Brain, Vol. 125, No. 3, 465-478,
March 2002
© 2002 Guarantors of Brain
MRI analysis of an inherited speech and language disorder: structural brain abnormalities
1 Developmental Cognitive Neuroscience Unit and 2 Radiology and Physics Unit, Institute of Child Health, 3 Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London Medical School, London, 4 Department of Experimental Psychology, University of Oxford, Oxford, UK and 5 Laboratory of Neuropsychology, National Institutes of Mental Health, Bethesda, Maryland, USA
Correspondence to: Kate Watkins, Cognitive Neuroscience Unit, Montreal Neurological Institute, 3801 University Street, Montreal, QC, Canada H3A 2B4 E-mail: kwatkins{at}bic.mni.mcgill.ca
Received February 21, 2001. Revised July 19, 2001. Accepted August 13, 2001.
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Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.
Keywords: developmental language disorders; verbal dyspraxia; caudate nucleus; morphometry; genetics
Abbreviations: CNV= caudate nucleus volume; ICV = intracranial volume; SMA = supplementary motor area; VBM = voxel-based morphometry
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MRI studies of developmental disorders of speech and language typically report, on visual inspection, no structural abnormalities that can be correlated with the disorder. The brain abnormalities are thought to be likely to take the form of anomalies in such variables as neuronal size and number, and degree of myelination, which may be detectable only by studies of brain morphometry. Post-mortem methods (Galaburda et al., 1985
; Cohen et al., 1989) and volumetric analysis of in vivo structural MRI scans (see Filipek et al., 1989; Jernigan et al., 1991; Plante et al., 1991; Abell et al., 1999) have revealed abnormal brain structure in association with developmental disorders such as dyslexia, specific language impairment and autism. Given the accumulation of evidence for a genetic aetiology in such disorders, the analysis of brain structure may provide neurobiological phenotypes and may also further our understanding of the neural bases of these disorders.
A striking example of a genetic disorder of speech and language is that seen in the KE family (see Fig. 1). Half of the members of the first three generations are affected by a severe disorder of speech and language. Genetic linkage studies in this family (Fisher et al., 1998) identified a locus, designated SPCH1, in chromosome 7q31. More recently, a point mutation has been identified in the affected family members, which alters an invariant amino acid residue in the DNA-binding domain of a forkhead/winged helix transcription factor, encoded by the gene FOXP2 (Lai et al., 2001). The nature of the behavioural phenotype shared by the 15 affected members of the KE family has been the subject of some debate (see Watkins et al., 2002), but is best characterized as a deficit in the sequencing of articulation patterns rendering speech sometimes agrammatical and often unintelligible. The results of a functional imaging (15O-PET) study and morphometric MRI analysis in the KE family were reported previously (Vargha-Khadem et al., 1998). Here, we focus on the MRI analysis and report the results of new analyses comparing the KE family with a matched control group and more detailed analyses of the caudate nucleus with respect to both size and shape. Finally, we present data on the relationship between the impairments demonstrated by the affected family members and the abnormalities revealed by analysis of their MRI scans.
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To analyse the structural MRIs obtained in the KE family, we used voxel-based morphometry (VBM; Wright et al., 1995
; Ashburner and Friston, 2000). This method has been used to determine changes in brain structure relating to age in normal development (Paus et al., 1999), and to abnormal development (Abell et al., 1999; Krams et al., 1999). VBM draws on statistical methods that were developed originally for PET studies. It compares regional grey matter volume on a voxel-by-voxel basis, thereby generating a large number of comparisons and the need for statistical correction. It was important, therefore, to generate hypotheses that predicted in advance the regions of the brain that would be structurally abnormal in the KE family.
The most obvious feature of the disorder in the affected members of the KE family, which is evident even to the naive observer, is the unintelligibility of their speech. On behavioural testing, every affected family member can be identified as such on the basis of impaired control of the oral musculature for both speech and non-speech movements (see Vargha-Khadem et al., 1998; Watkins et al., 2002). It was hypothesized, therefore, that the underlying neuropathology would involve one or more components of the motor system. Functional imaging, using PET (an 15O-labelled water study), in two affected family members revealed abnormalities of several motor regions, in accordance with our first hypothesis (Vargha-Khadem et al., 1998).
