1 Applied Schizophrenia Division, Mental Health Research Institute, Parkville, Victoria, Australia 3052, , 2 School of Psychological Sciences, La Trobe University, Bundoora, Victoria, Australia 3083 and , 3 Cognitive Neuropsychiatry Unit, Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia 3052
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Abstract |
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Introduction |
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To date there have been five post-mortem studies that have examined the gross morphology of the AC (Eberstaller, 1884; Weinberg, 1905
; Ono et al., 1990
; Vogt et al., 1995
; Ide et al., 1999
), but these have been methodologically limited. Initial post-mortem studies were based on qualitative judgements of AC morphological patterns and found hemispheric differences in the frequency of PCS observed (Eberstaller, 1884
; Weinberg, 1905
). More recent post-mortem studies have either been unable to examine hemispheric effects on AC morphology as a consequence of only one hemisphere being examined from each subject (Vogt et al., 1995
), or have used small sample sizes and found conflicting results. For example, Ono et al. (Ono et al., 1990
) found no hemisphere difference in the manifestation of a PCS, while Ide et al. (Ide et al., 1999
) found a hemispheric asymmetry such that the PCS was more often prominent in the left hemisphere.
In a large MRI study of 247 healthy young volunteers, Paus et al. (Paus et al., 1996a) found large variability in the morphological features of the AC region and identified a hemispheric asymmetry related to the presence and extent of the PCS, which contrasted with the variable findings of previous post-mortem studies (Weinberg, 1905
; Ono et al., 1990
; Ide et al., 1999
). They also found a previously unreported gender difference in the organization of the AC such that females were significantly more likely to be in the two extreme categories of the PCS, namely the prominent and absent PCS.
The lack of research into morphological variance may be due to an assumption that the gyrification/fissurization of the cortex, which occurs principally during the second and third trimester of gestation (Chi et al., 1977, Huang, 1991
; Naidich et al., 1994
), is a mechanical process that does not have any cytoarchitectural, connectional or functional relevance (Turner, 1948
; Richman et al., 1975
; Armstrong et al., 1991
). This view has been super seded due to recent evidence from twin studies that suggests that sulcal/gyral formation is influenced by both genetic and epigenetic factors (Oppenheim et al., 1989
; Steinmetz et al., 1994
, 1995
; Tramo et al., 1995
; Bartley et al., 1997
; Biondi et al., 1998
; Lohmann et al., 1999
) and, importantly, affected by underlying cytoarchitecture (Sanides, 1964
; Watson et al., 1993
; Rademacher et al., 1993
; Roland and Zilles, 1994
) and neural connectivity (Caviness et al., 1975, 1989
; Goldman-Rakic, 1981
; Rakic, 1988
). In this regard, it has been found that variations in sulcal/gyral pattern are associated with differences in the size and distribution of cytoarchitectonically defined regions within the AC region (Vogt et al., 1995
). Further, a systematic review of the evidence by Welker indicated that generally, gyrification has functional significance and that gyral crowns have qualitatively different organization and connectivity from sulcal walls and fundi (Welker, 1990
). Van Essen has argued that the greater connectivity within gyral crowns may predate their development, and play an important role in their formation (Van Essen, 1997
). There is also evidence from functional imaging studies that the morphological pattern within the AC is directly related to the location of functional activation peaks (Crosson et al., 1999
).
These findings suggest that description of AC morphology, particularly sulcal/gyral patterns, and the nature of its variability in a large cohort of healthy volunteers is important to understanding the relationship between AC structure and function. Further, morphological studies of this region may provide an alternative to volumetric structural neuroimaging methods, which are limited because of the morphological variability. Knowledge of the morphological variability of this region is also critically important in evaluating functional neuroimaging studies. The aim of the current study was to develop a reliable method by which to examine the gross structural morphology of the AC in a large cohort of healthy volunteers. The present study extends previous work (Paus et al., 1996a) by taking into account the morphological relationships (asymmetry) between the left and right AC regions for each individual. We also examined the influence of hemisphere and gender on this relationship, while controlling for the effects of age, overall hemispheric volume and hemispheric fissurization on AC morphology. The use of hemispheric fissurization as a control measure is necessary to determine the specificity of any systematic differences in AC morphology.
