Department of Neuroscience, , 1 Department of Communication Sciences and Disorders, and , 2 Department of Education Foundations, University of Florida Brain Institute, Gainesville, FL 32611, USA
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Abstract |
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Introduction |
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Phonological Processing
A large body of research has suggested that slow and inaccurate processing of the sound structure of language (phonology) is the core deficit in discrepant readers (Shankweiler et al., 1995) and they are frequently referred to as phonological dyslexics (PDs). A consensus is gradually building, however, that pure phonological deficits are rare and that most poor readers have deficits in additional linguistic areas such as semantics and syntax. As Bishop and Adams stated so eloquently:
Phonological factors are of particular theoretical interest because they seem to explain variation in reading acquisition that is not accounted for in terms of other, more general, verbal abilities. However, it should be emphasized that other language skills exert the major influence on reading progress. (Bishop and Adams, 1990, p. 1046)
Recent research has backed up this prescient statement. The contribution of oral language skills (Lombardino et al., 1997; Catts et al., 1999
) and general intelligence (Stringer and Stanovich, 2000
) to reading skill is not explained by a phonological deficit. Most poor readers, according to Manis and his colleagues (Manis et al., 1996
), do not exhibit discrepant profiles, they are just garden variety poor readers (Stanovich, 1988
).
Poor readers with linguistic deficits share many cognitive deficits with SLI. Whether PDs are part of that continuum is not clear. Tallal and her colleagues have proposed that all reading and language disorders stem from nonlinguistic auditory and visual temporal processing deficits (Tallal et al., 1993; Albert et al., 1999
). But the specificity of the link between nonlinguistic auditory discrimination and phonological ability is yet to be established (Mody et al., 1997
).
Resolution of this issue is critical to the design of informative genetic and neurobiological studies. Heterogeneous phenotypes make such studies uninterpretable. In a recent article, Andreason and her colleagues suggested that identification of neuroanatomical variants might provide a link between genotype and behavioral phenotype in complex disorders such as schizophrenia (Wassink et al., 1999). In the present study we applied that strategy to RD phenotypes.
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Anatomical Study of Language Disorders |
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The present study had three aims: (i) to replicate earlier findings of duplicated gyri and leftward asymmetry in a comprehensively tested sample of RD; (ii) to measure additional structures such as brain volume and the cerebellum, which might help characterize a consistent anatomical and behavioral phenotype; (iii) to determine if anatomical variation predicted cognitive deficits associated with RD.
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Materials and Methods |
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The main sample consisted of 30 college students, 28 of whom received magnetic resonance imaging (MRI) scans. Fifteen students (8 men/7 women) were certified as RD by the University of Florida Office of Student Services. These RD subjects were matched as a group with 15 controls on the fluid reasoning cluster of the Woodcock Johnson test of Cognitive AbilitiesRevised (WJ-Cog) (Woodcock and Johnson, 1989), sex, and a quantitative measure of handedness (QHP) (Briggs and Nebes, 1974
). All subjects signed an informed consent form and were paid $30 for participation. They completed the fluency portion of the Gray Oral Reading Test (GORT) (Wiederholt and Brayant, 1992
), the Wide Range Achievement Tests of Spelling (WRAT-SP) and Reading (WRAT-RD) (Jastak and Wilkinson, 1993
), and the Woodcock Reading Mastery tests [Word Attack (WA), a test of pseudo word reading; Word Identification (WI), a test of single word reading, and Passage Comprehension (PC), a test requiring a fill in the blank response] (Woodcock, 1987
).
The WJ-Cog was used to measure cognitive abilities (Woodcock and Johnson, 1989). Cognitive ability is multidimensional and cannot be reflected in a single intelligence quotient (IQ). On most IQ tests, only two or three factors can be extracted due to the limited number and diversity of their subtests (Carroll, 1993
; Keith and Witta, 1997
). The WJ-Cog, however, measures seven moderately independent factors: fluid reasoning, crystallized intelligence, visual and auditory processing, processing speed, and short- and long-term memory (McGrew and Murphy, 1995; Kranzler, 1997
). The WJ-Cog is psychometrically sound, having been normed on a sample of more than 6000 individuals aged 590 (Reschly, 1990
).
