Attention to single letters activates left extrastriate cortex.

Brain imaging studies examining the component processes of reading using words, non-words, and letter strings frequently report task-related activity in the left extrastriate cortex. Processing of these linguistic materials involves varying degrees of semantic, phonological, and orthographic analysis that are sensitive to individual differences in reading skill and history. In contrast, single letter processing becomes automatized early in life and is not modulated by later linguistic experience to the same degree as are words. In this study, skilled readers attended to different aspects (single letters, symbols, and colors) of an identical stimulus set during separate sessions of functional magnetic resonance imaging (fMRI). Whereas activation in some portions of ventral extrastriate cortex was shared by attention to both alphabetic and non-alphabetic features, a letter-specific area was identified in a portion of left extrastriate cortex (Brodmann's Area 37), lateral to the visual word form area. Our results demonstrate that while minimizing activity related to word-level lexical properties, cortical responses to letter recognition can be isolated from figural and color characteristics of simple stimuli. The practical utility of this finding is discussed in terms of early identification of reading disability.

Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p.

Eight extended dyslexic families with at least four affected individuals were genotyped with twelve genetic markers spanning the Rh (rhesus factor) locus. Eleven of these markers were located on the short arm and the other was on the long arm of chromosome 1. Five theoretically derived phenotypes were used in the linkage analyses: 1) phonemic awareness; 2) phonological decoding; 3) rapid automatized naming; 4) single word reading; and 5) vocabulary. In addition, a lifetime diagnosis of dyslexia was used as a phenotype. Both parametric and non-parametric genetic analyses were completed. The results supported the importance of a putative locus on 1p. In addition, two-locus analyses assuming the interaction between a 1p locus and a 6p locus, previously shown to be of interest for dyslexia, were conducted. As a result, the nonparametric linkage (NPL) scores for rapid automatized naming and phonological decoding were significantly increased. In particular, the NPL scores for rapid automatized naming exceeded 5.0 for certain markers. These results provide strong evidence for separate but jointly acting contributions of the 1p and 6p loci to the reading impairments associated with rapid naming and suggestive evidence for a similar mechanism involving phonological decoding.

Human GABA(B) receptor 1 gene: eight novel sequence variants.

GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain. The human GABA(B) receptor (GABBR1) maps to the human leukocyte antigen (HLA) region of chromosome 6. Its function and location in a susceptibility region for schizophrenia, epilepsy, and dyslexia make GABBR1 a candidate gene for neurobehavioral disorders. We report the characterization of GABBR1 gene mutations in 100 chromosomes from a mixed American population. Eleven distinct mutations were found, including two previously reported missense mutations (A20V and G489S) and a previously reported silent 1977 T>C transition. Here, we report four novel silent substitutions (39C>T, 1473T>C, 1476T>C, 1545T>C) and four novel intron variants. These DNA variants may be useful in association and linkage studies of neurobehavioral disorders, and in pharmacogenetic studies of drugs targeting GABBR1.

Emerging issues in the genetics of dyslexia: a methodological preview.

A review of the classic and recent evidence on the genetics of reading disability (RD) shows encouraging progress, and accumulating evidence of genetic risk factors that operate within families and are separately localizable to more than one chromosomal region. The accelerating pace of these findings, however, suggests the need to consider some methodological issues about the design and interpretation of current and future studies. A major issue is the shape of the distribution of reading ability in the population, and we offer three tests of increasing rigor for determining whether those distributions are categorical, and hence not suitable for analyses that depend on the assumption of a continuous normal distribution. These tests are as follows: a nonnormal preponderance of cases with RD (i.e., the hump in the lower end of the distribution); a difference in the within-group variance-covariance matrices for typical readers compared to those with RD; and a correlation between a neurogenetically relevant criterion and a categorical reading variable that is larger than the correlation between the same criterion and a continuous version of the same reading variable. We emphasize also the importance of interactive relationships between multiple genetic loci, the variations in genotypic range as well as type of affectedness, the need to account for remediation variance, and the importance of lifespan changes in the phenotypes.

Public library consumer health information pilot project: results of a National Library of Medicine evaluation.