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Materials and Methods |
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Classification of Anterior Cingulate Morphology
Classification Criteria
A protocol similar to that utilized by Paus et al. (Paus et al., 1996a) was generated, to classify the number of cingulate sulci (CS) and the explicitness of their folding. In addition, we described the explicitness of folding across two homologous areas of the same brain (asymmetry; described in more detail below). The type of AC surface morphology was classified according to the presence or absence of the PCS, as well as its antero-posterior extent. The PCS was defined as the sulcus located dorsal to the CS with a course clearly parallel to the CS. This yielded three categories of AC surface morphology prominent-PCS, present-PCS and absent-PCS depending upon the presence or absence of the PCS and its antero-posterior extent (see Fig. 1
).
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Classification-related Issues
A number of steps were taken to improve the reliability of the classification method.
We reduced the ambiguity in the anterior regions (Paus et al., 1996a) due to a confluence of the CS and PCS with the superior rostral sulcus (SRS; often anteriorly continuous with the CS or PCS). This was achieved by defining the origin of the CS and PCS as the point at which the sulcus extends posteriorly from an imaginary vertical line running perpendicular to the line passing through the anterior and posterior commissures (ACPC) and parallel to the VAC. This point is indicated by solid arrow for both the PCS (Fig. 2a
) and CS (Fig. 2b
).
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Classification Reliability
Intra-rater reliability for the classification of AC morphology was assessed by one rater (M.Y.) on 24 randomly chosen cases. In order to assess inter-rater reliability a second rater (G.S.) was provided with a manual describing the classification criteria before assessing the same 24 cases. Both raters were blind to subject details at all times. From all classifications derived (48 in all), only 2% of classifications were rated differently by the initial rater (M.Y.) and 10% between raters (M.Y. and G.S.). Intra- and inter-rater reliability (weighted kappa) for the classification of AC morphology were = 0.96 and = 0.90 respectively.
Anterior Cingulate Asymmetry Index
An asymmetry index was assigned to each individual based on the combination of left and right AC morphology. For example, the PCS in the prominent classification is more explicit (i.e. greater antero-posterior extent of the fissure) than the PCS in the present pattern, which in turn is more explicit than that in the absent pattern. Thus an asymmetry direction of leftward (left > right), symmetric (left = right), or rightward (left < right), could be assigned to each individual. Further, the magnitude of asymmetry could be by one or two categories in either direction: as absent versus present or present versus prominent (one category difference) or as absent versus prominent (two category difference). In addition there are three ways in which the morphology could be identical (absent versus absent, present versus present, prominent versus prominent). Therefore, the asymmetry index is made up of five values [left > right (2), left > right (1), left = right, left < right (1), left < right (2)] from the nine combinations of left versus right AC morphology. This index is reflective of the relationship between the hemispheres for each individual in terms of the extent of PCS fissurization, indicating whether an individual has a symmetrically or asymmetrically fissured AC, in which direction, and by how much.
The asymmetry index is an important value because it provides an alternative to the unpaired comparison that examines patterns of AC morphology across the population. That is, the combination of values from the left and right AC are paired for each individual and reduced to a single asymmetry index. As such, the individual's one cerebral hemisphere acts as a control for the other in deriving an asymmetry index value. Also, the use of the asymmetry index as a single dependent variable that is derived from the values from each hemisphere avoids the difficulty of analysing repeated-measures variables (i.e. left versus right) within this categorical analysis framework. Most widely available statistical packages for the analysis of categorical variables assume that the predictor variables are independent. They do not yet allow for the analysis of repeated measures by methods equivalent to those used in the general analysis of variance (ANOVA) framework for continuous dependent variables.
