Contrasting brain patterns of writing-related DTI parameters, fMRI connectivity, and DTI-fMRI connectivity correlations in children with and without dysgraphia or dyslexia.

Based on comprehensive testing and educational history, children in grades 4-9 (on average 12 years) were diagnosed with dysgraphia (persisting handwriting impairment) or dyslexia (persisting word spelling/reading impairment) or as typical writers and readers (controls). The dysgraphia group (n = 14) and dyslexia group (n = 17) were each compared to the control group (n = 9) and to each other in separate analyses. Four brain region seed points (left occipital temporal gyrus, supramarginal gyrus, precuneus, and inferior frontal gyrus) were used in these analyses which were shown in a metaanalysis to be related to written word production on four indicators of white matter integrity and fMRI functional connectivity for four tasks (self-guided mind wandering during resting state, writing letter that follows a visually displayed letter in alphabet, writing missing letter to create a correctly spelled real word, and planning for composing after scanning on topic specified by researcher). For those DTI indicators on which the dysgraphic group or dyslexic group differed from the control group (fractional anisotropy, relative anisotropy, axial diffusivity but not radial diffusivity), correlations were computed between the DTI parameter and fMRI functional connectivity for the two writing tasks (alphabet and spelling) by seed points. Analyses, controlled for multiple comparisons, showed that (a) the control group exhibited more white matter integrity than either the dysgraphic or dyslexic group; (b) the dysgraphic and dyslexic groups showed more functional connectivity than the control group but differed in patterns of functional connectivity for task and seed point; and (c) the dysgraphic and dyslexic groups showed different patterns of significant DTI-fMRI connectivity correlations for specific seed points and written language tasks. Thus, dysgraphia and dyslexia differ in white matter integrity, fMRI functional connectivity, and white matter-gray matter correlations. Of clinical relevance, brain differences were observed in dysgraphia and dyslexia on written language tasks yoked to their defining behavioral impairments in handwriting and/or in word spelling and on the cognitive mind wandering rest condition and composition planning.

Tract-based spatial statistics of diffusion tensor imaging in adults with dyslexia.

BACKGROUND AND PURPOSE: Diffusion tensor imaging is a tool that can be used to study white matter microstructure in dyslexia. We tested the hypothesis that dyslexics have a white matter structural change (as measured by directional diffusion of water, which can be affected by disruption in white matter tracts) between brain regions that previous functional connectivity studies showed were associated with phonologic processing. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) scans were acquired from 7 healthy adult normal readers and from 14 adults with dyslexia on a 1.5T scanner. Voxelwise statistical analysis of the fractional anisotropy data were carried out by using Tract-Based Spatial Statistics to compare dyslexic subjects versus control subjects in white matter tracts. RESULTS: Significant group difference map clusters (comparing adults with and without dyslexia) occurred in specific bilateral white matter tracts within the frontal lobe, temporal lobe, occipital lobe, and parietal lobe. CONCLUSION: The DTI fractional anisotropy results in the bilateral white matter showing higher fractional anisotropy in adult control subjects compared with adults with dyslexia (relating to white matter fiber tract integrity) are consistent with our previous functional connectivity results from seed points in the bilateral inferior frontal gyrus.

A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency.

Dyslexia is a common and complex developmental disorder manifested by unexpected difficulty in learning to read. Multiple different measures are used for diagnosis, and may reflect different biological pathways related to the disorder. Impaired phonological decoding (translation of written words without meaning cues into spoken words) is thought to be a core deficit. We present a genome scan of two continuous measures of phonological decoding ability: phonemic decoding efficiency (PDE) and word attack (WA). PDE measures both accuracy and speed of phonological decoding, whereas WA measures accuracy alone. Multipoint variance component linkage analyses (VC) and Markov chain Monte-Carlo (MCMC) multipoint joint linkage and segregation analyses were performed on 108 families. A strong signal was observed on chromosome 2 for PDE using both VC (LOD=2.65) and MCMC methods (intensity ratio (IR)=32.1). The IR is an estimate of the ratio of the posterior to prior probability of linkage in MCMC analysis. The chromosome 2 signal was not seen for WA. More detailed mapping with additional markers provided statistically significant evidence for linkage of PDE to chromosome 2, with VC-LOD=3.0 and IR=59.6 at D2S1399. Parametric analyses of PDE, using a model obtained by complex segregation analysis, provided a multipoint maximum LOD=2.89. The consistency of results from three analytic approaches provides strong evidence for a locus on chromosome 2 that influences speed but not accuracy of phonological decoding.