In October 1998, the National Library of Medicine (NLM) launched a pilot project to learn about the role of public libraries in providing health information to the public and to generate information that would assist NLM and the National Network of Libraries of Medicine (NN/LM) in learning how best to work with public libraries in the future. Three regional medical libraries (RMLs), eight resource libraries, and forty-one public libraries or library systems from nine states and the District of Columbia were selected for participation. The pilot project included an evaluation component that was carried out in parallel with project implementation. The evaluation ran through September 1999. The results of the evaluation indicated that participating public librarians were enthusiastic about the training and information materials provided as part of the project and that many public libraries used the materials and conducted their own outreach to local communities and groups. Most libraries applied the modest funds to purchase additional Internet-accessible computers and/or upgrade their health-reference materials. However, few of the participating public libraries had health information centers (although health information was perceived as a top-ten or top-five topic of interest to patrons). Also, the project generated only minimal usage of NLM's consumer health database, known as MEDLINEplus, from the premises of the monitored libraries (patron usage from home or office locations was not tracked). The evaluation results suggested a balanced follow-up by NLM and the NN/LM, with a few carefully selected national activities, complemented by a package of targeted activities that, as of January 2000, are being planned, developed, or implemented. The results also highlighted the importance of building an evaluation component into projects like this one from the outset, to assure that objectives were met and that evaluative information was available on a timely basis, as was the case here.

Hypersexuality and hemiballism due to subthalamic infarction.

OBJECTIVE: A 70-year-old right-handed man presented with a subthalamic infarction followed by persistent hypersexuality and hemiballism. A lacunar infarction 1 cm in diameter was observed on magnetic resonance imaging. We hypothesized that metabolic abnormalities would be detected in cortical areas related to his neurobehavioral symptoms. BACKGROUND: Statistical validation of the regional metabolic changes that may relate to neuropsychiatric symptoms has been elusive. Relating metabolic changes to neuropsychiatric symptoms is especially important in unique neurobehavioral cases. METHOD: Quantitative fluorodeoxyglucose positron emission tomography was obtained for a single-subject comparison with scans from 60 healthy subjects. RESULTS: Substantial glucose hypometabolism (p <0.001, uncorrected; [df = 56]) was identified in the subthalamic nucleus at the site of the lacunar infarction. Hypermetabolism (p <0.01) was identified within the basal forebrain and temporal lobes, anterior cingulate and medial prefrontal cortices (areas previously associated with hypersexuality), and striatum (p <0.001) ipsilateral to the stroke (areas known to relate to hemiballism). CONCLUSIONS: Single-subject statistical parametric mapping may improve our understanding of unique neurobehavioral cases.

Event-related potentials correlate with task-dependent glucose metabolism.

Cognitive processing is associated with brain electrical activity that is reflected in event-related potentials (ERP). ERP during a target detection task, and regional cerebral glucose metabolism (CMRglc) measured simultaneously, may be influenced by the same neurophysiologic processes. We tested the hypothesis that ERP factors could be directly correlated with CMRglc to derive functional brain maps of brain activity at 120, 160, 200, 280, and 400 ms following stimulus presentation in a target detection task. We controlled for the potential confounding effects of age, sex, and task accuracy, and correlate target-related and nontarget-related ERP separately. Increases and decreases in CMRglc at each time point were identified with statistical parametric mapping (P < 0.001, uncorrected). The 120- and 160-ms maps were the same for target and nontarget processing, while maps for 280 and 400 ms clearly distinguished between targets and nontargets. Extrinsic (early) cognitive processes that depend mainly on stimulus characteristics show less variation based on stimulus meaning (i.e., letter vs shape; target vs nontarget) than later (intrinsic) cognitive processes. These early effects are lateralized to the left hemisphere, for negative ERP factors, and positive ERP-PET correlations are more likely than negative ERP-PET correlations. Thus, brain areas related to task processing impact both ERP and CMRglc measures, suggesting a shared neurophysiologic mechanism for negative ERP factors and increased CMRglc. Direct statistical analysis of these two measures using statistical parametric mapping provides high spatial and temporal resolution in multisubject experiments, while requiring only a single (18)FDG PET scan per subject.

Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation.

In this study, which is a continuation and an extension of an earlier study, we enrolled two new families (N=31) and recruited more individuals from the previously ascertained families (N=56). The eight multiplex families (N=171) presented in this study were ascertained from a sample of adult probands whose childhood reading history is well documented through archival information. Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were (1) phonemic awareness (of spoken words); (2) phonological decoding (of printed nonwords); (3) rapid automatized naming (of colored squares or object drawings); (4) single-word reading (orally, of printed real words); (5) vocabulary; and (6) spelling (of dictated words). In addition, the diagnosis of lifelong dyslexia was established by clinical means. Genotyping was done with nine highly polymorphic markers from the 6p22.3-6p21.3 region. The results of two- and multipoint identity-by-descent and identity-by-state analyses supported the importance of a putative locus in the D6S464-D6S273 region for a number of dyslexia-related cognitive deficits.

Cortical activity related to accuracy of letter recognition.

Previous imaging and neurophysiological studies have suggested that the posterior inferior temporal region participates in tasks requiring the recognition of objects, including faces, words, and letters; however, the relationship between accuracy of recognition and activity in that region has not been systematically investigated. In this study, positron emission tomography was used to estimate glucose metabolism in 60 normal adults performing a computer-generated letter-recognition task. Both a region of interest and a voxel-based method of analysis, with subject state and trait variables statistically controlled, found task accuracy to be: (1) negatively related to metabolism in the left ventrolateral inferior temporal occipital cortex (Brodmann's area 37, or ventrolateral BA 37) and (2) positively related to metabolism in a region of the right ventrolateral frontal cortex (Brodmann's areas 47 and 11, or right BA 47/11). Left ventrolateral BA 37 was significantly related both to hits and to false alarms, whereas the right BA 47/11 finding was related only to false alarms. The results were taken as supporting an automaticity mechanism for left ventrolateral BA 37, whereby task accuracy was associated with automatic letter recognition and in turn to reduced metabolism in this extrastriate area. The right BA 47/11 finding was interpreted as reflecting a separate component of task accuracy, associated with selectivity of attention broadly and with inhibition of erroneous responding in particular. The findings are interpreted as supporting the need for control of variance due to subject and task variables, not only in correlational but also in subtraction designs.

Evaluation of brain activity in FDG PET studies.

PURPOSE: A tool (Gemini) was developed for quantifying regions of interest (ROIs) in registered MR and PET data. Its use was validated through phantom and simulated studies. METHOD: Hot spheres were imaged in a phantom (3:1 and 5:1 target-to-nontarget ratios). The computerized 3D Hoffman brain phantom was used to simulate PET studies. Spherical local activity features of two diameters (4 and 10 mm) and five intensities (5, 15, 25, 50, and 100% increase over gray matter) were added to the data in the thalamus and Brodmann area 37. The data were reprojected into sinograms and blurred with a 7 mm kernel. Poisson noise was added, and the sinograms were then reconstructed and analyzed using both SPM96 and Gemini spherical ROIs. RESULTS: Based on phantom and simulated data, the 95th percentile of intensity within a Gemini ROI afforded a reasonable joint optimization of variance (reliability) and accuracy (validity). SPM96 and Gemini results were similar for the larger (10 mm) feature, but in this application, Gemini was more sensitive than SPM96 for the small feature (4 mm). CONCLUSION: Gemini, a tool for display and measurement of spherical ROIs in registered PET and MR data, is precise and accurate for testing hypotheses of differences in localized brain activity, comparing favorably with SPM96.

Evaluating Internet end-to-end performance: overview of test methodology and results.