Hemispheric Volume and Hemispheric Fissurization Index
To account for differences in absolute cerebral hemispheric volume, and cerebral hemispheric fissurization, as well as the asymmetry between the two cerebral hemispheres with regards to overall hemispheric fissurization and volume, a semi-automated method was developed from which we were able to estimate these values for each individual. These measures, as well as age, were used both as independent variables as well as covariates in the analyses in order to ascertain the specificity of the results regarding AC fissurization.
Each MRI data set was registered linearly (six-parameter rigid body transform) using the Automated Image Registration package (AIR, version 3.0.8) (Woods et al., 1998) to a high-resolution template MRI (Collins et al., 1998
) placed into standard Talairach space (Talairach and Tournoux, 1988
). The signal intensity variance artefact often seen using MRI (variously referred to as RF inhomogeneity, shading artifact or intensity non-uniformity) was then corrected using the MNI_N3 non-parametric non-uniformity normalization package (version 1.04) (Sled et al., 1998
). Finally, the image dataset was resampled to subvoxel resolution (0.5 mm3, resulting in 368 coronal slices per brain) in order to increase sampling density and minimize sampling error when estimating hemispheric volume and hemispheric fissurization.
Hemispheric Volume and Hemispheric Volume Asymmetry
Having aligned the MRI and corrected the signal intensity artefact, the cerebral hemisphere of interest (excluding the cerebellar lobe and brainstem) was masked out from each brain image. The cerebral hemisphere of interest was then thresholded at a customized level based on the histogram of the image intensities to exclude only ventricular and intra-sulcal cerebrospinal fluid (CSF). The absolute volume of the hemisphere was then calculated.
Hemispheric Fissurization Index and Hemispheric Fissurization Index Asymmetry
To generate a fissurization index the original MR images were segmented at a harsher intensity threshold to remove a small amount of gray matter (in order to open up the sulci) (Magnotta et al., 1999; Nopoulos et al., 2000
). Once again, this procedure was customized for each individual brain image as above. A binary transformation was then applied to characterize brain tissue/non-tissue voxels. This enabled the more harshly thresholded volume to be estimated using simple voxel counts. The Roberts edge detection algorithm as implemented in MEDx was then applied to the image to detect the surface voxels of this volume within each coronal slice of the image (see Fig. 3
). The ratio of surface voxels to those of the total volume is an indirect measure of the degree of cortical folding, and is the basis of the automated estimate of hemispheric fissurization.
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Results |
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We first examined the overall volume and fissurization of the cerebral hemispheres in order to assess the AC morphology in the context of cerebral morphology, as shown in Table 1. As these variables were all continuous, ANOVA was used. The right cerebral volume was significantly larger than the left cerebral volume overall [F(1,169) = 31.29, P < 0.0001], and there was also a significant volume by gender interaction [F(1,169) = 11.46, P < 0.001]. This interaction reflects a larger right/left hemispheric volume difference for males. This difference can also be seen in the asymmetry values. A separate gender comparison for each hemisphere revealed that males had both larger left [F(1,169) = 81.56, P < 0.0001] and right [F(1,169) = 88.6, P < 0.0001] cerebral volumes. Correlational analyses revealed that left and right cerebral volumes were highly associated for both males (r = 0.984, P < 0.0001) and females (r = 0.994, P < 0.0001).
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Anterior Cingulate Morphology
While the CS was present in all hemispheres studied, its morphology was extremely variable within and between hemispheres. Across the entire sample and across both hemispheres, 68% of cingulate cortices showed evidence of a PCS, in either its present or prominent form. Table 2 (see totals) also shows that, overall, the PCS was more often prominent in the left hemisphere (left 49% versus right 28%) and absent in the right hemisphere (left 26% versus right 38%).
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Table 2 also shows the frequencies for all combinations of left versus right cingulate morphology in the overall sample, and separately for males and females. McNemar's test for symmetry (Siegel and Castellan, 1988
) was used to test whether the number of cases of asymmetry in one direction was counterbalanced by an equal number of cases with an asymmetry in the other direction. A significant value indicates an overall lack of symmetry in the sample a greater explicitness of fissurization in one direction. Overall, the proportion of cases showing a leftward fissurization bias was 42%, compared with only 21% in the opposite direction. This asymmetry is reflected in the significant McNemar statistic [
2(3) = 16.43, P < 0.001].
