Neurobiological studies of reading and reading disability.

UNLABELLED: Evidence from neuroimaging studies, including our own, suggest that skilled word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system appears to be functionally disrupted in developmental dyslexia. Relative to nonimpaired readers, reading-disabled individuals demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers, the dorsal circuit predominates at first, and in conjunction with premotor systems, is associated with analytic processing necessary for learning to integrate orthographic with phonological and lexical semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word form system, which underlies fluency in word recognition. LEARNING OUTCOMES: As a result of this activity, (1) the participant will learn about a model of lexical processing involving specific cortical regions. (2) The participant will learn about evidence which supports the theory that two dorsal LH systems may be disrupted in developmental dyslexia. (3) The participant will learn that individuals with reading impairment may rely on other regions of the brain to compensate for the disruption of posterior function.

The functional neural architecture of components of attention in language-processing tasks.

Using functional magnetic resonance imaging we examined three important dimensions of attentional control (selective attention, divided attention, and executive function) in 25 neurologically normal, right-handed men and women, using tasks involving the perception and processing of printed words, spoken words, or both. In the context of language-processing manipulations: selective attention resulted in increased activation at left hemisphere parietal sites as well as at inferior frontal sites, divided attention resulted in additional increases in activation at these same left hemisphere sites and was also uniquely associated with increased activation of homologous sites in the right hemisphere, and executive function (measured during a complex task requiring sequential decision-making) resulted in increased activation at frontal sites relative to all other conditions. Our findings provide support for the belief that specific functional aspects of attentional control in language processing involve widely distributed but distinctive cortical systems, with mechanisms associated with the control of perceptual selectivity involving primarily parietal and inferior frontal sites and executive function engaging specific sites in frontal cortex.

Network analysis of brain activations in working memory: behavior and age relationships.

Forty-six middle-aged female subjects were scanned using functional Magnetic Resonance Imaging (fMRI) during performance of three distinct stages of a working memory task-encoding, rehearsal, and recognition-for both printed pseudowords and visual forms. An expanse of areas, involving the inferior frontal, parietal, and extrastriate cortex, was active in response to stimuli during both the encoding and recognition periods. Additional increases during memory recognition were seen in right prefrontal regions, replicating a now-common finding [for reviews, see Fletcher et al. (1997) Trends Neurosci 20:213-218; MacLeod et al. (1998) NeuroImage 7:41-48], and broadly supporting the Hemispheric Encoding/Retrieval Asymmetry hypothesis [Tulving et al. (1994) Proc Natl Acad Sci USA 91:2016-2020]. Notably, this asymmetry was not qualified by the type of material being processed. A few sites demonstrated higher activity levels during the rehearsal period, in the absence of any new stimuli, including the medial extrastriate, precuneus, and the medial temporal lobe. Further analyses examined relationships among subjects' brain activations, age, and behavioral scores on working memory tests, acquired outside the scanner. Correlations between brain scores and behavior scores indicated that activations in a number of areas, mainly frontal, were associated with performance. A multivariate analysis, Partial Least Squares [McIntosh et al. (1996) NeuroImage 3:143-157, (1997) Hum Brain Map 5:323-327], was then used to extract component effects from this large set of univariate correlations. Results indicated that better memory performance outside the scanner was associated with higher activity at specific sites within the frontal and, additionally, the medial temporal lobes. Analysis of age effects revealed that younger subjects tended to activate more than older subjects in areas of extrastriate cortex, medial frontal cortex, and the right medial temporal lobe; older subjects tended to activate more than younger subjects in the insular cortex, right inferior temporal lobe, and right inferior frontal gyrus. These results extend recent reports indicating that these regions are specifically involved in the memory impairments seen with aging.

Functional neuroimaging studies of reading and reading disability (developmental dyslexia).

Converging evidence from a number of neuroimaging studies, including our own, suggest that fluent word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system is functionally disrupted in developmental dyslexia. Reading disabled readers, relative to nonimpaired readers, demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers the dorsal circuit predominates at first, and is associated with analytic processing necessary for learning to integrate orthographic features with phonological and lexical-semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word identification system which underlies fluent word recognition in skilled readers.

Adrenomedullary function during cognitive testing in attention-deficit/hyperactivity disorder.