Instructional treatment associated with changes in brain activation in children with dyslexia.

OBJECTIVE: To assess the effects of reading instruction on fMRI brain activation in children with dyslexia. BACKGROUND: fMRI differences between dyslexic and control subjects have most often involved phonologic processing tasks. However, a growing body of research documents the role of morphologic awareness in reading and reading disability. METHODS: The authors developed tasks to probe brain activation during phoneme mapping (assigning sounds to letters) and morpheme mapping (understanding the relationship of suffixed words to their roots). Ten children with dyslexia and 11 normal readers performed these tasks during fMRI scanning. Children with dyslexia then completed 28 hours of comprehensive reading instruction. Scans were repeated on both dyslexic and control subjects using the same tasks. RESULTS: Before treatment, children with dyslexia showed less activation than controls in left middle and inferior frontal gyri, right superior frontal gyrus, left middle and inferior temporal gyri, and bilateral superior parietal regions for phoneme mapping. Activation was significantly reduced for children with dyslexia on the initial morpheme mapping scan in left middle frontal gyrus, right superior parietal, and fusiform/occipital region. Treatment was associated with improved reading scores and increased brain activation during both tasks, such that quantity and pattern of activation for children with dyslexia after treatment closely resembled that of controls. The elimination of group differences at follow-up was due to both increased activation for the children with dyslexia and decreased activation for controls, presumably reflecting practice effects. CONCLUSION: These results suggest that behavioral gains from comprehensive reading instruction are associated with changes in brain function during performance of language tasks. Furthermore, these brain changes are specific to different language processes and closely resemble patterns of neural processing characteristic of normal readers.

fMRI auditory language differences between dyslexic and able reading children.

During fMRI, dyslexic and control boys completed auditory language tasks (judging whether pairs of real and/or pseudo words rhymed or were real words) in 30 s 'on' conditions alternating with a 30 s 'off' condition (judging whether tone pairs were same). During phonological judgment, dyslexics had more activity than controls in right than left inferior temporal gyrus and in left precentral gyrus. During lexical judgment, dyslexics were less active than controls in bilateral middle frontal gyrus and more active than controls in left orbital frontal cortex. Individual dyslexics were reliably less active than controls in left insula and left inferior temporal gyrus. Dyslexic and control children differ in brain activation during auditory language processing skills that do not require reading.

Comparison of fMRI and PEPSI during language processing in children.

The present study explored the correlation between lactate as detected by MR spectroscopy (MRS) and blood oxygenation level dependent (BOLD) responses in male children during auditory-based language tasks. All subjects (N = 8) participated in one proton echo planar spectroscopic imaging (PEPSI) and one functional magnetic resonance imaging (fMRI) session that required phonological and lexical judgments to aurally presented stimuli. Valid PEPSI data was limited in the frontal areas of the brain due to the magnetic susceptibility of the eye orbits and frontal sinuses. Findings from the remainder of the brain indicate that subjects show a significant consistency across imaging techniques in the left temporal area during the lexical task, but not in any other measurable area or during the phonological task. Magn Reson Med 45:217-225, 2001.

A connectionist approach to making the predictability of English orthography explicit to at-risk beginning readers: evidence for alternative, effective strategies.