An analysis by gender revealed that the proportion of males showing a leftward fissurization bias was 48%, compared with only 19% in the opposite direction. In contrast, females showed a much smaller degree of fissurization asymmetry, with 32% showing a leftward asymmetry and 23% showing a rightward asymmetry. This gender difference is reflected by the McNemar test showing a significant asymmetry for males [2(3) = 16.31, P < 0.001] but not for females, suggesting that the significant result obtained in the overall analysis was specific to males. Interaction effects could not be examined within this the analytic framework.
Gender by Hemispheric Differences
The effect of gender on AC morphology was further examined using polychotomous logistic regression (BMDP-PR) (Dixon et al., 1990) in which the AC morphology on the left or right (with three ordered categories) or asymmetry index (with five ordered categories; see Materials and Methods) were the dependent variables. In all analyses, gender and age were used as independent variables. For analyses of left or right AC morphology, the volume and fissurization index of the relevant hemisphere were also used in the analysis. When the AC asymmetry index was the dependent variable, hemispheric volume asymmetry and hemispheric fissurization index asymmetry were included in the analysis. Hemispheric volume asymmetry was derived from the combination of left hemisphere and right hemispheric volumes (left volume right volume), while the hemispheric fissurization index asymmetry was derived from the combination of left hemisphere and right hemispheric fissurization indices (left fissurization index right fissurization index). In both cases, positive values were reflective of a leftward asymmetry, while negative values reflected a rightward asymmetry. Note that standard significance tests, such as
2 and logistic regression, were not used because the dependent variables were inherently ordered (i.e. from absent to prominent), and had more than two categories (three or five).
Table 3 shows the results of the significance tests carried out using polychotomous logistic regression analysis. This table as well as Figure 4
shows that, relative to females (represented as the 0% line), males were significantly more likely to have a prominent-PCS and less likely to have an absent-PCS in the left hemisphere (by ~22%).
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Gender by Asymmetry Index Differences
The data in Table 4 represent the morphological relationship of the AC between the hemispheres, indicating whether left and right hemispheres for each individual were symmetrically or asymmetrically fissured, in which direction, and by how much. Examination of gender revealed a significant effect on the explicitness of fissurization between the left and right AC with males tending to have a more leftward pattern of fissurization (males 48% versus females 32%) and females tending to have a symmetric pattern (males 32% versus females 44%). These results were unchanged after controlling for the effects of overall hemispheric fissurization index asymmetry, overall hemispheric volume asymmetry and age.
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While the effects of handedness could not be comprehensively assessed due to the small number of left-handed individuals, a restricted analysis with data from only right-handed individuals (n = 118) was carried out. All of the previously reported significant effects remained.
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Discussion |
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To our knowledge, no previous studies have examined AC fissurization asymmetry by comparing the left and right AC in the same individual. Therefore, our finding of a gender effect on AC asymmetry index cannot be compared with other studies. There have been few previous studies that have examined the morphology of the AC in a single hemisphere. Methodological inconsistencies in these studies limit the ability to make direct comparisons, except for the more recent imaging study of Paus et al. (Paus et al., 1996a). Initial studies of AC morphology were based on qualitative judgements of morphological patterns and their frequencies (Eberstaller, 1884
; Weinberg, 1905
), while recent studies have been limited to a small series of post-mortem brains (Ono et al., 1990
; Vogt et al., 1995
; Ide et al., 1999
). All post-mortem studies that have examined AC morphology have been limited methodologically (Ono et al., 1990
; Vogt et al., 1995
). In the study by Vogt et al. (Vogt et al., 1995
) of brain specimens from older people, laterality could not be investigated as only one hemisphere was examined from each subject (13 left and 10 right hemispheres from different males and females). In the study by Ono et al., asymmetry was not observed in their small sample and no details about age or gender of the subjects were presented (Ono et al., 1990
). In addition, not all studies describe the methods used to characterize the AC in sufficient detail. Despite these limitations, our findings of a lateralized pattern of surface morphology in the AC of normal subjects are consistent with the findings of Weinberg (Weinberg, 1905
) and more recently those of Ide et al. (Ide et al., 1999
). In these post-mortem studies the PCS was more often prominent in the left hemisphere. Our findings are also consistent with the only other MRI-based study of AC gross morphology in a large sample of normals (Paus et al., 1996a
). Our sample, however, showed a greater proportion of individuals in which the PCS was >20 mm in length, although the nature of the asymmetry was similar across the two studies.