MRI
All control subjects and 13 of the original 15 RD subjects received a volumetric MRI scan in a GE 3 T scanner at the Veterans' Administration Medical Center. Parameters were TR = 10 ms, TE = 2.9 ms, flip angle = 20°, matrix = 256 x 128 x 128, image voxel size = 0.94 x 0.94 x 1.3 mm. Headers containing identifying characteristics were removed, images were concatenated into a series, assigned a randomly chosen blind numbers and reformatted into 1 mm thick slices in the Talairach planes. Two raters blind to subject characteristics made each measurement and differences were resolved by discussion.
Principles Guiding Choice of Anatomical Measures
Cerebral size was measured because a number of studies have found that cerebral size is related to measured intelligence (Willerman et al., 1991; Reiss et al., 1996
), an ability that contributes to reading proficiency (Stringer and Stanovich 2000
). Hemispheric volume asymmetries were measured in light of a recent report (Sisodiya et al., 1995
) that marked (>4%) hemispheric asymmetries were associated with a radiological diagnosis of dysplasia, a pathological finding that has characterized the brains of a few dyslexics examined post mortem. Cerebellar size and asymmetry were measured because of Fawcett and Nicolson's proposal that automatization deficits in dyslexia are accompanied by cerebellar mediated deficits in coordination and balance (Fawcett and Nicolson, 1994). The planum temporale of the temporal lobe was measured because of its reported association with language ability (Leonard et al., 1996
; Rumsey et al., 1997
). The surface area of Heschl's gyri were measured because duplications of these gyri are heritable and were found in a previous study of RD (Leonard et al., 1993
; Eckert and Leonard 1999
).
Technical Details
Cerebral Hemispheres
The volume of each cerebral hemisphere was measured by tracing the area enclosed by the dura on every fourth sagittal image, and summing the averages of adjacent areas after multiplying by the width of the inter image gap. (Volumes calculated with this method correlate 0.98 with volumes calculated from measurements of every image.) The midsection was traced twice and half the slab volume added to each hemisphere. This measure includes intra-sulcal CSF and thus reflects original cerebral capacity before the onset of age-related cortical loss. Inter-rater reliability of this measure is >0.9 (intra-class correlation). The coefficient of asymmetry of the cerebral hemispheres (coacer) was calculated by dividing the left/right difference by the average volume of the two hemispheres.
Cerebellar Hemispheres
The posterior lobe in each hemisphere was outlined on every other 1 mm thick axial section. Volumes were calculated by summing these areas after multiplication by the section gap (2 mm). Reliability for these measurements was 0.9. (Volumes calculated with this method agree 0.96 with volumes calculated from measurements of every image). The anterior lobes were measured in sagittal images. Every 1 mm thick section on which the primary fissure could be seen was outlined and the areas added to calculate the volume in each hemisphere. As the primary fissure becomes indistinct laterally, the lateral boundary of the anterior lobe was defined as the image on which the superior cerebellar vessels disappeared. Reliability for this measurement was 0.87. Separate coefficients of asymmetry were calculated for the anterior (coaant) and posterior lobes (coapost).
Planum Temporale
The surface area of the temporal bank of the planum (PT) was measured between the posterior boundary of the first transverse gyrus of Heschl (Heschl's sulcus), and the termination of the Sylvian fissure, which in most cases was marked by a small elevation in the planum (see Fig. 1) and a bifurcation into a descending ramus and the posterior ascending ramus (PAR). The small posterior descending ramus which originated from a bifurcation was not included in the measure. In cases where the posterior ascending ramus originated proximally to the termination of the sylvian fissure (inverted formation) (Ide et al., 1996
) the large extent of sylvian fissure posterior to PAR was included in the planum measurement. The posterior ascending ramus was measured from the bifurcation to its dorsal termination. In the small number of cases where no elevation or bifurcation marked the origin of PAR, the knife cut method was used (Witelson and Kigar, 1992
). In cases where the sylvian fissure merged with the superior temporal sulcus or other occipitoparietal sulci, the planar measurement was terminated at the point of the merge.
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The values for the temporal bank and PAR were summed (PT+) and a coefficient of asymmetry was calculated. PT+ is generally symmetrical because leftward asymmetry in PT is mitigated by rightward asymmetry of PAR. Summing the coefficients of asymmetry for PT and PAR provides an index of the relative strengths and direction of the asymmetries of the two banks (sumppar).