A case is made (and illustrated with empirical data with children) for connectionist models that are not only computationally explicit but also instructionally explicit. First-graders (N = 128) at the bottom of their classes in reading (average 11.5 percentile on nationally normed tests) participated in a 3-layer intervention. In the first layer, kept constant for all treatment groups, the alphabet principle was taught, making functional spelling units and alternations explicit. In the second layer, which varied systematically across treatment groups, children received different kinds of tutor modeling in learning a set of words of varying spelling-sound predictability, using different connections between printed and spoken words, singly or in combination. In the third layer, also kept constant, children read and discussed illustrated books. Over the 4-month, 24-lesson intervention, all 7 treatment groups in the second layer improved more in word-specific learning than a contact control group that received phonological and orthographic awareness training without explicit instruction on orthographic-phonological connections. Of these 7, only 3 kinds of explicit modeling (whole word, letter-phoneme, and combined whole word and letter-phoneme) resulted in greater transfer to untrained words than the contact control or the other 4 kinds of explicit modeling. Results are discussed in reference to the controversy over whether dual route or connectionist models best account for the acquisition of reading.

Segregation analysis of phenotypic components of learning disabilities. I. Nonword memory and digit span.

Dyslexia is a common and complex disorder with evidence for a genetic component. Multiple loci (i.e., quantitative-trait loci [QTLs]) are likely to be involved, but the number is unknown. Diagnosis is complicated by the lack of a standard protocol, and many diagnostic measures have been proposed as understanding of the component processes has evolved. One or more genes may, in turn, influence these measures. To date, little work has been done to evaluate the mode of inheritance of individual component-as opposed to composite-phenotypes, beyond family or twin correlation studies that initially demonstrate evidence for a genetic basis of such components. Here we use two approaches to segregation analysis in 102 nuclear families to estimate genetic models for component phenotypes associated with dyslexia: digit span and a nonword-repetition task. Both measures are related to phonological skills, one of the key component processes in dyslexia. We use oligogenic-trait segregation analysis to estimate the number of QTLs contributing to each phenotype, and we use complex segregation analysis to identify the most parsimonious inheritance models. We provide evidence in support of both a major-gene mode of inheritance for the nonword-repetition task, with approximately 2.4 contributing QTLs, and for a genetic basis of digit span, with approximately 1.9 contributing QTLs. Results obtained by reciprocal adjustment of measures suggest that genes contributing to digit span may contribute to the nonword-repetition score but that there are additional QTLs involved in nonword repetition. Our study adds to existing studies of the genetic basis of composite phenotypes related to dyslexia, by providing evidence for major-gene modes of inheritance of these single-measure component phenotypes.

Effects of a phonologically driven treatment for dyslexia on lactate levels measured by proton MR spectroscopic imaging.

BACKGROUND AND PURPOSE: Dyslexia is a language disorder in which reading ability is compromised because of poor phonologic skills. The purpose of this study was to measure the effect of a phonologically driven treatment for dyslexia on brain lactate response to language stimulation as measured by proton MR spectroscopic imaging. METHODS: Brain lactate metabolism was measured at two different time points (1 year apart) during four different cognitive tasks (three language tasks and one nonlanguage task) in dyslexic participants (n = 8) and in control participants (n = 7) by using a fast MR spectroscopic imaging technique called proton echo-planar spectroscopic imaging (1 cm3 voxel resolution). The age range for both dyslexic and control participants was 10 to 13 years. Between the first and second imaging sessions, the dyslexic boys participated in an instructional intervention, which was a reading/science workshop. RESULTS: Before treatment, the dyslexic boys showed significantly greater lactate elevation compared with a control group in the left anterior quadrant (analysis of variance, P = .05) of the brain during a phonologic task. After treatment, however, brain lactate elevation was not significantly different from that of the control group in the left anterior quadrant during the same phonologic task. Behaviorally, the dyslexic participants improved in the phonologic aspects of reading. CONCLUSION: Instructional intervention that improved phonologic performance in dyslexic boys was associated with changes in brain lactate levels as measured by proton echo-planar spectroscopic imaging.