The current study also found gender differences in the gross morphology of the AC. Compared with females, males were significantly more likely to have the most fissured type of AC (prominent-PCS) in the left hemisphere. These results are inconsistent with the study by Ide et al. (Ide et al., 1999), which failed to find any significant gender differences in fissurization patterns. Further, although, Paus et al. (Paus et al., 1996a
) found a significant gender by hemisphere effect, the nature of this effect was different, such that females were more likely to be in the two extreme categories (i.e. absent- or prominent-PCS), while males tended to cluster in the middle (i.e. present-PCS). While the hemispheric effect is qualitatively similar to that found by Paus and colleagues, it is difficult to reconcile the differences in frequencies of PCS observed across the three categories, and the nature of the gender effects found. It is possible that methodological issues such as ambiguity in the definition of the anterior origin of the PCS (see Materials and Methods) may explain the differing findings in the two studies. In addition, MR images in the study of Paus et al. (Paus et al., 1996a
) were acquired as 2 mm thick slices, resampled by interpolation into Talairach space and resliced into 0.75 mm sagittal images. In contrast, our images were acquired at 1.5 mm, there was no subsequent warping, and the brain volumes were resliced into 1 mm cubic voxels. These differences are likely to have resulted in lower image resolution in the study of Paus et al. (Paus et al., 1996a
). While lower image resolution may explain some of the differences in subtyping AC morphological patterns, however, they are unlikely to explain the overall observed discrepancy. Indeed, we found a higher proportion of subjects with a PCS extending >20 mm than did Paus et al. (Paus et al., 1996a
), despite our definition of the PCS being more conservative. Thus it is more likely that the hemispheric and gender differences found between the studies are representative of either a sampling bias or true population differences. It should be noted that in a subsequent volumetric study, Paus et al. (Paus et al., 1996b
) found significant hemispheric and gender differences in the volume of gray matter buried within the PCS such that there was more intra-sulcal gray matter in the left PCS overall and more so in males. These volumetric effects correspond to our morphometric findings of greater fissurization in the left PCS and particularly in males.
What Might Cause these Systematic Anatomical Variations?
In the present study we found that, relative to females, a higher proportions of males have a prominent left PCS. To the extent that differences in morphology reflect differences in underlying structural organization, our findings suggest that there may exist hemispheric and gender differences in the underlying cytoarchitectonic size and distribution, as well as in the pattern of connectivity in the left and right hemispheres (Welker, 1990; Vogt et al., 1995
; Van Essen, 1997
). Specifically, Vogt et al. (Vogt et al., 1995
) found that the paracingulate gyrus, when present, always contained a large part of Brodmann's area 32 (BA32). When the paracingulate gyrus was absent, BA32 always began in the depths of the cingulate sulcus, occupying the dorsal wall of that sulcus (Vogt et al., 1995
). Thus, the characteristics of the underlying cytoarchitecture and connectivity may be different between cingulate cortices with and without a PCS. For example, having a PCS (particularly in its prominent form) may be the consequence of stronger internal connectivity within this area, given that it occupies a gyral crown (Welker, 1990
). In contrast, not having a PCS may be the consequence of a stronger external connectivity of this area with adjacent areas, given that it occupies the dorsal wall of the sulcus. If these systematic morphological differences have cytoarchitectonic and connectional significance, they are likely to have a neurodevelopmental basis and may also be of evolutionary significance (Zilles et al., 1988
, Welker, 1990
). It has been suggested that an increase in the cortical folding of a particular brain area is indicative of a progressive evolution of this region in humans (Zilles et al., 1988
). Accordingly, the higher incidence of the prominent PCS in the left hemisphere of males may reflect the relative expansion in terms of connectivity and/or volume of the left paralimbic (BA32) cortex in males. However, the cognitive and behavioral significance of altered morphology in this region is unknown.