Heschl's Gyri
The surface areas of the first Heschl's gyrus (H1) and, when present, a second gyrus (H2) were traced between their limiting sulci on consecutive sagittal images between x = 34 and x = 48. Examples of H1 and H2 are shown in Figure 1. Two operators measured 10 H1 and all H2 to determine inter-rater reliability. Intraclass correlations were 0.9 for H1 and 0.85 for H2.
Data Analysis
All variables were entered into spreadsheets and analyzed with PC-SAS. Means and standard deviations were calculated and the t-statistic (with Bonferroni correction) was calculated to test for significance of differences in group means. (The scores for the WRMT-WA were converted to ranks because of the presence of one extremely high score in the RD group). A paired t-test was used to test the significance of structural asymmetries in each group separately.
For variables where the distributions in the RD and controls groups differed, both nonparametric and parametric analyses were used to define a quantitative threshold that separated diagnosed individuals from controls (anatomical risk factor). Nonparametric analyses were used to examine the frequency of combinations of extreme values. Parametric analyses were used to incorporate information from the entire range of measurements.
In the nonparametric analysis, the anatomical measures were converted to ranks and the individuals with the seven scores in the quartile containing the tail of the distribution were defined as having an anatomical risk factor. In the parametric analyses, the anatomical measures were first entered into a discriminant analysis and then converted to z-scores using the control means and standard deviations and adjusting the sign to indicate a consistent direction of risk. The four z-scores were summed and plotted against behavioral variables. Pearson rs were calculated to characterize the strength of the relationships between anatomical and cognitive variables.
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Results |
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Identification of these findings required separation of subjects with PD (n = 11, 9 of whom returned to be scanned) from the remainder of the RD group. A phonological deficit was defined as a pseudo-word decoding score (WRMT-WA) <90 (<27th percentile). The other four RD subjects had WRMT-WA scores in the average (100, 99, 101) or superior range (141). Since each one had a somewhat different cognitive profile but scored in the 27th percentile on at least one reading or spelling test, they will be referred to as URD (unspecified reading deficit).
The results section is organized as follows: (i) characterization of the two original samples and the PD subgroup; (ii) description of the anatomical characteristics that distinguish the PD subgroup; (iii) nonparametric categorical analysis of combinations of risk factors; (iv) parametric analysis of normalized and cumulative measures; (v) identification of a separate risk factor for comprehension deficits.
Comparison of Original RD Sample with Controls
The means and standard deviations for the demographic and behavioral variables on which the groups were matched are given in Table 1. The control and RD groups did not differ in age, handedness, male/female composition or fluid reasoning ability (WJ-Cog Test of Analysis/Synthesis).
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As reported previously for a clinically diagnosed group of dyslexic adults and children (Leonard et al., 1993), the RD group as a whole tended to have more marked leftward asymmetry of the PT, although the group difference was not significant. Both the RD and control groups had significant leftward asymmetry of the planum temporale and the summed coefficients of PT and PAR (Table 2
). There were no group differences in the ratios of the planum temporale to PAR on either the left or the right. Unlike previous reports, there was no evidence of a transfer of tissue from the PT to the PAR and the coefficients of asymmetry of PT, PAR and PT+ did not predict scores on any reading or cognitive test (Leonard et al., 1996
; Rumsey et al.,1997; Eckert et al., 1998
).
Heschl's Gyri
Both groups had a significant leftward asymmetry of the first but not the second transverse gyrus of Heschl (see Table 2). All subjects, with the exception of one control, had a larger H1 on the left than the right. This asymmetry is even more consistent than reported by Penhune and her colleagues (Penhune et al., 1996
) and agrees with a previous post mortem study (Musiek and Reeves, 1990
).
Anatomical Risk Factors for PD
Most subjects had leftward asymmetry of the PT and rightward asymmetry of PAR, a consistent finding in previous studies (Steinmetz et al., 1990; Leonard et al., 1993
; Witelson and Kigar, 1992
). Three of 15 controls, 2/4 URD and 0/9 PD had rightward asymmetry or symmetrical PT. Rightward asymmetry of both PT and PAR was found in one URD subject. Leftward asymmetry of both PT and PAR was found in five PD subjects, a highly unusual finding (Jäncke et al., 1997
).
The PD group had greater rightward asymmetry of the cerebral hemispheres, greater leftward asymmetry of the anterior lobe of the cerebellum, greater leftward asymmetry of the summed planum and PAR and a larger surface area of H2 (Table 3). The three asymmetries and LH2 surface area are plotted against pseudo-word decoding score in Figure 2
. Note that all four risk factors discriminate the nine PD subjects from those with URD. The URD subjects always cluster near symmetry or at the opposite asymmetry from the PD group.