Familial aggregation of dyslexia phenotypes.

There is evidence for genetic contributions to reading disability, but the phenotypic heterogeneity associated with the clinical diagnosis may make identification of the underlying genetic basis difficult. In order to elucidate distinct phenotypic features that may be contributing to the genotypic heterogeneity, we assessed the familial aggregation patterns of Verbal IQ and 24 phenotypic measures associated with dyslexia in 102 nuclear families ascertained through probands in grades 1 through 6 who met the criteria for this disorder. Correlations between relatives were computed for all diagnostic phenotypes, using a generalized estimating equation (GEE) approach. GEE is a recently developed semiparametric method for handling correlated data. The method is robust to model misspecification and flexible in adjusting for the subjects' characteristics and pedigree sizes as well as for the ascertainment process, while estimating the correlations between related subjects. The Nonword Memory (NWM) subtest of a prepublication version of the Comprehensive Test of Phonological Processing (CTOPP) and Phonemic Decoding Efficiency (PDE) subtest of a prepublication version of the Test of Word Reading Efficiency (TOWRE) showed correlation patterns in relatives that are strongly supportive of a genetic basis. The Wechsler Scale Digit Span, the Word Attack subtest of the Woodcock Reading Mastery Test--Revised, and the Spelling subtest of the Wide Range Achievement Test--Third Edition had slightly weaker evidence of a genetic basis. Five additional phenotypes (the Spelling subtest of the Wechsler Individual Achievement Test, the Accuracy, Rate, and Comprehension subtests of the Gray Oral Reading Test--Third Edition, and Rapid Automatized Naming of Letters and Numbers) gave suggestive evidence of such a pattern. The results cross-validate in that evidence for a pattern consistent with a genetic basis was obtained for two measures of phonological short-term memory (CTOPP Nonword Memory and WISCIII or WAIS-R Digit Span), for two measures of phonological decoding (WRMT-R Word Attack and TOWRE Phonemic Decoding Efficiency), and for two measures of spelling from dictation (WRAT-3 Spelling and, to a lesser extent, WIAT Spelling). These measures are thus good candidates for more sophisticated segregation analyses that can formulate models for incorporation into linkage analyses.

Dyslexic children have abnormal brain lactate response to reading-related language tasks.

BACKGROUND AND PURPOSE: Children with dyslexia have difficulty learning to recognize written words owing to subtle deficits in oral language related to processing sounds and accessing words automatically. The purpose of this study was to compare regional changes in brain lactate between dyslexic children and control subjects during oral language activation. METHODS: Brain lactate metabolism was measured during four different cognitive tasks (three language tasks and one nonlanguage task) in six dyslexic boys and in seven control subjects (age- and IQ-matched right-handed boys who are good readers) using a fast MR spectroscopic imaging technique called proton echo-planar spectroscopic imaging (1-cm3 voxel resolution). The area under the N-acetylaspartate (NAA) and lactate peaks was measured to calculate the lactate/NAA ratio in each voxel. RESULTS: Dyslexic boys showed a greater area of brain lactate elevation (2.33+/-SE 0.843 voxels) as compared with the control group (0.57+/-SE 0.30 voxels) during a phonological task in the left anterior quadrant. No significant differences were observed in the nonlanguage tasks. CONCLUSION: Dyslexic and control children differ in brain lactate metabolism when performing language tasks, but do not differ in nonlanguage auditory tasks.

Early intervention for reading disabilities: teaching the alphabet principle in a connectionist framework.

