300 ms, TE = 35 ms) and proton density (as for T2 scan, but with TE = 120 ms) image volumes of the whole head. Each image volume underwent a non-uniformity correction (Sled et al.1998) to remove variations in signal intensity related to radio-frequency inhomogeneity. The 142 T1-weighted brain volumes were stereotaxically transformed using nine parameters (Collins et al.1994
) to match the Montreal Neurological Institute 305 average template (MNI305). These 142 T1-weighted linearly transformed image volumes and their mirror images were averaged to create a new symmetrical template. This new template was created because the MNI305 template is structurally asymmetric and may introduce or increase asymmetry of the original data. The MNI305 template is an average of 305 brain scans and thus reflects the average asymmetry of such a population; for example, the frontal and occipital petalias are clearly seen in this template. Each original T1-weighted, T2-weighted and proton density image volume was then linearly transformed to match the new symmetrical template. This transformation effectively normalized the volumes for between-subject differences in brain size and aligns the images in the standardized stereotaxic space of Talairach and Tournoux (1988). Transformation to a symmetrical template also improved the spatial homology between the two hemispheres in each subject. The symmetrically transformed images were then classified into gray matter, white matter and cerebrospinal fluid by means of INSECT (Zijdenbos et al.1998
), an automatic tissue-classification algorithm. Briefly, INSECT relies on an artificial neural network classifier, which labels each voxel based on the MRI signal in each of the three (T1-, T2-, and proton density weighted) input MRI volumes. The classifier was trained for each brain volume by providing it with the coordinates of voxels that have a minimum likelihood of 90% for belonging to one of the target tissue classes. A binary mask of gray matter voxels was extracted from the classified image and smoothed using a Gaussian smoothing kernel of 10 mm full-width at half-maximum. Smoothing serves a number of purposes: it converts the binary data into a range of continuous data, which is required for the statistical analyses used in this study; it weights the signal at each voxel according to the signal in neighboring voxels, thereby reflecting the amount of gray matter within the smoothing kernel (i.e. its regional density or concentration); and it reduces the effect of spatial differences between hemispheres and also that of between-subject differences in the exact spatial location of gyri and sulci. Thus, the analysis of smoothed data, combined with the large number of brains analyzed and the use of a symmetric template, reduces the likelihood of finding a false positive asymmetry. Smoothing the data also increases the detection of asymmetries whose spatial extent matches the width of the smoothing kernel (i.e. 10 mm in our study) and increases the validity of the Gaussian assumption, making the false positive rates more accurately determined. The probability of false negative findings is high, however, because the use of a symmetric template might increase the symmetry of the brains, also because differences with spatial extents smaller than the size of the smoothing kernel may not be detected, but mainly because of the stringent statistical correction for multiple comparisons. Negative findings should, therefore, be interpreted cautiously.
In order to examine within-subject cerebral asymmetries, a new set of images was generated by flipping each smoothed gray matter volume about the parasagittal plane through x = 0 (i.e. the midline), thereby creating a mirror image. In each subject, this mirror image was subtracted voxel-by-voxel from the unflipped smoothed gray matter image to create an image representing the differences in the amount of gray matter between the two hemispheres. The longitudinal fissure might not coincide exactly with the parasagittal plane through x = 0, however, particularly in its posterior portion; differences in the midline, therefore, must be considered with caution. Even so, the most common deviation of the posterior midline is toward the right (i.e. a larger left occipital region), which would result in more gray matter erroneously being assigned to the right hemisphere and an unexpected finding of a rightward asymmetry or an underestimate of the expected leftward asymmetry.
In the difference images, positive voxel values on the left side of the image indicated that the left hemisphere had higher signal (i.e. more gray matter) than the right, and positive voxel values on the right side of the image indicated that the right hemisphere had higher signal than the left. These images were then analyzed using a t-test at each voxel. A threshold for the t-statistic of >5.0 was calculated (Worsley et al.1996) based on 141 degrees of freedom, a voxel size of 1 mm3, smoothness of 10 mm, a volume of interest of 1000 cc, and a significance level of P < 0.05, corrected for multiple comparisons. It should be noted that the cerebellum was masked (i.e. its signal was removed) in the MRI volumes during these analyses and, therefore, only differences in cerebral gray matter were analyzed.
