Elsevier

NeuroImage

Volume 32, Issue 1, 1 August 2006, Pages 388-399
NeuroImage

Hemispheric asymmetries in language-related pathways: A combined functional MRI and tractography study

https://doi.org/10.1016/j.neuroimage.2006.03.011Get rights and content

Abstract

Functional lateralization is a feature of human brain function, most apparent in the typical left-hemisphere specialization for language. A number of anatomical and imaging studies have examined whether structural asymmetries underlie this functional lateralization. We combined functional MRI (fMRI) and diffusion-weighted imaging (DWI) with tractography to study 10 healthy right-handed subjects. Three language fMRI paradigms were used to define language-related regions in inferior frontal and superior temporal regions. A probabilistic tractography technique was then employed to delineate the connections of these functionally defined regions. We demonstrated consistent connections between Broca's and Wernicke's areas along the superior longitudinal fasciculus bilaterally but more extensive fronto-temporal connectivity on the left than the right. Both tract volumes and mean fractional anisotropy (FA) were significantly greater on the left than the right. We also demonstrated a correlation between measures of structure and function, with subjects with more lateralized fMRI activation having a more highly lateralized mean FA of their connections. These structural asymmetries are in keeping with the lateralization of language function and indicate the major structural connections underlying this function.

Introduction

The 19th century lesion-deficit model proposed by Broca and Wernicke recognized that language function depends upon both frontal and temporal cortical regions and the white matter tracts connecting them. In 1861, Broca reported a postmortem study of a patient with impaired speech production, finding an area of damage in the third frontal convolution of the left hemisphere (Broca, 1861). Subsequently, Wernicke reported a postmortem study of a patient who had an impairment of speech comprehension with damage to the left posterior superior temporal cortex (Wernicke, 1874). Wernicke's theory that damage to the connecting tracts would result in a specific language deficit, with intact speech comprehension and production but a deficit in repetition, was confirmed by the first reporting of a case of ‘conduction aphasia’ (Lichtheim, 1885).

Around the same time the dissections of Dejerine (1895) identified the trajectories of major white matter fiber bundles, and these pathways were subsequently visualized in three dimensions (Ludwig and Klinger, 1956). The superior longitudinal or arcuate fasciculus (SLF), a long association tract connecting frontal, parietal, and temporal cortex, was seen to originate in the inferior and middle frontal gyri, projecting posteriorly before arching around the insula into the temporal lobe. Lesions causing conduction aphasias typically lie in the inferior parietal cortex and therefore cause an interruption of these fibers as they pass between Broca's and Wernicke's area.

The lateralization of language function is a striking feature of human brain function and one that was recognized by both Broca and Wernicke. Two recent functional magnetic resonance imaging (fMRI) studies have demonstrated 94% (Springer et al., 1999) and 96% (Pujol et al., 1999) of right-handed subjects to be left hemisphere dominant for language function. These findings are in keeping with studies of previously normal patients with aphasias secondary to stroke (Geschwind, 1970) and epilepsy patients who did not have early brain injuries (Rasmussen and Milner, 1977). Greater atypical (bilateral and right-hemisphere) dominance is seen in left-handed subjects (Pujol et al., 1999) and in those with early left-hemisphere lesions (Adcock et al., 2003, Rasmussen and Milner, 1977, Springer et al., 1999).

An important question is the extent to which structural differences between left and right hemispheres underlie the lateralization of function, and whether this structural lateralization reflects the degree of functional lateralization from subject to subject. One brain region where asymmetry is evident is the upper surface of the temporal lobe adjacent to the sylvian fissure. In his original description of the anterior transverse gyrus (Heschl's gyrus), Heschl noted asymmetries in cortical folding (Galaburda et al., 1978a), and the area of superior temporal cortex posterior to this, the planum temporale, has also been demonstrated to be larger on the left than the right (Geschwind and Levitsky, 1968, Habib et al., 1995). This macroscopic asymmetry was reflected at the cellular level in the greater extent of the cytoarchitectonic area Tpt (temporoparietal cortex) on the left side (Galaburda et al., 1978b). More recently, volumetric MRI studies (Barrick et al., 2005, Pujol et al., 2002) and voxel-based morphometry (Good et al., 2001) have revealed white matter asymmetries in temporal and frontal lobes.