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Scores on the four anatomical variables were ranked and a PD risk factor was defined as a value falling in the bottom quartile. Table 4 gives the distribution of risk factors in the three adult groups. Not one of the URD subjects has a risk factor, half the controls have one risk factor, while 8/9 PD subjects have two or more risk factors [
2 (df = 6) = 25.9, P < 0.0002]. Table 5
gives the relative frequency of different risk factor combinations.
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Two analyses were performed to determine if there was a cumulative quantitative effect of brain structure on the risk of PD. First, scores from the measures graphed in Figure 2 were converted to standard scores with the sign adjusted so that positive scores would predict a phonological deficit. The standard scores were then summed for each individual. This new variable completely separates the PD and URD groups (see Figure 3
top). All nine PD subjects have positive scores. Only two controls and no URD subjects have positive scores.
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Separate Anatomical Risk Factors for Coding and Comprehension Deficits
Pearson correlation coefficients were calculated between all anatomical variables, the cumulative risk factor score and the WJ-Cog Cluster scores. When significant correlations were found at the Cluster level, the Subtest correlations were examined to determine specificity. A consistent pattern emerged, with cerebral volume demonstrating significant correlations with a number of related abilities such as reasoning, comprehension and oral language skill. The cumulative risk factor score, by contrast, predicted deficits in Short-Term Memory and Long-Term Retrieval of arbitrary phonological information (Table 6). The relationship between reversed digit span (Numbers Reversed) and the cumulative risk factor score is plotted in Figure 3
(upper right).
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Discussion |
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Cumulative Risk
Imaging studies of the relation between cognitive function or behavioral disease and brain structure are hard to replicate (Stevens, 1997; Zuffante et al., 2000
). The relations are rarely strong and frequently disappear with doubling of the sample size (Chua and McKenna, 1995
). However, a recent study of schizophrenia found that while measurements of individual structures did not distinguish patients and controls, there was a cumulative effect of extreme anatomy. When cerebral volume, third ventricle volume and measures of temporal and frontal sulcal continuity were put into a discriminant analysis, 75% of the schizophrenics were properly classified (Leonard et al., 1999
). These anatomical measures also combined to produce a highly accurate estimate of full-scale IQ. Patients with higher numbers of extreme measurements tended to have lower measured intelligence. The patients in that study were not given the WJ-Cog, so it was not possible to determine if different anatomical variables were related to particular cognitive abilities. Nevertheless, the findings are consistent with the idea that schizophrenia and other complex behavioral disorders evolve from the random combination of many factors, with each one conferring a relatively low risk in isolation.
This is the third study from our laboratory that has identified an elevated risk associated with the combination of a Heschl duplication and an anomalous sylvian fissure. In the first study, performance on a phonological processing test decreased as the number of perisylvian anomalies increased (Leonard et al., 1993). In the second study, male subjects with a mutation in the thyroid receptor gene were more likely to have multiple perisylvian anomalies than family members without a mutation (Leonard et al., 1995
). In the present study, PDs had a higher risk for combinations of perisylvian anomalies. Future work should determine whether the likelihood of a behavioral diagnosis is elevated due to either specific genetic or cognitive alterations associated with each separate risk factor or nonspecific effects of genetic load (Waddington, 1957
; Markow, 1994
).
Separate Risk Factors for Comprehension and Coding Deficits
Subjects who maintained good comprehension in the presence of severe phonological deficits had extreme scores on measures of brain asymmetry and gyral duplication, while subjects whose phonological ability was consistent with their comprehension level did not. The three subjects with RD whose comprehension and phonology were unexpectedly low for college students had low cerebral volume and symmetrical brain structures. It may be overly concrete to suggest that a restriction in processing sites associated with low cerebral volume restricts the number of associations that can be made and the amount of knowledge that can be accumulated. It should be noted, however, that reduction of the number of nodes in a computational model is associated with semantic (comprehension) not phonological deficits (Manis et al., 1996).