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Results |
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Discussion |
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The methods of voxel-based analyses of structural imaging data have been described in detail by Ashburner and Friston (Ashburner and Friston, 2000). Our analysis differs slightly in that we used a multispectral image-acquisition protocol to obtain T1-, T2-and proton-density weighted images in each subject. The advantage of the multispectral approach is that it increases the accuracy of tissue classification by providing the classifier with information regarding signal intensity from sequences sensitive to different classes of tissue. Previous studies, however, have successfully analyzed images obtained using only T1-weighted acquisition protocols (Vargha-Khadem et al.1998
; ,Paus et al.1999
).
The analysis of asymmetry required an additional processing step: mirror images were created and subtracted from the original smoothed gray-matter images, resulting in images reflecting within-subject (between hemisphere) differences in amounts of gray matter. The ideal requirement for such a subtraction would be perfect spatial homology between structures in each hemisphere. It is known, however, that the same structure may have a slightly different spatial location in each hemisphere, which may or may not be related to a difference in size. The use of a symmetrical template, linear transformation to this template and smoothing of the data all served to reduce the effect of between hemisphere differences in spatial homology. It is likely also that such within-subject differences are smaller than between-subject differences in the spatial location of structures so the use of a large sample results in spatial averaging of these differences. As already noted, the precautions taken in the image processing stages minimize the likelihood of finding false positive asymmetries but the stringent statistical criteria adopted to control for the number of comparisons increases the likelihood of false negatives.
As described in the Introduction, the asymmetries between the left and right occipital and frontal lobes and between the left and right planum temporale were initially revealed by analysis of post-mortem specimens, measurements of skulls, and analysis of brain scans acquired using computed tomography or MRI (Geschwind and Levitsky, 1968; LeMay, 1977
,1984
; Chui and Damasio, 1980
; ,Falk et al.1991
; Steinmetz and Galaburda, 1991
). The distributions of these asymmetries in our analysis are comparable with those of previous reports, although they differed in their estimation of the number of subjects who showed symmetry; very few of our subjects had no difference between their left and right hemispheres at these voxels. The method used in our study differs from the previous methods because it does not require a priori definition of boundaries and does not involve decisions to be made by a rater. The replication of these established hemispheric asymmetries with similar population distributions demonstrates the validity of this method.
In addition to replicating the presence of the above asymmetries, our analysis revealed several other significant gray matter asymmetries. These are less established in the literature, but in several cases, are consistent with previous observations made in region-of-interest volumetric analyses. For example, the R > L asymmetry of the caudate nucleus reported here, is consistent with region-of-interest studies of this nucleus (Ifthikharuddin et al.2000). On the medial surface of the frontal lobe, the anterior cingulate sulcus demonstrated R > L asymmetry, and the superiorrostral sulcus L > R asymmetry. These findings are consistent with a previous volumetric analysis of MRI scans (Paus et al.1996
). In the temporal lobe, the uncus, superior temporal sulcus, and inferior temporal gyrus demonstrated R > L asymmetry. A post-mortem study of temporal lobe gyri (Highley et al.1999
) revealed R > L asymmetry for the volume of the middle temporal gyrus; this is consistent with our finding of R > L asymmetry in the superior temporal sulcus.
The inferior portion of the anterior insular cortex demonstrated a highly significant (see Table 2; t = 10.20) R > L asymmetry. To our knowledge, there have been no previous reports of such an asymmetry in the insular cortex and, thus, this finding may be novel. There was also a less significant asymmetry (see Table 1
; t = 5.29) favoring the left hemisphere in a more superior part of the anterior insula. It is likely, therefore, that in a region-of-interest analysis these two asymmetries may have been combined resulting in an appearance of symmetry for this region. Further analyses are required to confirm and elucidate these asymmetries.
Consistent with the functional specialization of the left hemisphere for language, regions subserving language functions in this hemisphere were shown to have more gray matter than their counterparts in the right hemisphere. In addition to the planum temporale, such regions included the posterior fusiform and angular gyri. Studies of post-mortem data and MRI analysis in these gyri also report L > R asymmetry in normal healthy individuals (Eidelburg and Galaburda, 1984; ,McDonald et al.2000
; ,Niznikiewicz et al.2000
). In view of these L > R asymmetries for posterior language areas, it might be expected that a similar asymmetry existed in the anterior language areas, namely Broca's area or other regions in inferior frontal cortex. Region-of-interest studies of these areas, however, have failed to demonstrate conclusively any structural asymmetry (Tomaiuolo et al.1999
), except for the cortical surface area of the pars triangularis and pars opercularis (Foundas et al.1998
). Our results are consistent with the negative findings for volume differences in this region.
