Analysis of neural mechanisms underlying verbal fluency in cytoarchitectonically defined stereotaxic space—The roles of Brodmann areas 44 and 45

Abstract

We investigated neural activations underlying a verbal fluency task and cytoarchitectonic probabilistic maps of Broca's speech region (Brodmann's areas 44 and 45). To do so, we reanalyzed data from a previous functional magnetic resonance imaging (fMRI) [Brain 125 (2002) 1024] and from a cytoarchitectonic study [J. Comp. Neurol. 412 (1999) 319] and developed a method to combine both data sets. In the fMRI experiment, verbal fluency was investigated in 11 healthy volunteers, who covertly produced words from predefined categories. A factorial design was used with factors verbal class (semantic vs. overlearned fluency) and switching between categories (no vs. yes). fMRI data analysis employed SPM99 (Statistical Parametric Mapping). Cytoarchitectonic maps of areas 44 and 45 were derived from histologic sections of 10 postmortem brains. Both the in vivo fMRI and postmortem MR data were warped to a common reference brain using a new elastic warping tool. Cytoarchitectonic probability maps with stereotaxic information about intersubject variability were calculated for both areas and superimposed on the functional data, which showed the involvement of left hemisphere areas with verbal fluency relative to the baseline. Semantic relative to overlearned fluency showed greater involvement of left area 45 than of 44. Thus, although both areas participate in verbal fluency, they do so differentially. Left area 45 is more involved in semantic aspects of language processing, while area 44 is probably involved in high-level aspects of programming speech production per se. The combination of functional data analysis with a new elastic warping tool and cytoarchitectonic maps opens new perspectives for analyzing the cortical networks involved in language.

Introduction

Broca first conjectured that the posterior part of the left inferior frontal gyrus was crucially implicated in the production of “articulate language” (Broca, 1861). This conclusion was based on both clinical and neuropathologic, macroscopic examination of an aphasic patient who became known as “Tan Tan” (Signoret et al., 1984). The behavioral syndrome described has subsequently been called “Broca's aphasia”. Tan Tans's lesion involved the posterior part of the inferior frontal gyrus where the opercular and triangular parts are found (Duvernoy, 1991). Broca did not analyze Tan Tan's brain or those of his subsequent patients with respect to microstructure and also refrained from relating lesions to cortical areas. Considering the location of the lesions in these historical brains Castaigne, 1979, Signoret et al., 1984, it has been hypothesized that Brodmann (1909) areas (BA) 44 and 45 are the cytoarchitectonic correlates of Broca's region Aboitiz and Garcia, 1997, Uylings et al., 1999.

Recent functional imaging techniques allow the neural substrate of language to be investigated in healthy subjects (for an overview, see Bookheimer, 2002). For example, verbal fluency, in the sense of producing a series of words from a predefined category, a task which is often impaired in Broca's aphasia (e.g., Goodglass et al., 1967) and which may involve functional distinctions such as different grammatical classes (Caramazza, 2000), has frequently been analyzed with both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) Audenaert et al., 2000, Ravnkilde et al., 2002, Schlosser et al., 2002. More specific aspects of language perception and production such as phonologic and syntactic processing Ben-Shachar et al., 2003, Clahsen and Featherstone, 1999, Featherstone et al., 2000, Friederici et al., 2003, Groß et al., 1998, Indefrey et al., 2001, Keller et al., 2001, Knösche et al., 2000, Mecklinger et al., 1995 have also been explored using functional imaging. Such studies increased our knowledge of neurolinguistic aspects of language processing. They do not, however, answer the question which cortical areas participate in the various aspects of language processing.

There is, at present, no way to analyze function and microstructure in one and the same human brain, although some very recent, high-resolution MR studies with a spatial resolution at almost microscopic level are promising in that respect Barbier et al., 2002, Fatterpekar et al., 2002, Walters et al., 2003. At present, the anatomical interpretation of functional activations is typically based on the atlas system of Talairach and Tournoux (1988), which uses Brodmann's schematic surface drawings of an architectonic map (Brodmann, 1909) as the basis for an architectonic parcellation. Thus, Brodmann's areas were simply transferred to the atlas brain by trying to identify corresponding sulcal patterns in both brains, assuming a strong association between the sulcal pattern and the borders of the cortical areas. Such an association, however, was already doubted by Brodmann himself. He mentioned that “…a schematic drawing can reflect only the major spatial relationships, and therefore, precise topographic associations cannot be considered in general or only in a distorted manner; this is true in particular for all those cortical regions which have borders in the neighborhood of sulci and those regions which are located in the depths of such a cortical region” (translated from Brodmann, 1908).

We have previously been able to confirm that this statement is true for the vast majority of cytoarchitectonic areas, for example, of the parietal lobe, motor, visual and temporal cortex (for overviews, see Amunts et al., 2002, Zilles et al., 2002a, Zilles et al., 2002b), and for BA 44 and 45 in particular (Amunts et al., 1999). Although both areas always occupy the posterior part of the inferior frontal gyrus, the precise locations of their borders vary considerably. For example, BA 44 occupies in most of the cases the opercular part, but can also encroach on the triangular part. BA 45 is located at the triangular part, but may also reach aspects of the opercular part. BA 44 may border BA 6 in the anterior or in the posterior bank of the fundus of the precentral sulcus (Amunts et al., 1999). BA 45 may occupy parts of the middle frontal gyrus (Rajkowska and Goldman-Rakic, 1995). In addition to the variability of areal borders with respect to sulci, there also exists a large intersubject variability of the sulcal pattern of the frontal lobe itself Ono et al., 1990, Tomaiuolo et al., 1999.

To overcome these problems, cytoarchitectonic probability maps of BA 44 and 45 (Amunts et al., 1999) have been developed for structural–functional analysis of language Horwitz et al., 2003, Indefrey et al., 2001. Such analysis, however, is dependent on the precision of the localization of functional activations with respect to the cytoarchitectonic parcellation of the cerebral cortex. At least two methodologic aspects are crucial in this context: (i) the application of a common reference brain for both the fMRI in vivo and the postmortem cytoarchitectonic data, and (ii) a uniform warping approach to the common reference brain of all data modalities irrespective of the different quality and spatial resolution [in vivo, functional echo planar imaging (EPI), and structural anatomical, as well as postmortem, cytoarchitectonic data].

The aim of this combined anatomical and fMRI study was to test the hypothesis that cytoarchitectonically-defined BA 44 and 45 of the left hemisphere are involved differentially in a verbal fluency task in healthy volunteers. To test this hypothesis, we combined and reanalyzed data from a previous fMRI study of verbal fluency (Gurd et al., 2002) and of the cytoarchitecture of BA 44 and 45 (Amunts et al., 1999). To answer the neuroscientific question, we approached the methodologic problems outlined above by developing and applying a method for the integration of fMRI data analyzed using SPM99 (Statistical Parametric Mapping) with a non-SPM, elastic warping algorithm, and probabilistic cytoarchitectonic maps. The present study, thus, not only combines fMRI data with probabilistic cytoarchitectonic maps, but also presents a new methodologic approach to analyzing the relationship of cortical microstructure and cerebral function.