When a focal lesion to the dominant hemisphere is acquired during childhood, gross or persistent disturbance of speech and language is rarely seen (Hécaen, 1976), presumably because of a capacity for reorganization of these functions. When language functions fail to reorganize following childhood insults, bilateral pathology is suspected (Vargha-Khadem et al., 1985). Indeed, some of the previous morphometric studies, including the early post-mortem findings in dyslexia, reported bilateral abnormalities in the brains of developmentally disordered populations (Galaburda et al., 1985; Humphreys et al., 1990). The impairment affecting the KE family is evident throughout development and persists into adulthood. Therefore, a second hypothesis was proposed, namely that the underlying neuropathology would be bilateral.
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Subjects
Ten affected and seven unaffected family members were scanned. Of the affected family members, four were adults from the first and second generations of the family, and the remaining six were third-generation members ranging in age from 9 to 21 years. The unaffected family members were from the third generation and ranged in age from 9 to 27 years. The scans of 17 age- and sex-matched controls were selected from a database of scans of normal volunteers.
Data acquisition
The Ethics Committee of Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health approved these procedures; subjects gave informed consent. Family members and controls were scanned using a 1.5 T clinical imaging system with a standard quadrature head coil. Three-dimensional (3D) data sets of the whole head were collected using a T1-weighted MPRAGE sequence (repetition time = 10 ms, echo time = 4 ms, inversion time = 200 ms, flip angle = 12°, matrix size = 256 x 256, field of view = 250 mm, partition thickness = 1.25 mm, 128 sagittal partitions, acquisition time = 8.3 min). The neuroradiological reports based on these scans stated that there were no overt focal abnormalities detectable on visual assessment.
Voxel-based morphometry
Image processing
Before statistical analyses were carried out on these 3D data sets, the images were processed using methods implemented in Statistical Parametric Mapping (SPM96) software (Wellcome Department of Cognitive Neurology, London, UK).
Each data set was processed in three stages: normalization, segmentation and smoothing. The first stage involved spatial normalization to a template image: a 12-parameter affine registration followed by a non-linear registration using 756 parameters. The images were resampled to produce voxels of 1.5 x 1.5 x 1.5 mm using nearest-neighbour interpolation to preserve the original voxel intensities. All images, including those of the youngest subjects (aged 9 years), were normalized successfully to the template image. These normalized images were segmented (partitioned) into grey matter, white matter, CSF and scalp images (Ashburner and Friston, 1997). Finally, the resulting grey matter images were smoothed using a 12-mm full-width at half-maximum isotropic Gaussian kernel. This method creates a spectrum of intensities, which can be thought of as images representing the local volume, or regional density of grey matter.
Statistical analysis
The processed images of the third-generation family members and their controls were compared statistically using the SPM software. The first- and second-generation family members were excluded from this analysis because there were no unaffected family members in this age group with whom they could be compared. An analysis of covariance with six planned linear contrasts was run with three groups, affected family members (n = 6), unaffected family members (n = 7) and an age-matched control group (n = 13). The global amount of grey matter was used as a covariate in this analysis. Thus, the data underwent normalization for the amount of grey matter in each data set, thereby allowing regional differences between data sets to be detected irrespective of the global differences in the total amount of grey matter. The VBM analyses that we carried out assumed equal variances among the groups. This is not necessarily the case given the relatedness of the affected and the unaffected groups. Our main findings, however, are based on measurements of the caudate nucleus volume (CNV), for which the VBM results are corroborated by quantitative morphometry. Results are reported for voxels with a corrected P value of <0.05. An uncorrected P value of <0.0005 was used for regions that had been predicted in advance: those that were functionally abnormal in the PET study, or were in other known anterior language or motor regions, or were the contralateral, homologous regions to any of the regions already identified. The coordinates of significant foci are given in standard stereotaxic space using a template image, which conforms to the 3D coordinate system of Talairach and Tournoux (1988).
Quantitative volumetry of the caudate nucleus
Caudate nucleus volume
The original MRI data sets were reformatted manually into 1-mm thick contiguous transverse slices parallel to the horizontal plane through the anterior and posterior commissures (AC–PC line) and orthogonal to the vertical plane through the longitudinal fissure. The cross-sectional areas of the caudate nucleus were measured (using XdispIm software; Plummer, 1992) for each slice from the dorsal surface of the nucleus, where it appears lateral to the lateral ventricles, to its ventral limit at the level of the anterior commissure (AC), where it merges into the nucleus accumbens. Although the body and head of the caudate nucleus were easily seen on all slices, the tail was often indistinguishable from the nearby ventricle and hippocampus/amygdala and so was not measured. The volumes were calculated (according to Cavalieri’s principle; see Gundersen et al., 1988) from the sum of the cross-sectional areas, in pixels, multiplied by the slice thickness (1 mm) and pixel size (calculated from the matrix size: 256 x 256 pixels; and field of view: 250 mm; pixel size = 0.9537 mm2).