OBJECTIVE: An evaluation of Internet end-to-end performance was conducted for the purpose of better understanding the overall performance of Internet pathways typical of those used to access information in National Library of Medicine (NLM) databases and, by extension, other Internet-based biomedical information resources. DESIGN: The evaluation used a three-level test strategy: 1) user testing to collect empirical data on internet performance as perceived by users when accessing NLM Web-based databases, 2) technical testing to analyze the Internet paths between the NLM and the user's desktop computer terminal, and 3) technical testing between the NLM and the World Wide Web ("Web") server computer at the user's institution to help characterize the relative performance of Internet pathways. MEASUREMENTS: Time to download the front pages of NLM Web sites and conduct standardized searches of NLM databases, data transmission capacity between NLM and remote locations (known as the bulk transfer capacity [BTC]), "ping" round-trip time as an indication of the latency of the network pathways, and the network routing of the data transmissions (number and sequencing of hops). RESULTS: Based on 347 user tests spread over 16 locations, the median time per location to download the main NLM home page ranged from 2 to 59 seconds, and 1 to 24 seconds for the other NLM Web sites tested. The median time to conduct standardized searches and get search results ranged from 2 to 14 seconds for PubMed and 4 to 18 seconds for Internet Grateful Med. The overall problem rate was about 1 percent; that is, on the average, users experienced a problem once every 100 test measurements. The user terminal tests at five locations and Web host tests at 13 locations provided profiles of BTC, RTT, and network routing for both dial-up and fixed Internet connections. CONCLUSION: The evaluation framework provided a profile of typical Internet performance and insights into network performance and time-of-day/day-of-week variability. This profile should serve as a frame of reference to help identify and diagnose connectivity problems and should contribute to the evolving concept of Internet quality of service.

Selective predictive value of rapid automatized naming in poor readers.

This study considers the differential predictive value of rapid naming tests for various aspects of later reading, where the differential is between nondisabled and poor readers. Two large-N longitudinal samples of students who have been evaluated from third through eighth grades are studied: (a) a randomly accessed, normally distributed group including students with varying degrees of reading ability (N = 154), and (b) a group of poor readers whose single-word reading in third grade is at or below the population 10th percentile (N = 64). Outcomes in fifth and eighth grade were measured in both groups. Single-word reading in both grades was strongly predicted from third-grade rapid naming only within the poor readers, even when IQ, socioeconomic status, and third-grade single-word reading were statistically controlled. Although rapid naming had predictive value within the large, normally distributed group, its predictive power was entirely absent in the average-reading nondisabled students who were between the 10th and 90th percentiles (n = 122). The fact that rapid naming has predictive power only for poor readers but not for average readers is interpreted as suggesting that impaired readers are qualitatively different from the normal-reading population and are not simply the "tail" of a normal distribution of reading ability. It also seems that it is the automaticity of retrieval, not the knowledge of names itself (as in confrontational naming tasks), that gives the predictive power in rapid naming. These data are considered in light of the one- and two-factor theories of the underlying processes involved in reading disability or dyslexia.

Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.

Six extended dyslexic families with at least four affected individuals were genotyped with markers in three chromosomal regions: 6p23-p21.3, 15pter-qter, and 16pter-qter. Five theoretically derived phenotypes were used in the linkage analyses: (1) phonological awareness; (2) phonological decoding; (3) rapid automatized naming; (4) single-word reading; and (5) discrepancy between intelligence and reading performance, an empirically derived, commonly used phenotype. Two-point and multipoint allele-sharing analyses of chromosome 6 markers revealed significant evidence (P < 10(-6)) for linkage of the phonological awareness phenotype to five adjacent markers (D6S109, D6S461, D6S299, D6S464, and D6S306). The least compelling results were obtained with single-word reading. In contrast, with chromosome 15 markers, a LOD score of 3.15 was obtained for marker D15S143 at theta = 0.0 with single-word reading. Multipoint analyses with markers adjacent to D15S143 (D15S126, D15S132, D15S214, and D15S128) were positive, but none reached acceptable significance levels. Chromosome 15 analyses with the phonological awareness phenotype were negative. Parametric and nonparametric linkage analyses with chromosome 16 markers were negative. The most intriguing aspect of the current findings is that two very distinct reading-related phenotypes, reflecting different levels in the hierarchy of reading-related skills, each contributing to different processes, appear to be linked to two different chromosomal regions.

Transitioning to the Internet: results of a National Library of Medicine user survey.