Forty-eight children referred by teachers at the end of first grade for difficulty in reading were randomly assigned to three treatments, all of which modeled connections between written and spoken words but did not teach phonics rules, for eight half-hour individual tutoring sessions. The children were taught 48 words of varying orders of spelling-sound predictability (Venezky, 1995) using a whole-word method, for making connections between a word's name and its constituent letters; a subword method, for making connections between each color-coded spelling unit and its corresponding phonemes; or a combined whole-word and subword method. Regardless of the method used, children improved reliably on standardized reading measures and the taught words, showing that they could make connections between written and spoken words at the whole word and subword levels, even when rules were not taught. By posttest, the subword method showed a reliable advantage on a standardized test of real word reading. Knowledge of sounds associated with both multiletter and single-letter spelling units predicted reading achievement. Order of spelling-sound predictability (easy, moderate, difficult) was correlated with standardized measures of reading at pretest and posttest, and the magnitude of the relationship increased as a result of the intervention. Individual differences in verbal intelligence, rapid automatized naming, and phonological and orthographic skills predicted response to the intervention. Instructional implications of the results are discussed.

Individual differences in children's working memory and writing skill.

The purpose of this research is to address (a) whether individual differences in working memory (WM) and writing are related to a general or process-specific system, (b) whether WM tasks operate independently of phonological short-term memory (STM) on measures of writing and reading, and (c) whether working memory predicts variance in writing beyond that predicted by reading alone. The present study correlated several WM and phonological STM measures with writing and reading measures. The study showed among the memory measures that a four-factor model reflecting phonological STM, verbal WM span, executive processing, and visual-spatial WM span best fit the multivariate data set. Working memory was correlated significantly with a number of writing measures, particularly those related to text generation. WM measures contributed unique variance to writing that was independent of reading skill, and STM measures best predicted transcription processes and reading recognition, whereas WM measures best predicted text generation and reading comprehension. Both verbal and visual-spatial working memory measures predicted reading comprehension, whereas only WM measures that reflect executive processing significantly predicted writing. In general, the results suggest that individual differences in children's writing reflect a specific capacity system, whereas reading comprehension draws upon a multiple capacity system.

Relationship of finger function to beginning writing: application to diagnosis of writing disabilities.

Finger function tasks designed to elicit soft neurological signs or to measure sensory-motor integration were administered to 100 first-, 100 second- and 100 third-grade children as part of a multivariate study of normal writing acquisition in an unreferred sample. The finger-succession task--a measure of motor planning and programming of complex, sequential movements--had the best reliability and validity for assessing handwriting and composition. However, of the developmental measures, the alphabet task--requiring the child to retrieve and produce alphabet letters in sequence, thereby integrating orthographic symbols and motor output--had the best concurrent validity for assessing handwriting, spelling and composition. The authors recommend that clinicians use the finger-succession and alphabet tasks for early identification of 'at-risk' children in order to prevent severe writing disabilities later in development.

Interventions based on the multiple connections model of reading for developmental dyslexia and acquired deep dyslexia.

This paper deals with intervention strategies for developmental and acquired dyslexia. In Study 1 two alternative strategies for developmental surface dyslexia (dysfunctional connection between the whole word orthographic code and the phonetic or name code) were compared. In both the initial study and replication study, a modification of the selective reminding technique was superior to a traditional multisensory technique in beginning readers, presumably because it facilitated word finding or prelexical access to a phonetic code. In Study 2 an adolescent with acquired deep dyslexia (dysfunctional connection between letter and phonemic codes) who had had his angular gyrus (site of grapheme-phoneme correspondence) surgically removed, recovered reading function after a four-month phonemic analysis training program. Further research is needed to evaluate the efficacy of theory-based intervention strategies in children with developmental reading disorders unrelated to focal lesions and in adults with acquired reading disorders related to focal lesions.

Orchestration of multiple codes in developing readers: an alternative model of lexical access.

