Anatomical Variability and Functional Areas

4.1 Relationships Between Macroscopic Anatomy and Cytoarchitectonic Microanatomy

Prior to the advent of functional imaging, the microscopic anatomy, or cytoarchitecture, of a brain region was assumed to be a direct indication of the function of that region. This assumption holds true if one considers the brain region designated as Brodmann area 4, also known as the primary motor area, lesion of which produces motor deficits. But even for primary cortical regions (those regions that either receive direct sensory input or generate direct motor output), there is not an exact overlay of cytoarchitectonic anatomy and function, as demonstrated for the primary visual area located in the calcarine sulcus [32]. Nonetheless, microanatomy represents a step toward a better understanding of the functional organization of the cortex. In pursuit of this improved understanding, some authors have investigated not only the precise relationship between function and cytoarch-tecture, but also the relationships between function and neurotransmitter receptor densities, enzyme densities, and myeloarchitecture. Based on their observations, they have reached the conclusion that a functional cortical field should be defined on multiple criteria [33].

If consideration is restricted to architectonic fields as defined on the basis of neuronal density, very nice work has been conducted by Rademacher et al, who studied the relationships between macroanatomy and cytoarchitecture ([34], Fig. 8). In 20 hemispheres, they showed that the architectonic fields often bear a characteristic relationship to sulcal and gyral landmarks that can be defined with aMRI. The

FIGURE 8 Relationships between cytoarchitectonic and macroscopic anatomy in the primary cortices [34]. The temporal transverse gyrus or Heschl's gyrus, which is the site of the primary auditory cortices, is shown. Brodmann's cytoarchitectonic area 41 is represented in dashed lines. Note the good overlay between the gyrus and the cytoarchitectonic area, although they are not strictly superimposed. Reprinted with permission from J. Rademacher, V. S. Caviness, H. Steinmetz, and A. M. Galaburda, Topographical variation of the human primary cortices: implications for neuroimaging, brain mapping, and neurobiology, Cerebral Cortex, vol. 3, pp. 313-329, 1993.

FIGURE 8 Relationships between cytoarchitectonic and macroscopic anatomy in the primary cortices [34]. The temporal transverse gyrus or Heschl's gyrus, which is the site of the primary auditory cortices, is shown. Brodmann's cytoarchitectonic area 41 is represented in dashed lines. Note the good overlay between the gyrus and the cytoarchitectonic area, although they are not strictly superimposed. Reprinted with permission from J. Rademacher, V. S. Caviness, H. Steinmetz, and A. M. Galaburda, Topographical variation of the human primary cortices: implications for neuroimaging, brain mapping, and neurobiology, Cerebral Cortex, vol. 3, pp. 313-329, 1993.

variability of these relationships could be divided into two classes: In one class the variability was closely predictable from visible landmarks, and the interindividual variability of gross individual landmarks was prominent. This was the case for the four primary cortical fields they studied: Brodmann's areas 17, 41, 3b, and 4. However, within these same cortical fields, a second class of cytoarchitectonic variability could not be predicted from visible landmarks, for example, area 4 at the level of the paracentral lobule. A consistent relationship between cytoarchitecture and macroanatomy also applies to the planum temporale, which almost covers the cytoarchitec-tonic area Tpt [35], although Tpt extends beyond the boundaries of the planum toward the external and posterior part of the superior temporal gyrus. Finally, in the inferior frontal gyrus some authors suggest that there is a good agreement between Brodmann area 44 and the pars opercularis of the inferior frontal gyrus and between Brodmann area 45 and the pars triangularis of the inferior frontal gyrus [13]. In higher-order cortices, such as more frontal regions, no strong relationship has been found between cytoarchitectural variations and individual anatomical landmarks. For instance, the individual variability in terms of anatomical extent and position of Brodmann areas 9 and 46 has been found to be very large [36].

As a generalization, variations in macroanatomy seem to parallel those in microanatomy in the primary cortical regions and in language areas, but this close relationship becomes looser in higher-order, integrative cortical regions. This may be related to the fact that higher functions develop later than primary ones and may be more extensively influenced by the environment or by plasticity induced through learning. However, this point of view is disputed by K. Zilles and P. Roland, who consider the evidence supporting a relationship between macro- and microanatomy to be very scarce [37]. To approach the question of relationships between function and microarchitecture, they seek to eliminate macroscopic anatomic variability as a factor by using powerful registration software that can transform a three-dimensional MRI brain volume into a single standard brain, even within the depths of the sulci [38]. The underlying idea is that any brain can be fitted onto a template brain that they have chosen as the most representative of their MRI database. Their approach is very important, since these authors developed it to bring myeloarchitectonic, cytoarchitectonic, and receptor images into a common database. The resulting probabilistic maps of microarchitecture, can then be directly compared with functional probabilistic maps [33]. However, this approach does not obviate the need to pursue the study of micro/ macroanatomic relationships, since the question of whether one brain can be transformed into another without destroying the underlying anatomy in highly variable regions such as the angular gyrus (see the earlier discussion) remains to be evaluated.