The data for the subtests in the Short-Term Memory Cluster were particularly informative about the relation between anatomy and the ability to use contextual cues to support phonological associations. As the cues provided by context increase through the three subtests (Numbers Reversed < Memory for Words < Memory for Sentences), the influence of cerebral volume increases, performance becomes less discrepant with measured intelligence, and the influence of the PD risk factors becomes insignificant. If further work supports this proposal that different anatomical variables predict the ability to use contextual cues (comprehension) and memory for arbitrary phonological symbol associations (coding), it would provide a neurobiological explanation for the ability of some RD subjects to comprehend without being able to decode.
These anatomical findings add neurological support to the emerging consensus that two independent factors contribute to reading ability: phonology and general intelligence or oral language ability (Manis et al., 1996; Lombardino et al., 1997
; Catts et al., 1999
; Stringer and Stanovich, 2000
). Children with SLI resemble the URD subjects in the present study, in that their oral language deficits are associated with perisylvian symmetry and low cerebral volume (Jernigan et al., 1990
; Gauger et al., 1997
; Preis et al., 1998
). Symmetry and marked asymmetry may be complementary signs of disordered interhemispheric regulation during neural development. Disorders of interhemispheric regulation that result in symmetry are apparently associated with different cognitive consequences than disorders that result in marked asymmetries. It is even possible that marked asymmetries mitigate some of the negative consequences of low cerebral volume. For the subjects in the bottom quartile of cerebral volume, the mean Passage Comprehension score for subjects with risk factors was 16 points higher than that for subjects with no risk factors.
Reading and Language Disorders
The present results do not support a common etiology for all reading and language disorders. These results, together with previous studies in SLI (Bishop and Adams, 1990; Jernigan et al., 1990
; Plante et al., 1991
; Gauger et al., 1997
), suggest that the neuroanatomical correlates and prognoses of phonological and comprehension deficits are qualitatively, not just quantitatively different. The cognitive abilities that make up the Oral Language and Fluid Reasoning clusters are predicted by cerebral volume (Table 6
). Cerebral volume does not predict the Short-Term Memory and Long-Term Retrieval deficits that characterize the group of PD subjects.
Only Sound Patterns performance showed a dependence on both cerebral volume (0.41, P < 0.01) and the anatomical risk factors (0.34, P < 0.08). This dual relationship may explain why auditory temporal processing is disturbed in both PD and SLI. Mody et al. have argued that the temporal order of judgment tasks (of which the Sound Patterns Subtest is an example) is not a pure test of auditory processing because of the demands on working memory (Mody et al., 1997). Perhaps the working memory component makes the task difficult for phonologically impaired subjects while the auditory component makes the task difficult for subjects with oral language problems. Superficially similar deficits could arise through different mechanisms.
Anatomical Specificity
Heschl's Gyrus
A previous structural imaging study of dyslexia reported an elevated incidence of gyral duplications and missing gyri in both dyslexics and their family members. A second Heschl's gyrus was found in either the left or the right hemispheres of 4/9 members of the dyslexic group (Leonard et al., 1993). Elevated frequencies of H2 were also found in a study of families with a genetic mutation of the thyroid receptor associated with attention deficit disorder (Hauser et al., 1993
) but the presence of H2 was not associated with the behavioral diagnosis of ADHD. Although the mutation is also associated with language problems, reading and phonological decoding scores were, unfortunately, not available.
A measure of sensory processing efficiency (visual inspection time) is slower in both college students and children with H2 in the left hemisphere (Grudnik et al., 2000). In the visual inspection test, two lines of different length are exposed briefly and the subject must press a button below the longer line (Nettelbeck, 1982
, 1987
). Reaction time and movement time are not included in the measure. Future work could investigate whether a long inspection time impedes response automatization and increases the error rate in arbitrary phonological associations, such as those between graphemes and phonemes. Since the presence of an H2 runs in families (Leonard et al., 1995
; Eckert and Leonard, 1999
), investigation of its heritability has the potential to provide an informative phenotypic marker for genetic studies of dyslexia.
Marked Asymmetries
Several structural asymmetries were examined in this study, each justified by a different line of previous research. In a previous study of epilepsy, marked asymmetry was associated with cortical dysplasia but not hippocampal sclerosis Sisodyaet al., 1995). The fact that marked cerebral asymmetries were found in some PD subjects in the present study does not necessarily imply that they have cortical dysplasia. Marked asymmetries may represent one extreme of a developmental continuum. Such asymmetry could even result from compensatory neuroplasticity and signify that the developmental relationship between the two hemispheres is under flexible control.