Our analyses failed to reveal any differences in the asymmetry of the two hemispheres according to sex or handedness. This result is somewhat surprising but in accord with the findings of another large sample study of asymmetry of the frontal and occipital lobes (Koff et al.1986). Other studies, however, have reported sex-and handedness-related differences in hemispheric asymmetries (Bear et al.1986
; ,Amunts et al.2000
). Our sample was divided fairly evenly according to sex with substantial numbers in each group and should, therefore, have had enough statistical power to reveal differences in asymmetry between the sexes. When the group of male subjects were reanalyzed separately, increases in the t-statistics were observed for the asymmetries reported in the initial analysis of all 142 subjects, particularly for the R > L asymmetries in the frontal lobes. This suggests that the degree of asymmetry in these regions is either larger or less variable in males than in females. For handedness, the population demonstrated the normal incidence of left-handedness, namely around 10%. When the 14 left-handed subjects were excluded and the subsample of 128 right-handed subjects was reanalyzed separately, considerable increases in the t-statistics were observed for most of the asymmetries reported in the initial analysis. This also suggests that asymmetries in right-handed subjects are either larger or less variable than those in left-handed subjects. Analyses with a larger comparison group of left-handed individuals may reveal significant differences in asymmetries related to cerebral dominance for handedness. The results of these separate analyses emphasize the importance of matching for sex and handedness when comparing asymmetries between groups of subjects.
In order to understand the relationship between functional and structural asymmetries, the basis of the asymmetries demonstrated by this method need to be addressed. Using MRI it is not possible to determine the specific contributions of neurons and glia to the volume of gray matter, but their number, size and density are probable influences. Cytoarchitectural studies have revealed that volume asymmetries in homologous regions are the result of a decrease in neuronal number in the smaller of the two areas (Rosen et al.1991), probably reflecting unilateral ontogenetic cell loss. Asymmetric areas also have fewer interhemispheric connections than symmetric areas, perhaps as a result of increased axonal pruning (Galaburda et al.1990
). Two recent studies of the cytoarchitecture of posterior temporal tissue have revealed asymmetries favoring the left hemisphere in the thickness of the axonal myelin sheath (Anderson et al.1999
) and in the separation between, and amount of non-neuronal space within, cell columns (Buxhoeveden and Casanova, 2000
).
Given that several structural asymmetries are present very early in life (Witelson and Pallie, 1973; ,Chi et al.1977
), it seems likely that they share a genetic basis with functional predispositions and are for the most part independent of the postnatal environment. The known plasticity of the brain, however, suggests that the possibility remains for experience-dependent changes in brain structure (Maguire et al.2000
). Also, not all asymmetries necessarily have a common genetic basis, as suggested by a recent study of patients with situs inversus totalis (Kennedy et al.1999
). These patients had the typical left lateralization for language function determined by functional MRI, but reversed frontal and occipital petalia and normal L > R asymmetry of the planum temporale. This led to the suggestion that the genetic basis for the frontal and occipital petalias might be linked to that for other asymmetric visceral organs, whereas the asymmetry of the planum temporale has a different ontogenesis.
We conclude that the method described here is a useful and valid technique for detecting structural asymmetries. The results can be used to direct more detailed searches by traditional region-of-interest methods to determine the precise nature of the asymmetry. This method may also be useful in the study of patient populations in whom abnormal asymmetry is suspected. Statistical analyses such as those presented here are particularly important for patient studies due to the large heterogeneity in such groups. Using a large database such as ours, statistical maps of gray matter differences can be calculated for comparison with individual patients in order to detect regions with anomalous amounts of gray matter (e.g. more than two standard deviations of the mean). Further developmental studies will contribute to our understanding of the relative contributions of pre-and post-natal factors to the ontogenesis of structural asymmetries.
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Notes |
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Address correspondence to Kate Watkins, Rm 276, Montreal Neurological Institute, 3801 University, Montreal, Quebec H3A 2B4, Canada. Email: kwatkins{at}bic.mni.mcgill.ca.
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References |
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