4.2 Relationships Between Macroscopic

Anatomical Variability and Functional Areas

Early methods that were developed to study brain function with positron emission tomography (PET) used skull tele-radiography within the PET suite to transform the individual brains into a common space, the so-called Talairach stereo-tactic space, using constrained affine transformations [39]. Subsequently, methods were developed to normalize PET images directly into this stereotactic space using anatomical information contained within the images themselves [40]. Once the functional images had been placed into this common space, localization of the detected activations relied on a brain atlas, usually the Talairach atlas [21], but the accuracy of such localization depended on interindividual variability after normalization. At this stage, the available methodology required researchers in the functional imaging field to overlook any possible functional impact of anatomical variability. Subsequently, however, the development of improved normalization procedures has allowed this question of interindividual variability and the effects of normalization on individual and averaged images to come to the foreground.

Within this context, some teams chose to account for individual variability by developing interindividual averaging methods that parcellated the brain of each individual into anatomical regions of interest [41]. The intersubject averaging was then performed using an anatomical filter, defined by these manually delineated ROIs. These methods were rarely used with PET because the time required to perform the parcellation was large, the spatial resolution was limited to the size of the ROI, and direct comparisons with other results reported in stereotactic coordinates were not possible. However, with the advent in the 1990s of functional MRI (fMRI), detection of activations in individual subjects has become commonplace, and these activations are often localized within the context of the subject's own anatomy. Anatomically defined ROIs and individually identified anatomic sites of functional activation now both provide complementary approaches that can be used to directly investigate the links between structure and function.

Most of the works dealing with this question have studied the spatial relationship between a precise anatomical landmark and a related function in primary cortical areas. We shall begin with two studies concerning the Rolandic sulcus. The first one was based on a hypothesis generated by anatomists who had manually measured the length of the Rolandic sulcus on a three-dimensional reconstruction of its surface. They hypothesized that a curve, known as the genu of the Rolandic sulcus, which corresponded to particularly large measured surface area, might be the cortical representation of the hand. To test this hypothesis they used a vibration paradigm with PET, and after two-dimensional registration of the activated areas onto the corresponding MRI axial slices, they demonstrated in each subject that the hand area was indeed located at the level of the Rolandic genu [6,42]. Using three-dimensional extraction and visualization of the Rolandic sulcus after it was manually outlined on T1 weighted axial MRI slices, another group has established that this sulcus could be divided into three different regions that were linked with functional anatomy, since the middle segment, which includes the genu of Rolando, corresponded to the hand area detected using this same vibration paradigm with PET [43].

In the visual system, a very illustrative study of structure/ function relationships was conducted by Watson et al. on area V5, the visual motion area in humans [44]. In a first report [45], this team identified the location of color and motion areas in a group of subjects and noticed that considerable individual variability remained in the location of V5 in stereotactic space. They pursued this work with identification of V5 in each individual and, after registration onto each individual's MRI, studied the relationship between this functional area and the underlying anatomy. They demonstrated that V5 bears a consistent relationship to the posterior continuation of the inferior temporal sulcus within the occipital lobe, while emphasizing in their article that this portion of the sulcus shows a variety of anatomic forms. This macroanatomic variability is consistent with the fact that this sulcus was shown by Bailey and von Bonin to appear during the 30th week of gestation [44]. In keeping with the assertion mentioned earlier, that a cortical field should be defined on the basis of numerous markers [33], Watson et al. also noted that this sulcus corresponds precisely to the field of early myelina-tion in the developmental atlas of Fleschig. This result is thus very consistent with the idea that functions that develop early, such as vision, maintain strong relationships with both macro-and microanatomy, even when the macroanatomy alone shows considerable variability.

When moving into high-order cognitive functions, the link between gross anatomical landmarks and functional anatomy is less obvious. However, the frontal language areas are an exception where close linkage is maintained. Within the framework of a coordinated European project, several PET centers studied six right-handed male volunteers using the same verb generation paradigm. In our laboratory, the average result demonstrated an activation site restricted to the left inferior frontal gyrus. However, individual analysis revealed that one subject among the six had significantly activated only the right inferior frontal gyrus. The study of the spatial relationship of this activation with surrounding sulci revealed that it was located in an area that was the exact symmetric homologue of the left hemisphere area activated in the other subjects, located near the ascending branch of the Sylvian fissure [46]. Using the same task, another European group used individual anatomofunctional analysis to demonstrate a consistent relationship of the activation with this branch in five subjects of the seven they studied [47].

Another way to explore a possible relationship between structural and functional images is to consider that anatomy may be an imprint of the developmental precursors to cognitive functions and to search for relationships that might not be limited to the immediate vicinity. This is what we have done concerning the hemispheric organization for language. Since the asymmetry of the planum temporale is present after the 32nd gestational week [48], and since the common leftward asymmetry can be absent in non-right-handers, this early anatomical asymmetry might reflect the functional hemispheric dominance for language. To test this hypothesis we conducted a correlation study between the planum temporale surface area and the functional maps for language comprehension in 10 subjects, including 5 non-right-handers. We showed that the larger the left planum temporale, the larger the functional responses measured with PET in left temporal regions, particularly in the temporal pole, which is located far from the planum [49]. This result makes the anatomical variability more than just a statistical variable that blurs functional or anatomical image averaging. Moreover, since this anatomical marker can reflect brain function, and since these regions exhibit a great variability in terms of surface (for example, the left planum temporale surface can vary from 200 to 1000 mm2), a question then arises: What will happen to a functional area lying within a large planum after its brain has been transformed in the stereotactic space? For example, will it appear to belong to the superior temporal region? In such a case, we would overlook a specific role of this asymmetrically developed cortex.

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