Absolute CNVs were corrected by reference to intracranial volumes (ICVs), which were estimated from the original sagittal slices of the 3D data sets as described by van Paesschen et al. (1995). There was a significant correlation between ICV and CNV measurements for the comparison group, which consisted of the entire normal control group (n = 17) and the unaffected family members (n = 7). The Pearson’s correlation coefficients between ICV and CNV were 0.48 (P = 0.018) for the left caudate nucleus and 0.42 (P = 0.041) for the right. The slopes of the two regression lines, one each for the left and right CNVs with ICV, were used to calculate CNVs corrected for ICV for each subject.
Behavioural and cognitive testing
Watkins et al. (2002) described procedures for a number of behavioural and cognitive tests, which were administered to the affected and unaffected members of the KE family. The scores for the tests that revealed the affected family members to be significantly impaired relative to the unaffected family members were used in correlational analyses with the CNV measurements. These tests were: verbal and performance intelligence subtests of the Wechsler Intelligence Scale, lexical decision, Test for Reception of Grammar, word and non-word repetition, object naming, verbal fluency, morphological production, past tense production, non-word reading and spelling, and oral praxis (WISC-III and WAIS-R; see Watkins et al., 2002; and references therein).
Statistical analysis
The volumetric data (absolute and corrected CNVs, ICVs and asymmetry coefficients) were analysed by a one-way ANOVA (analysis of variance) comparing the groups of affected family members, unaffected family members and controls. This was carried out twice, with and without the affected family members of the first and second generations. The second analysis was run because there are no age-matched unaffected family members to compare with the affected family members from the first and second generations. Because the results of the two analyses did not differ, only those for the third-generation family members (affected, n = 6; unaffected, n = 7) and their age-matched controls (n = 13) are reported here.
Caudate nucleus volume distribution
In addition to the above analyses, the cross-sectional areas of the slices through the caudate nucleus were plotted as a function of slice position as described by Cook et al. (1992) for a similar analysis of the hippocampus. The cross-sectional areas were first corrected for ICV using a correction factor for each individual subject. The control data were plotted for the left and right caudate nucleus separately, with each graph having three curves, one representing the mean caudate nucleus cross-sectional area for each slice position, and the two others representing the mean ± 2 SDs (see Fig. 6). The total areas under these curves were equated to the mean CNV and to this volume ± 2 SDs of the mean, respectively. Using the same method, the data for family members (corrected for ICV) were plotted with the control graphs to allow visualization of where, in terms of slice position, the volume differences occurred.
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Voxel-based morphometry
The contrasts between the unaffected family members and the control group did not reveal any areas of significant difference in grey matter volume that survived a correction for multiple comparisons. There were no hypotheses about structural differences between these two groups, and therefore no regions were predicted in advance to be structurally abnormal. Of the regions that survived an uncorrected statistical threshold of P < 0.0005, none was a region shown to be abnormal in the comparisons involving the affected family members.
In the comparison of the affected family members and controls, a number of regions were found to be abnormal. Those in which the affected group had significantly less grey matter than the controls included the head of the caudate nucleus, areas within the sensorimotor cortex, the posterior inferior temporal cortex and the posterior lobe of the cerebellum (lobule VIIIB; Schmahmann et al., 1999). All of these areas showed bilateral abnormality (see Table 1 and Fig. 2A–C). The affected family members had significantly more grey matter than controls in anterior insular cortex bilaterally, the left inferior frontal gyrus, the putamen and motor cortices bilaterally, the posterior lobe of the right cerebellum (lobule VI; Schmahmann et al., 1999) and medial occipitoparietal cortex, clearly on the left but perhaps bilaterally (see Table 1 and Fig. 3A–C).