Although most theoretical work in dyslexia has focused on auditory cortex in the left hemisphere, one group (Nicolson and Fawcett, 1990) has argued for a critical role of timing mechanisms in the cerebellum. The anterior lobe is associated with spinal and brainstem pathways controlling eye movements, balance and postural control (Bastian et al., 1999
), while the posterior lobe, by contrast, acts as a modulator of voluntary cortical activity. The RD subjects differed from the controls in mean asymmetry of both the posterior and anterior lobes. Asymmetry of the posterior lobe was the only measure that distinguished reading disability on which the distributions of URD and PD overlapped. The group difference did not survive correction for multiple comparisons and needs verification in a prospective study. By contrast, asymmetry of the anterior lobe made a significant contribution to the discriminant function that differentiated PD from the remainder of the sample. The three PD subjects with the most extreme leftward asymmetries were ambidextrous males whose scores on short-term phonological memory were in the bottom quartile. Future work should investigate whether there is an interaction between ambidextrality, phonological automatization and marked anterior lobe asymmetry that is modulated by sex. Functional imaging studies that visualize anterior lobe activity during speeded testing in RD subjects might prove enlightening.
Sylvian Fissure Asymmetry
It is remarkable that the PD subjects had marked leftward asymmetry of the horizontal and vertical banks of the sylvian fissure. How can this finding be reconciled with reports of leftward planar asymmetry predicting verbal and reading skill (Leonard et al., 1996; Rumsey et al., 1997
)? Data from studies in our laboratory suggest a possible answer (Maron et al., 2000
; Eckert et al., 2001
). Perhaps planar asymmetry is more closely associated with comprehension than pure phonological ability. Such a relationship would explain why reversed planar asymmetry is more frequently reported in studies of children with SLI than dyslexia (Eckert and Leonard, 2000
). It is somewhat paradoxical that planar asymmetry is related to comprehension, as fMRI studies report equivalent activation in the planum during linguistic and nonlinguistic tasks (Binder et al., 1996
). It is possible that good comprehension is associated with information processing abilities directed by the right parietal lobe and that a short right sylvian fissure allows increased right parietal dominance. Future fMRI studies could investigate possible information processing differences in individuals with large and small parietal asymmetries.
The summed asymmetry of the planum and PAR is a novel measure of hemispheric relationships and its usefulness needs prospective confirmation. We created this index after Jäncke et al.'s report of parallel leftward asymmetry of these structures in an individual with callosal agenesis who had normal intelligence and language ability (Jäncke et al., 1997). None of the 200 normal individuals in the Düsseldorf database had substantial leftward asymmetry of these structures. Remarkably, five PD subjects in the present study had such parallel asymmetries. The fact that the acallosal patient had normal language function suggests the possibility that marked asymmetry might be associated with the ability to develop compensatory strategies.
Strengths and Limitations of the Study
The most serious limitation is the post hoc nature of this analysis. The subjects were separated into PD and URD groups after extreme anatomical measures were found to cluster in subjects with poor pseudo-word decoding (Word Attack). We gained confidence in the analysis upon finding that the anatomical measures that characterized the PD group also predicted deficits in short- and long-term phonological memory, skills that could reasonably be expected to facilitate the routine automatic encoding and retrieval of graphemephoneme associations. The emergence of a consistent story somewhat allayed concern over the post hoc initial step of the data analysis. The strength of the results, as well as the pracical implications for treatment and remediation, if the findings are confirmed, encouraged us to seek publication, so that other groups could examine their data for similar relationships.
The second limitation is that the study is of college students, an unrepresentative sample of the reading disabled, and it is questionable how the results will generalize to the school age population. Our own sample of 104 normal children provides limited support for the findings presented here: (i) the incidence of all the risk factors was low, with the exception of cerebellar asymmetry; (ii) there were very few cases of risk factor combinations and (iii) cerebral volume predicted text comprehension (C.M. Leonard, unpublished data).
Strengths of the study include the extensive battery of well-normed, theoretically motivated tests, the high-resolution volumetric scan and the well-matched groups. Future studies will demonstrate whether the separate anatomical risk factors identified here will prove useful for diagnosis and the design of remediation.
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Notes |
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Address correspondence to Christiana M. Leonard, PO Box 100244, Department of Neuroscience, University of Florida Brain Institute, Gainesville, FL 32611, USA. Email: leonard{at}ufbi.ufl.edu.
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