A non-invasive method of studying pathways of anatomical connectivity in vivo is magnetic resonance imaging (MRI) tractography, a technique derived from diffusion-weighted imaging. Diffusion-weighted imaging (DWI) is an MRI technique that evaluates brain structure through the three-dimensional measurement of water molecules' diffusion in tissue. Obstructions in the path of the molecules such as cell membranes affect the measured diffusion, an effect that is highly directional in white matter fibers. Via the use of the diffusion tensor and other methods the degree of diffusion (diffusivity), the directionality of the motion (anisotropy) and the principal orientation(s) of diffusion for each voxel (Jansons and Alexander, 2003, Pierpaoli et al., 1996, Pierpaoli and Basser, 1996, Tournier et al., 2004, Tuch et al., 2002, Tuch et al., 2003, Tuch, 2004) may be calculated. This information can be used to evaluate connectivity between voxels and to generate streamlines corresponding to estimated fiber trajectories (Basser et al., 2000, Conturo et al., 1999, Jones et al., 1999, Mori et al., 1999, Parker et al., 2002a, Parker et al., 2002b, Poupon et al., 2000). Newer probabilistic tractography algorithms adapt the commonly used streamline approach by incorporating the uncertainty in the orientation of the principal direction of diffusion defined for each voxel to generate maps of probability of connection to chosen start points (Behrens et al., 2003a, Behrens et al., 2003b, Lazar and Alexander, 2005, Parker et al., 2003, Parker and Alexander, 2003).

A limitation of tractography algorithms has been their failure to take into account the presence of crossing fiber bundles. Recent developments have allowed the estimation of crossing fibers within voxels (Jansons and Alexander, 2003, Tournier et al., 2004, Tuch et al., 2002, Tuch, 2004). This is of particular importance when studying the SLF where it crosses the corona radiata.

Two recent studies have used tractography to study the connections of Broca's and Wernicke's areas (Catani et al., 2005, Parker et al., 2005), using anatomical guidelines to define starting points for fiber tracking. While both provide interesting new insights into the course of the SLF, both used a two volume-of-interest approach, whereby the analysis is constrained to only include pathways passing through both regions. In addition, manual definition of starting regions may be prone to observer bias.

The combination of fMRI to identify cortical regions involved in specific functions and MR tractography to visualize pathways connecting these regions offers an opportunity to study the relationship between brain structure and function by providing a selective tracing of connectivity within a behaviorally characterized network (Mesulam, 2005). The use of fMRI-derived starting points also minimizes observer bias. This combination has previously been used to investigate the motor (Guye et al., 2003, Johansen-Berg et al., 2005) and visual (Toosy et al., 2004) systems.

In this study, we use these two imaging techniques to examine connectivity between functionally defined language areas in frontal and temporal lobes and test the hypothesis that in the functionally dominant left hemisphere, there would be stronger connections between language areas than between equivalent areas in the right hemisphere. We also aimed to extend the findings of previous studies by looking for a correlation between subjects' degree of functional asymmetry and the lateralization of the structural connections seen. If the pattern of structural connections truly reflected the underlying function, then we would expect those subjects with more lateralized language function to have more lateralized structural connections.

Section snippets

Subjects

We studied 10 right-handed native English-speaking healthy volunteers with no history of neurological or psychiatric disease. Handedness was determined using the Edinburgh Hand Preference Inventory (Oldfield, 1971). The age range was 23–50 years (median 29.5). The study was approved by the National Hospital for Neurology and Neurosurgery and the Institute of Neurology Joint Research Ethics Committee and informed written consent was obtained from all subjects.

MR data acquisition

MRI studies were performed on a

fMRI

Verbal fluency and verb generation were associated with areas of activation in the left inferior frontal gyrus, left middle frontal gyrus, and left insula (Table 1, Figs. 1A and B). Reading comprehension was associated with areas of activation bilaterally in the superior temporal gyri, adjacent to the superior temporal sulci (Fig. 1C) as well as a further area in the left posterior superior temporal gyrus (Fig. 1D). From these areas of activation, we created four VOIs for initiating fiber

Discussion

We used MR tractography to demonstrate the structural connections of the cortical regions activated by expressive and receptive language tasks. A direct connection, corresponding to the SLF, was traced bilaterally between the inferior frontal and posterior temporal lobes, but visual inspection showed that there was a clear structural asymmetry with greater connectivity in the left hemisphere than the right. This asymmetry was most striking in the pattern of connectivity from the inferior

Summary

In summary, we have combined functional MRI language tasks and probabilistic tractography to study the pattern of language related pathways in right-handed healthy control subjects. We demonstrated an asymmetry in the pattern of connectivity with greater connections between frontal and temporal lobes on the left, reflecting the lateralization of language function. The findings described here are from a group of strongly right-handed subjects, and it will be important to compare these results

Acknowledgments

This work was supported by the Wellcome Trust (Programme Grant No.067176, HWRP, MRS), the National Society for Epilepsy (MJK, JD) and Action Medical Research (PB).

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