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In the most critical comparison, that between the affected and unaffected family members, again a number of regions was found to be abnormal. The affected family members had significantly less grey matter than the unaffected members in the regions listed in Table 2 (see also Fig. D–F). These included two regions in the left inferior frontal cortex dorsal to the operculum, the head of the caudate nucleus bilaterally and a region within the supplementary motor area (SMA). Finally, the affected family members had significantly more grey matter than the unaffected members in the left frontal operculum, including anterior insular cortex and pars triangularis, the superior temporal cortex, including the planum temporale bilaterally, the putamen bilaterally, a region within right sensorimotor cortex and the tail of the right caudate nucleus (see Table 2 and Fig. D–F).
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Quantitative volumetry of the caudate nucleus
Volume measurements
For the ICVs, there were no significant differences (F < 1) among the three groups (affected and unaffected family members and their controls; see Table 3).
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For the absolute CNVs, however, the affected family members were found to have significantly smaller volumes for both left [F(2,23) = 8.71, P = 0.002] and right [F(2,23) = 9.07, P = 0.001] caudate nuclei compared with both the unaffected group (left caudate nucleus t = 3.30, P = 0.007; right caudate nucleus t = 3.58, P = 0.004) and the controls (left caudate nucleus t = 3.88, P = 0.001; right caudate nucleus t = 3.91, P = 0.001).
For the corrected CNVs, an identical pattern of results was observed. There was a significant group difference for both left [F(2,23) = 9.95, P < 0.001] and right [F(2,23) = 9.18, P = 0.001] corrected CNVs. The affected group had significantly smaller volumes than both the unaffected group (left t = 3.97, P = 0.002; right t = 3.88, P = 0.003) and the control group (left t = 3.91, P = 0.001; right t = 3.87, P = 0.001) (see Fig. A).
There were no significant differences among the three groups for the asymmetry coefficients [F(2,23) = 1.89, P = 0.17; see Fig. B], although there was a trend towards smaller mean coefficients in the affected group than in the other two groups, because three out of the six affected members showed positive asymmetry coefficients (i.e. left CNV greater than right CNV, or reverse asymmetry from normal). One of these three affected family members was the only left-handed subject. In contrast, all but one member of the unaffected group, and all of the controls, showed the expected negative asymmetry coefficients (i.e. right CNV greater than left CNV). The asymmetry coefficient of one affected family member, although negative, was larger than that seen for any of the unaffected family members and controls. A test of homogeneity of variance between the affected group and the controls was significant (P = 0.024) but a t-test for the difference in the means was not significant. The means and standard deviations for each group are given in Table 3.
Correlations with caudate nucleus volume measures
Correlations between the affected family members’ CNVs and their behavioural test scores revealed the following. The oral praxis scores correlated significantly with the left CNVs (
= 0.685, P = 0.004; see Fig. 5A) and the asymmetry coefficients ( = 0.807, P = 0.005; see Fig. B). The scores for non-word repetition requiring complex articulation were found to correlate significantly with the right CNVs ( = –0.727, P = 0.017; see Fig. C) and with the sums of the left and right CNVs ( = –0.722, P = 0.018; see Fig. D); the direction of these correlations was unexpectedly negative. The only other significant correlation, also a negative one, was between the scores on the coding subtest of the Wechsler Intelligence Scale and the asymmetry coefficients ( = –0.639, P = 0.047; see Fig. E).
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For the unaffected family members, significant correlations were revealed for performance IQs, and the Block Design subtest scores, with the asymmetry coefficients (
= 0.815, P = 0.025, and = 0.860, P = 0.013, respectively).
Caudate nucleus volume distribution
The cross-sectional areas of the left and right caudate nuclei are plotted as a function of slice position in Fig. . Examination of the graph for the left caudate nucleus (Fig. A) shows that the affected family members of all three generations have reduced CNV in the more dorsal (superior) slices compared with both the unaffected family members and the control group. Starting approximately half way through the slices, however, the cross-sectional areas of the affected third generation fall within the 2 SD limit of the control mean; then, in more ventral (inferior) slices, they match the mean of the control groups; and, finally, in the most ventral (inferior) slices, they slightly exceed the upper 2 SD control limit. An almost identical pattern is seen for the measurements of the right caudate nucleus (Fig. B).