An alternative model of lexical access, based on recent PET scan studies showing localized coding operations in multiple brain sites, is proposed. Lexical access is viewed as a process of orchestrating multiple connections between corresponding visible language and oral language coding operations instead of a place--the internal lexicon--to which stimulus words gain access directly or indirectly. In both Study 1 (end of 1st grade) and Study 2 (mid 2nd and mid 4th grade) speed of naming phonically regular words, in which every letter can be phonemically coded, and of naming phonically irregular words, in which every letter cannot be phonemically coded, was not significantly different, indicating that naming can be based on a phonetic code connection rather than phonemic code connections. In both Study 1 and Study 2 speed of correctly accepting phonically regular real words was significantly faster than speed of correctly rejecting nonsense words on lexical decision, showing that absence of a semantic code is not detected as quickly as presence of a semantic code is. In both Study 1 and Study 2 speed of naming a phonically regular real word was significantly faster than speed of naming a nonsense word, demonstrating that naming is facilitated when two connections--between a printed word and its phonetic code and between a printed word and its semantic code--are activated. These findings held whether a key press (Study 1) or voice key (Study 2) response was used. Taken together, the results suggest that the whole word-phonetic code connection may be completed before the whole word-semantic code connection, both of which may precede the letter-phoneme connection in time.

A test of the multiple connections model of reading acquisition.

Within the framework of Society of Mind Theory (Minsky, 1986), learning to read is conceptualized as a process of creating new communication links or neural connections between an existing visual society and an existing linguistic society. Four visual-linguistic connections may become functional: letter-phonemic code, whole word-semantic code, whole word-name code, letter sequence-aural syllabic code. The hypothesis was tested that more than one of these visual-linguistic connections must be taken into account in predicting reading achievement. Results showed that the combination of the composite letter-phoneme variable and the composite whole word-semantic code variable accounted for significantly more variance in oral reading than did either single variable at the end of the first grade. Groups with large absolute discrepancy (1 or more standard scores) or small absolute discrepancy (1/3 standard score or less) on corresponding visual and linguistic skills differed significantly in both oral (whole word-semantic code composite) and silent reading (whole word-semantic code and letter sequence-aural syllabic code composites). There was a relationship between the number of large discrepancies and reading achievement. Results are discussed in reference to neuropsychological models of connectionism (Rumelhart & McClelland, 1986) and working brain systems (Luria, 1973).

Acquisition of linguistic procedures for printed words: neuropsychological implications for learning.

A microcomputerized experiment, administered to 45 children in the 2nd, 5th, and 8th month of first grade, manipulated three variables: (a) stimulus unit (whole word or letter-by-letter presentation), (b) nature of stimulus information (phonically regular words, phonically irregular words, nonsense words, and letter strings, which differ in whether phonemic, orthographic, semantic, and/or name codes are available), and (c) linguistic task (lexical decision, naming, and written reproduction). Letter-by-letter presentation resulted in more accurate lexical decision and naming but not more accurate written reproduction. Interactions between nature of stimulus information and linguistic task occurred. Throughout the year, accuracy was greater for lexical decision than for naming or written reproduction. The superiority of lexical decision cannot be attributed to the higher probability of correct responses on a binary choice task because only consistently correct responses on repeated trials were analyzed. The earlier development of lexical decision, a receptive task, than of naming or written reproduction, production tasks, suggests that hidden units (Hinton & Sejnowski, 1986) in tertiary cortical areas may abstract visual-linguistic associations in printed words before production units in primary cortical areas can produce printed words orally or graphically.

Modified WAIS-R for patients with speech and/or hand dysfunction.

A feasibility study showed that the research edition of the modified WAIS-R for patients with speech and/or hand dysfunction has promise. Four Verbal Scale subtests and three Performance subtests of the modified WAIS-R were correlated with the standard version. The Verbal IQs of an experimental group (n = 16 severely physically handicapped) and Performance IQs of a control group (n = 32 able-bodied adults) on the two versions were not significantly different. In a comparison study of nonretarded patients with severe cerebral palsy (n = 14) or with spinal cord injury (n = 14), the spinal cord group's mean Verbal IQs and Performance IQs on the modified WAIS-R were significantly higher than those of the severe cerebral palsy group, but the difference was relatively larger for Performance IQs than Verbal IQs. Acquisition of motor dysfunction early in development (severe cerebral palsy) compared to later in development (spinal cord injury) may constrain nonverbal intelligence more than verbal intelligence.