OBJECTIVE: Reported correlations between epinephrine (EPI) excretion and classroom performance, the cognition-enhancing effects of EPI infusion, increased EPI excretion with stimulants, and reports of decreased EPI excretion in attention-deficit/hyperactivity disorder (ADHD) suggest that sympathoadrenomedullary function might be altered in ADHD. This hypothesis was tested by examining sympathetic and adrenomedullary functioning during cognitive testing in boys with diagnosed ADHD. METHOD: Urinary excretion of EPI and norepinephrine during a 3-hour cognitive test battery was assessed in 7- to 13-year-old boys. Excretion rates (nanograms per hour per square meter of body surface area) were determined in 200 individuals with ADHD (diagnosed according to DSM-IV criteria), with or without co-occurring oppositional defiant/conduct disorder or learning disorder. A non-ADHD contrast group (n = 51) with similar comorbidity was also studied. RESULTS: Substantially lower (mean +/- SE) urinary EPI excretion was observed in the ADHD-inattentive subtype (n = 71) compared with the control group (200 +/- 22 versus 278 +/- 24 ng/hr/m2; F = 5.99, p = .015, critical alpha = .017). No diagnostic group differences were seen for norepinephrine excretion. Correlational analysis of both parent- and teacher-rated behaviors revealed that inattention factors consistently negatively predicted urinary EPI excretion. CONCLUSIONS: The data extend findings of lower adrenomedullary activity during cognitive challenge in individuals with ADHD and suggest that the alteration is associated with inattentive behavior.

An event-related neuroimaging study distinguishing form and content in sentence processing.

Two coordinated experiments using functional Magnetic Resonance Imaging (fMRI) investigated whether the brain represents language form (grammatical structure) separately from its meaning content (semantics). While in the scanner, 14 young, unimpaired adults listened to simple sentences that were either nonanomalous or contained a grammatical error (for example, *Trees can grew.), or a semantic anomaly (for example, *Trees can eat.). A same⁄different tone pitch judgment task provided a baseline that isolated brain activity associated with linguistic processing from background activity generated by attention to the task and analysis of the auditory input. Sites selectively activated by sentence processing were found in both hemispheres in inferior frontal, middle, and superior frontal, superior temporal, and temporo-parietal regions. Effects of syntactic and semantic anomalies were differentiated by some nonoverlapping areas of activation: Syntactic anomaly triggered significantly increased activity in and around Broca's area, whereas semantic anomaly activated several other sites anteriorly and posteriorly, among them Wernicke's area. These dissociations occurred when listeners were not required to attend to the anomaly. The results confirm that linguistic operations in sentence processing can be isolated from nonlinguistic operations and support the hypothesis of a specialization for syntactic processing.

The angular gyrus in developmental dyslexia: task-specific differences in functional connectivity within posterior cortex.

Converging evidence from neuroimaging studies of developmental dyslexia reveals dysfunction at posterior brain regions centered in and around the angular gyrus in the left hemisphere. We examined functional connectivity (covariance) between the angular gyrus and related occipital and temporal lobe sites, across a series of print tasks that systematically varied demands on phonological assembly. Results indicate that for dyslexic readers a disruption in functional connectivity in the language-dominant left hemisphere is confined to those tasks that make explicit demands on assembly. In contrast, on print tasks that do not require phonological assembly, functional connectivity is strong for both dyslexic and nonimpaired readers. The findings support the view that neurobiological anomalies in developmental dyslexia are largely confined to the phonological-processing domain. In addition, the findings suggest that right-hemisphere posterior regions serve a compensatory role in mediating phonological performance in dyslexic readers.

Persistence of dyslexia: the Connecticut Longitudinal Study at adolescence.

OBJECTIVE: The outcome in adolescence of children diagnosed as dyslexic during the early years of school was examined in children prospectively identified in childhood and continuously followed to young adulthood. This sample offers a unique opportunity to investigate a prospectively identified sample of adolescents for whom there is no question of the childhood diagnosis and in whom highly analytic measures of reading and language can be administered in adolescence. DESIGN: Children were recruited from the Connecticut Longitudinal Study, a cohort of 445 children representative of those children entering public kindergarten in Connecticut in 1983. Two groups were selected when the children were in grade 9: children who met criteria for persistent reading disability in grades 2 through 6 (persistently poor readers [PPR]; n = 21) and a comparison group of nondisabled children, subdivided into average readers (n = 35) and superior readers (n = 39). In grade 9, each child received a comprehensive assessment of academic, language, and other cognitive skills. RESULTS: Measures of phonological awareness (but not orthographic awareness) were most significant in differentiating the 3 reading groups, with smaller contributions from measures of word finding and digit-span. Academic measures that best separated good from poor readers were decoding and spelling, whereas measures of math and reading comprehension did not. Measures of phonological awareness, followed next by teacher rating of academic skills were the best predictors of decoding, reading rate, and reading accuracy. In contrast, the best predictor of reading comprehension was word finding, with digit span and socioeconomic status also contributing significantly. Using a growth curve model (quadratic model of growth to a plateau) all 3 groups demonstrated similar patterns of growth over time, with the superior group outperforming the average group, and the average group outperforming the PPR group. There was no evidence that the children in the PPR group catch up in their reading skills. CONCLUSIONS: Deficits in phonological coding continue to characterize dyslexic readers even in adolescence; performance on phonological processing measures contributes most to discriminating dyslexic and average readers, and average and superior readers as well. These data support and extend the findings of previous investigators indicating the continuing contribution of phonological processing to decoding words, reading rate, and accuracy and spelling. Children with dyslexia neither spontaneously remit nor do they demonstrate a lag mechanism for catching up in the development of reading skills. In adolescents, the rate of reading as well as facility with spelling may be most useful clinically in differentiating average from poor readers.