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Discussion |
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A previous PET study carried out during performance of a word repetition task revealed abnormal activation of several motor-related brain regions in the affected family members (Vargha-Khadem et al., 1998
). One of these regions, the left caudate nucleus, was overactive in the affected family members and was found here to have significantly less grey matter bilaterally compared with both the unaffected members and the control group. In view of this converging evidence of functional and structural abnormality of the caudate nucleus, we examined this nucleus in greater detail using a quantitative volumetric method. Although special attention to the caudate nucleus thus seemed warranted, and specific additional abnormalities in this nucleus were in fact uncovered, caudate abnormalities were clearly not the only ones that were found to be associated with the speech and language disorder in the affected members of the KE family. The following discussion first reviews the findings from the caudate nucleus studies. We then review the other brain abnormalities that were revealed by the VBM analysis and discuss these and the caudate nucleus abnormalities with reference to the neuropathology reported in other language-impaired populations and to the functional neuroimaging literature. Finally, we discuss possible relationships between variations in the size of a brain region and variations in its evoked activation and in its functional contributions.
Caudate nucleus abnormalities in the KE family
Reduced caudate nucleus volume
A robust and highly significant result of the VBM analysis was that the caudate nucleus had less grey matter bilaterally in the group of affected family members compared with either the group of unaffected members or the matched controls. Analyses of quantitative volumetric data for the caudate nuclei confirmed the results of the VBM, in that the affected family members have significantly reduced CNVs bilaterally relative to both unaffected and control groups, and these two groups were not significantly different from each other.
Although the caudate nucleus was shown by the above analyses to be reduced in volume in the affected family members as a group, this is not true for each of the individuals in the group, i.e. some affected family members have CNVs equal to or greater than some unaffected family members or controls. A small caudate nucleus cannot be said, therefore, to be characteristic of the disorder that the affected family members share (i.e. a neurobiological phenotype). It is possible, however, that the caudate nucleus, even if apparently normal in size and shape in some affected members, nevertheless is functionally abnormal. The PET study carried out with two affected family members showed overactivation during word repetition when compared with normal controls. The corrected CNVs in these two affected family members were below the means for the affected group reported in Table 3. It remains to be determined whether the other affected family members, including those with normal or near normal CNVs, also demonstrate a functional abnormality for this nucleus.
The graphs of the mean cross-sectional area as a function of slice position indicate that, as a group, the affected family members have a smaller than normal volume in more dorsal (superior) slices of the caudate nucleus. This pattern of volume loss is similar to that reported in Huntington’s disease (Vonsattel et al., 1985). It should be noted, however, that precise localization of volume change is difficult; a loss of volume centrally in this nucleus might result in an apparent reduction at its ventricular surface.
Caudate nucleus asymmetry
Asymmetry coefficients for the caudate nucleus were not significantly different among the three groups, for although three of the affected family members showed greater volumes on the left than on the right, one of the affected family members showed an asymmetry coefficient in favour of the right caudate nucleus that was even larger than that seen in any of the controls. The typical pattern of asymmetry in the caudate nuclei is for the right to be larger than the left (Castellanos et al., 1996; Frazier et al., 1996; Reiss et al., 1996). This was the pattern observed in all of the controls and in all but one of the unaffected family members, but in only three of the six affected family members. A loss of caudate nucleus asymmetry has been reported in association with other developmental disorders, such as attention deficit hyperactivity disorder (Castellanos et al., 1996) and childhood-onset schizophrenia (Frazier et al., 1996).
Relationship between volume and behaviour
The relationship between the size of the caudate nucleus and performance on a number of behavioural and cognitive tests was examined directly in the affected family members using correlational analyses. These interesting relationships merit some discussion but, given the small number of individuals analysed and the number of correlations run, they should be considered suggestive until corroborated by further data.
The only significant positive relationships found were those for the scores on a test of oral praxis with the volumes of the left caudate nucleus and with the asymmetry coefficients. A small volume for the left caudate nucleus may result in a more negative asymmetry coefficient. It seems likely, therefore, that both of these correlations are due to the relationship between the left caudate nucleus volume and the oral praxis score, namely the smaller the volume of the left caudate nucleus, the lower the score on the test of oral praxis. Significant correlations were also found for the scores on a test of non-word repetition involving complex articulation with the volumes of the right caudate nucleus and the sum of the volumes of the left and right caudate nuclei. These correlations, however, were unexpectedly negative, indicating that the smaller the right caudate nucleus or the smaller the total volume of these nuclei, the better the performance on this test. Like oral praxis, repetition of non-words with complex articulation is thought to be a measure of the primary deficit of the behavioural phenotype in the affected family members (see Watkins et al., 2002). Thus, this unexpected finding is intriguing. One possible explanation of the finding is that the degree of the pathology of the caudate nuclei in some affected family members may have reached a threshold that forced reorganization of function or compensatory mechanisms to come into play, resulting in improved function. A significant negative relationship was also found between the coding subtest scores and the asymmetry coefficient. In this case, the negative relationship is easier to explain, as a negative asymmetry coefficient typically is seen in control populations. In the affected family members, those with the atypical, positive asymmetry coefficient had lower scores on the coding subtest.