In late 1995, several months prior to the introduction of Internet Grateful Med, the National Library of Medicine (NLM) conducted a customer survey as part of its efforts to make a transition from Grateful Med to new forms of electronic information access and retrieval. A questionnaire survey was mailed to a sample of 2,500 online users randomly selected from domestic users (excluding fixed-fee users) who searched NLM databases during the second quarter of 1995. The final response rate was nearly 83% of eligible respondents. About 70% of NLM customers responding already had access to the Internet, and of those, more than 90% had access to the World Wide Web. However, only 26% of customers with Internet access were using the Internet to access NLM databases. Health care providers account for about 46% of NLM customers but, as a group, search NLM databases relatively infrequently even though they have higher-end equipment. Librarians and information professionals represent about one-fifth of NLM customers and are by far the most intensive users, but tend to have lower-end equipment. Overall, the survey results provide a strong basis for the transition to Internet-based delivery of NLM online database services, including Internet Grateful Med and the NLM family of World Wide Web sites. However, Internet access is uneven, especially in rural areas and at hospitals. This reinforces the need for continuing special outreach efforts directed at improving access for rural and hospital-based users and rural libraries, upgrading computer equipment for medical librarians, and training health care providers in more effective use of Internet-based biomedical information resources.

Differences in visuospatial judgement in reading-disabled and normal children.

Both visual and verbal impairments have been reported in two independent streams of research into the etiology of dyslexia or reading-disability. To address the question of the presence of either abnormality in reading-disabled children, visuospatial and phonological ability were assessed and contrasted in 39 Normal and 26 Reading-disabled children. To assess whether these deficits are unique to dyslexia, scores were also compared to those of a group of 12 Poor Readers ("garden-variety" backward readers with low IQs). The Benton Judgement of Line Orientation Test was used for its simplicity and clinical reliability: Reading-disabled subjects performed significantly worse than Normal readers (but similar to Poor Readers). Reading-disabled subjects performed worse for lines in the left-hemifield compared to Normal subjects and also had a greater tendency to scan the task in reverse order (left-to-right) from the usual right-to-left scanning pattern observed in the Normal group when performing this test. When both verbal and visuospatial variables were combined in a multiple regression analysis, 71% of reading variance could be accounted for. These results suggest that Reading-disabled children not only have poor phonological awareness, but they also show visuospatial deficits. However, poor performance on both these tasks was also observed in the group of Poor Readers, suggesting that these deficits are not unique to children with specific reading disability. The results lend further evidence to the hypothesis that reading disability cannot solely be attributed to left-hemisphere dysfunction resulting in phonological impairment. There are other behavioral deficits, possibly caused by a common mechanism, some of which, like visuospatial ability, can be measured by simple behavioral tests such as the Judgment of Line Orientation Test.

Temporal and spatial processing in reading disabled and normal children.

The ability to process temporal and spatial visual stimuli was studied to investigate the role these functions play in the reading process. Previous studies of this type have often been confounded by memory involvement, or did not take into account the evidence which suggests a visual transient deficient in some dyslexics. Normal (n = 39), reading disabled (n = 26), and backward reading children (n=12) were compared on a visual computer game, which consisted of a temporal and a analogous spatial dot counting task. Reading disabled children performed significantly worse than normal children on the Temporal Dot Task, but were only mildly impaired on the Spatial Dot Task, Backward readers were not significantly better than the reading disabled group on either task, suggesting that poor poor visual temporal processing is not specific to dyslexia. In a group of 93 children, a regression model including age, verbal IQ, phonological awareness, and visual temporal processing ability, predicted 73% of the variance of reading ability. The results suggest that dyslexics perform worse in tasks that require fast, sequential processing and that this impairment may be partially responsible for their reading difficulties.

Verbal and visual problems in reading disability.

Most individuals interested in reading disability favor the view that disordered language processing is the main cause of children's reading problems and that visual problems are seldom, if ever, responsible. Nevertheless, in a preliminary study (Eden, Stein, & Wood, 1993) we showed that visuospatial and oculomotor tests can be used to differentiate children with reading disabilities from nondisabled children. In the present study we investigated a larger sample of children to see if these findings held true. Using 93 children from the Bowman Gray Learning Disability Project (mean age = 11.3 years; 54 boys, 39 girls), we compared the phonological and visuospatial abilities of nondisabled children (children whose reading at fifth grade rated a Woodcock-Johnson reading standardized score between 85 and 115), and children with reading disability (whose reading standardized score was below 85 on the Woodcock-Johnson). In addition to performing poorly on verbal tests, the children with reading disability were significantly worse than nondisabled children at many visual and eye-movement tasks. A high proportion of the variance (68%) in reading ability of both the nondisabled children and those with reading disability could be predicted by combining visual and phonological scores in a multiple regression. These results provide further support for the hypothesis that reading disability may, to some extent, result from dysfunction of the visual and oculomotor systems.