The present study suggests that in the normal male brain there exist morphological asymmetries at both the cerebral and local (AC) levels that are less apparent in the female brain. These asymmetries and gender-related differences are principally determined in utero and may have important implications for understanding the organization, development and functional anatomy the paracingulate region of the AC cortex. It is perhaps relevant that there have been reports of hemispheric and gender differences in the rate of brain maturation indicating that the male brain matures later than that of the female, and the left hemisphere matures later than the right (Geschwind and Galaburda, 1985). Whether or not the general rate of brain maturation is associated with volumetric and fissurization asymmetry is a question that warrants further investigation. However, such gender differences may also be consequent on sex chromosomal differences (Crow, 1990
) or the hormonal environment of the fetus, since males are exposed to testosterone in utero (Geschwind and Galaburda, 1985
).
Our data also suggest that the fissural pattern of the left and right AC is relatively independent of each other. That is, having a prominent pattern of PCS in the left hemisphere has no, or minimal, influence on the pattern in the right hemisphere (i.e. an individual with a prominent-PCS in the left is equally likely to have an absent, present or prominent pattern on the right). In contrast, left and right fissurization as well as left and right volumes of the cerebral hemispheres were highly interrelated. Thus, the developmental trajectory of the left and right AC morphology, but not the cerebral hemispheres, shows a degree of independence during neurodevelopment. While a genetic contribution to morphological differences is indicated by twin studies (Oppenheim et al., 1989; Biondi et al., 1998
; Lohmann et al., 1999
), these studies also suggest that there are important environmental influences that affect morphology to a greater degree than volume (Bartley et al., 1997
; Steinmetz et al., 1994
, 1995
). Further, the available studies implicate genetic influences that may explain hemispheric differences in cerebral morphology (Tramo et al., 1995
; Bartley et al., 1997
), which may be relevant to the observed differences in the AC.
We did not find any relationship between AC morphological complexity and age, consistent with a neurodevelopmental model of the genesis of the AC. Therefore, given that cortical folding has been principally defined during the second and third trimester of embryogenesis (Chi et al., 1977; Huang, 1991
; Naidich et al., 1994
; Armstrong et al., 1995
), the great proportion of environmental influences on the pattern of gyri and sulci must necessarily occur during fetal life. The likely influences during fetal development include nutritional factors, blood supply, hormonal and other factors (Geschwind and Galaburda, 1985
). In contrast to gyral/sulcal pattern, gyral size may be modulated considerably postnatally (Kennedy et al., 1998
), suggesting that size differences may continue to change during postnatal life. This may be influenced by nutritional factors, and has also been found to be modulated by experience; for example, the size of certain brain regions has been shown to be increased in response to highly over-learned activities (Schlaug et al., 1995a
,b
; Amunts et al., 1997
). However, no studies to date have examined the association between experience or cognition and the size or morphology of the AC.
What Implications for Functional Neuroimaging can be Drawn from these Findings?
In the current study, not only did the arrangement of AC surface morphology differ from person to person, but it also displayed hemispheric and gender differences. Previous studies have also confirmed these marked individual (Ono et al., 1990; Vogt et al., 1995
), hemispheric (Paus et al., 1996a
,b
; Ide et al., 1999
) and gender-related differences (Paus et al, 1996a
,b
). As stated in the introduction, variations in sulcal/gyral pattern correlate with varying degrees to underlying cytoarchitecture (Sanides, 1964
; Welker, 1990
; Watson et al., 1993
; Rademacher et al, 1993
), and this has also been demonstrated specifically in the case of the cingulate region (Vogt et al., 1995
). To the extent that specific cortical regions are associated with local anatomy, this complicates the goals of combining functional and anatomical data from more than one subject (Rademacher et al., 1993
; Roland and Zilles, 1994
). At present, most neuroimaging studies use a template or stereotaxic coordinate-based system (Talairach and Tournoux, 1988
) that makes no allowance for individual anatomical variation. An alternative method involves unfolding the cortical surface to form a flat map (Van Essen and Drury, 1997
). To the extent that functional regions are associated with specific anatomical landmarks that vary between individuals, unfolding may actually lead to a dispersion of sites of activation in the resulting two-dimensional map.