These results provide the first direct evidence of a relationship between a brain abnormality and the behavioural phenotype in the KE family. The causal nature of this relationship, however, has yet to be determined, and the finding of a negative correlation between CNV and non-word repetition implies that this relationship is not straightforward.
The correlational analyses in the unaffected family members revealed significant positive correlations between performance IQs (and scores on the Block Design subtest of the performance scale) and the asymmetry coefficients. Thus, the more symmetrical the caudate nuclei, the higher the scores on non-verbal intelligence tests. These results are partially consistent with those of Reiss et al. (1996), who reported that subcortical grey matter volume predicts a small but significant portion of the variance in IQ in childhood.
Insights from other language-impaired populations and from functional imaging studies
The other brain abnormalities in the affected members of the KE family that were revealed by the VBM analyses warrant further investigation using complementary methods such as quantitative volumetry. Nevertheless, as described below, the results of studies of other language-impaired populations and of functional imaging studies are consistent with the abnormalities reported here.
Caudate nucleus and specific language impairment
The present finding that abnormal caudate nucleus structure and function are associated with a developmental disorder of speech and language is in line with the results of two other studies in language-impaired children. Jernigan et al. (1991) performed a morphometric analysis using MRI scans and reported the caudate nucleus to be reduced in volume bilaterally in a group of children with specific language impairment compared with matched controls. Also, Tallal et al. (1994) reported bilateral damage to the head of the caudate nucleus in a 10-year-old boy with a history of specific language impairment and behavioural difficulties. Expressive language and articulation had been severely impaired in this boy at age 4 years, although by age 8 years he had improved considerably.
Striatum and language
In addition to the reduced amount of grey matter in the caudate nucleus, the affected family members were found to have increased amounts of grey matter in the putamen bilaterally relative to the unaffected group and the controls (see Fig. ). Pathology of the putamen and caudate nuclei has been reported in association with aphasic symptoms in adult patients (Lieberman et al., 1992; Ullman et al., 1997; Pickett et al., 1998) and some with this combined pathology also show oral and verbal dyspraxias (Blumstein et al., 1987; Speedie et al., 1993; Aglioti et al., 1996). Further evidence of basal ganglia involvement, in particular of the putamen, in the articulation and motor control of speech, comes from functional imaging studies (Klein et al., 1994; Wise et al., 1999).
Frontal operculum and language
The VBM analysis showed that the affected family members had an abnormally large amount of grey matter in the left frontal opercular regions (pars triangularis and anterior insular cortex; see Fig. ) and, in the comparison with controls, this abnormality was also present in the right operculum. The abnormal region in the pars triangularis revealed by the VBM analysis is located close to the area that Price et al. (1996) suggested is involved in perceptual speech processes, and 14 mm anterior to the inferior frontal region that they found to be involved in speech production. Dronkers (1996) reported that a lesion to a specific area of left anterior insular cortex was necessary to produce an apraxia of speech in adult patients who had suffered stroke. Also, in a post-mortem study of a young girl with delayed expressive language and oromotor impairment, Cohen et al. (1989) reported a dysplastic gyrus in the insular cortex of the left hemisphere. The affected family members are impaired on both expressive and receptive language tasks, although the most severe deficits are seen in the former. The structural abnormalities reported here in the inferior frontal cortex may be related to both sets of functional impairment, but the proximity of the abnormality in pars triangularis to that in anterior insular cortex suggests that a widespread frontal opercular abnormality is most probably linked to the articulatory/expressive deficits seen in affected family members.