Electrophysiological indicants of black-white discrimination performance for letter and non-letter patterns.

This study examined event-related potentials (ERPs) and behavioral measures, considered to be sensitive to the selective processing of black versus white letter and non-letter patterns, in a group of seventy-four randomly selected 6 to 8 year old children. Results demonstrated faster and more accurate behavioral performance on the experimental task for the letter than for the non-letter patterns. The ERP measures provided complementary information regarding this letter facilitation effect, indicating that the selective neural processing of letter as compared to non-letter patterns was present in the electrophysiological waveform within the initial 100-140 ms after stimulus presentation. Later ERP measures (200-260 and 500-600 ms post-stimulus) in response to the letter stimuli showed greater differences as a function of task relevance over the left than over the right hemisphere. The results from the present study indicate a remarkably early facilitative influence of stimulus type (letter versus non-letter patterns) on the luminance discrimination of these stimuli and are consistent with an overlap of linguistic and perceptual processing.

Event related potentials in adults diagnosed as reading disabled in childhood.

The purpose of this study was to identify electrophysiological correlates of reading disability (RD) in adults with psychometrically documented childhood reading histories. Specific a-priori hypotheses for these correlates were generated from the findings of Harter, Anllo-Vento, Wood & Schroeder (1988a); Harter, Diering & Wood (1988b). The subjects were 32 males with normal intelligence and no history of attention deficit disorder or current major psychopathology. Event related potentials were recorded over O1, O2, C3', C4', F3, and F4 to letter stimuli using an intralocation selective attention paradigm. Subjects with RD showed a general reduction in positivity starting at 150 ms and continuing up to 500 ms. The reduced positivity at left central P240 replicated the findings of Harter et al. (1988b) with children. However, adult RD was associated with more diffuse, bilateral reduction in electrophysiological response to all stimuli. A possible relationship between the bilaterality of the neural deficit and the severity of the dyslexia was proposed: that a bilateral deficit may be involved in severe cases.

Differences in eye movements and reading problems in dyslexic and normal children.

It has been suggested that eye movement abnormalities seen in dyslexics are attributable to their language problems. In order to investigate this claim, we studied eye movements in dyslexic children, during several non-reading tasks. Dyslexic children were compared to normal and backward readers on measures of fixation, vergence amplitude, saccade and smooth pursuit. The results were compared to the children's phonological ability. Dyslexic children (n = 26) had significantly worse eye movement stability during fixation of small targets than normal children (n = 39). Vergence amplitudes were lower for dyslexics than for controls. A qualitative assessment of saccadic eye movements revealed that dyslexics exhibit fixation instability at the end of saccades. Assessment of smooth pursuit revealed poor smooth pursuit in the dyslexic group, particularly when pursuing a target moving from left to right. Dyslexic children also performed significantly worse than normal children on a test of phonological awareness (Pig Latin). Eye movement results were studied in the light of the findings on phonological awareness: dyslexics with small vergence amplitudes also always have poor phonemic awareness. However, poor fixation control is found in dyslexics with or without poor phonological ability. The backward reading children performed similar to the dyslexics on all tests, suggesting that the deficiencies observed in this study are not specific to children with dyslexia. The problems experienced by the children (revealed by a questionnaire) are in agreement with those measured in terms of eye movement recordings and phonemic awareness. Sex, handedness, IQ or the presence of attention deficit disorder (ADD) did not appear to influence the children's performances on any of the eye movement tasks. The presence of oculomotor abnormalities in a non-reading task strongly suggests that the underlying deficit in the control of eye movements seen in dyslexics is not caused by language problems alone.