Another alternative method is to use a probabilistic atlas, where particular locations are assigned statistical probabilities of being located on an anatomical feature (Mazziotta et al., 1995) or within a cytoarchitectonic region. This approach was used by Paus (Paus et al., 1996a
, 1998
) to identify functional subregions within the cingulate/paracingulate cortex. This approach will be most effective when, in the absence of a paracingulate sulcus, the spatially corresponding region of the cortex carries out the same function. However, in a direct examination of this morpho-functional relationship, Crosson et al. (Crosson et al., 1999
) conducted a functional MRI study of the cingulate region of 28 neurologically normal right-handed participants. Twentyone of the 28 in the sample were reported as demonstrating a prominent-PCS. Activity increases for word generation were centered in the PCS in 18 of these 21 and rarely extended into the cingulate sulcus (CS; 3/21). Remarkably, if there was no prominent PCS, activity nearly always extended into the CS (6/7 cases). Thus, the balance of evidence indicates that variation in the morphology of the AC usually reflects underlying functional anatomy, consistent with the anatomical findings of Vogt et al. (Vogt et al., 1995
).
Therefore, problems may arise using methods that do not allow the possibility that functional regions are associated with specific anatomical features, and which attempt to correct for intersubject variability by anatomical standardization of individual brains. These two factors potentially reduce the spatial resolution of functional images by adding noise in two ways: by standardizing images spatially, and by virtue of a lack of correspondence in activation sites between individuals in the standardized space. This may explain why investigators are still uncertain about which specific areas of the AC are involved in particular functions. There needs to be greater focus on individual morpho-functional correspondences such as intra-subject averaging techniques (Steimetz et al., 1991).
What Implications for Anterior Cingulate Function can be Drawn from these Findings?
The presence of a PCS indicates that BA32 is likely to be located on a gyral crown, whereas the absence of a PCS indicates that this area is likely to be buried within a sulcal wall (Vogt et al., 1995). Given the argument of Van Essen (Van Essen, 1997
) that there exists greater connectivity within gyral crowns, this raises the possibility that individuals with a paracingulate gyrus may show qualitative differences in cognitive and neuropsychological function compared to those without a paracingulate gyrus. Similarly, these differences may be apparent between males and females, function may be lateralized more or less among individuals. The nature of these differences remains unclear, mainly because the specific function of the AC and its subregions is also unclear. For example, regions broadly corresponding to BA32' (posteriordorsal paracingulate regions) have been activated in various functional studies by tasks involving language, novelty and word generation (Raichle et al., 1994
), memory, response selection and conflict detection (Grasby et al., 1993
; Carter et al., 1998
, Carter et al., 2000
), task-related difficulty (Paus et al., 1998
), and general cognitive functions. Regions corresponding broadly to BA32 (rostral paracingulate regions) have been activated in functions involving emotion including judgements of affective content (George et al., 1995
) [reviewed by Vogt and Devinsky (Vogt et al., 1992
; Devinsky et al., 1995
)]. It would be interesting to examine whether the paracingulate region involves any gender-related lateralized functions. The leftright asymmetry and gender differences observed in the present study would provide a neuroanatomical substrate for such findings.
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Notes |
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Address correspondence to Murat Yücel, Cognitive Neuropsychiatry Unit, c/o Mental Health Research Institute, Locked Bag 11, Parkville, Victoria, Australia 3052. Email: murat{at}neuro.mhri.edu.au.
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