Medial and lateral motor cortex and language
The affected family members had significantly less grey matter than the unaffected members in the left SMA. This region in the affected members was also found to be functionally abnormal in the PET study, in that it did not show the difference in activation between the baseline and the word repetition condition that is seen typically in normal controls. In intraoperative cortical stimulation studies (Penfield and Welch, 1951), stimulation of this medial frontal region was reported to interfere with voluntary limb and speech activities. Patients with lesions of the left medial frontal cortices are often mute postoperatively but recover with some residual deficits in spontaneous expression (Jonas, 1981; Ziegler et al., 1997). The SMA is thought to play a role in the preparatory aspects of sequential movements (Ziegler et al., 1997), especially in conditions involving short-term buffering of the motor response; such conditions obviously apply to fluent speech.
The VBM analysis in the affected members of the KE family revealed additional structural abnormalities of two regions of primary motor cortex. The region with reduced grey matter in the affected group corresponds to the region identified in the PET study as functionally underactive during word repetition (see Vargha-Khadem et al., 1998). This region was identified by Murphy et al. (1997) as one that is activated bilaterally during speech, when breathing and language content are controlled for.
Cerebellum and language
In the VBM analyses, two regions of the posterior lobe of the cerebellum were found to have abnormal amounts of grey matter in the affected family members compared with the control group. In the more inferior aspects of the cerebellum, hemispheric lobule VIIIB (Schmahmann et al., 1999), the affected family members had significantly less grey matter than the control group, whereas they had significantly more grey matter than the controls in hemispheric lobule VI. The contribution of the cerebellum to articulation is well documented; patients with cerebellar lesions commonly are dysarthric (Ackermann et al., 1992). More recently, functional imaging studies have suggested a non-motor contribution of the cerebellum to language function (Fiez and Raichle, 1997). Dysarthric symptoms are associated most commonly with lesions of the anterior and vermal lobules of the cerebellum, whereas cerebellar activations in imaging studies of word generation are observed to lie in more inferior and lateral regions. The latter were the regions in which the structural abnormalities were seen in the affected members of the KE family.
Planum temporale and language impairment
The VBM analyses also revealed abnormal brain structure outside the motor system in regions more commonly associated with receptive language function; the affected family members had significantly more grey matter in the planum temporale bilaterally. Abnormal volumes of the planum temporale have been reported in association with many developmental disorders, including language impairment and developmental dyslexia (Galaburda et al., 1985; Humphreys et al., 1990; Plante et al., 1991). It should be noted, however, that in these studies the abnormality was usually reflected as an increase in the size of the planum temporale of the right hemisphere. Just as for other findings of abnormally large volumes of grey matter, the relevance of an increased size of the planum temporale is still unclear (see Geschwind and Behan, 1982; Galaburda et al., 1985).
Relating size and activity, and size and function
As described earlier, the caudate nucleus showed abnormal activity in the PET study (Vargha-Khadem et al., 1998), as did the SMA and areas within inferior frontal and sensorimotor cortices, all of which were revealed to be structurally abnormal in the VBM analyses. Because the two affected family members studied with PET were not included in the VBM analyses reported here, the relationship between the amount of grey matter in a region and its relative activity is still unknown. Tentatively, however, it appears that in the case of the caudate nucleus, reduced volume was associated with increased activity. One possible explanation for this finding is that an area with less than the normal amount of grey matter must increase activity above normal levels to produce behaviour similar to that produced when its size is normal. An alternative possibility is that a behavioural impairment, such as poorly articulated speech, could be associated with overactivity in a region and yet result in its underdevelopment, thereby rendering its grey matter volume abnormally small. In the case of the SMA, in contrast, reduced volume appeared to be associated with decreased activity. These differential results in the two regions thus point to two different types of pathological size–activity relationships.
With regard to the relationship between size and function, there may again be two quite different types. Thus, in the case of the caudate nucleus, the greater its reduction on the left, the poorer the performance on a test of oral praxis, whereas the greater its reduction on the right, the better the performance on a test of non-word repetition requiring complex articulation. In view of these contrasting findings, caution is called for in interpreting a larger volume in a particular structure as imparting an advantage, or a smaller volume as imparting a disadvantage, to the individual.
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We are indebted to the members of the KE family for their continued cooperation with our research programme. We wish to thank Cheryl Johnson, David Porter, Wim van Paesschen and Stephen Wood for assistance with collection and analysis of the MRI data, and Elizabeth Isaacs and Cathy Price for useful discussion on this manuscript. This research was funded in part by the Wellcome Trust. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from Research and Development funding from the NHS Executive.
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