The cerebellum's role in reading: a functional MR imaging study.

BACKGROUND AND PURPOSE: Long considered to have a role limited largely to motor-related functions, the cerebellum has recently been implicated as being involved in both perceptual and cognitive processes. Our purpose was to determine whether cerebellar activation occurs during cognitive tasks that differentially engage the component processes of word identification in reading. METHODS: Forty-two neurologically normal adults underwent functional MR imaging of the cerebellum with a gradient-echo echo-planar technique while performing tasks designed to study the cognitive processing used in reading. A standard levels-of-processing paradigm was used. Participants were asked to determine whether pairs of words were written in the same case (orthographic processing), whether pairs of words and non-words rhymed with each other, respectively (phonologic assembly), and whether pairs of words belonged to the same category (semantic processing). Composite maps were generated from a general linear model based on a randomization of statistical parametric maps. RESULTS: During phonologic assembly, cerebellar activation was observed in the middle and posterior aspects of the posterior superior fissure and adjacent simple lobule and semilunar lobule bilaterally and in posterior aspects of the simple lobule, superior semilunar lobule, and inferior semilunar lobule bilaterally. Semantic processing, however, resulted in activation in the deep nuclear region on the right and in the inferior vermis, in addition to posterior areas active in phonologic assembly, including the simple, superior semilunar, and inferior semilunar lobules. CONCLUSION: The cerebellum is engaged during reading and differentially activates in response to phonologic and semantic tasks. These results indicate that the cerebellum contributes to the cognitive processes integral to reading.

Comorbidity of learning and attention disorders. Separate but equal.

Children with learning and attention disorders commonly present with symptoms of both types of disorders. In many children, this co-occurrence represents comorbid disorders that are separate but overlapping. Because of comorbidity, the presence of one disorder signals the need to evaluate for the other disorders. Evaluation and treatment approaches must address both disorders when present.

Executive functioning deficits in attention-deficit/hyperactivity disorder are independent of oppositional defiant or reading disorder.

OBJECTIVE: To evaluate deficits of executive functions in children with attention-deficit/hyperactivity disorder (ADHD) classified by type (combined [CT] or predominantly inattentive [IT]) and comorbidity with oppositional defiant disorder (ODD) and reading disorder (RD). METHOD: The Wisconsin Card Sorting Test (WCST) and Tower of Hanoi (TOH) were administered to 28 community volunteers and 359 children (7.5-13.5 years old) divided into ADHD types, RD, and ODD. RESULTS: ADHD/CT children solved fewer puzzles and violated more rules on the TOH than ADHD/IT or non-ADHD subjects. On the WCST there were no differences between diagnostic samples in perseverativeness, but ADHD/CT patients made more nonperseverative errors than ADHD/IT children. ODD was associated with moderately better TOH performance and RD with excessive rule breaks. CONCLUSIONS: Executive functioning deficits were found for only ADHD/CT children and were independent of comorbidity with RD or ODD.

A school-aged child with delayed reading skills.

During a health supervision visit, the father of a 7.5-year-old African American second-grader asked about his son's progress in reading. He was concerned when, at a recent teacher-parent conference to review Darren's progress, the teacher remarked that Darren was not keeping up with reading skills compared with others in his class. She said that he had difficulty sounding out some words correctly. In addition, he could not recall words he had read the day before. The teacher commented that Darren was a gregarious, friendly child with better-than-average verbal communication skills. His achievement at math was age-appropriate; spelling, however, was difficult for Darren, with many deleted letters and reversals of written letters. A focused history did not reveal any risk factors for a learning problem in the prenatal or perinatal periods. Early motor, language, and social milestones were achieved on time. Darren had not experienced any head injury, loss of consciousness, or chronic medical illness. He had several friends, and his father denied any behavioral problems at home or at school. His teacher completed a DSM-IV-specific behavioral survey for attention-deficit/hyperactivity disorder (ADHD). It did not show any evidence of ADHD. Darren's father completed 1 year of college and is currently the manager of a neighborhood convenience store. His mother had a high school education; she recalled that she found it difficult to complete assignments that required reading or writing. She is employed as a waitress. Darren does not have any siblings. The pediatrician performed a complete physical examination, the results of which were normal, including visual acuity, audiometry, and a neurological examination. It was noted that Darren seemed to pause several times in response to questions or commands. On two occasions, during finger-nose testing and a request to assess tandem gait, directions required repetition. Overall, he was pleasant and seemed to enjoy the visit. His pediatrician concluded that he had a learning problem but she was uncertain about the next step. She asked herself, "Is there anything else I can do in the office to evaluate Darren's problem with learning? Should I quickly refer him for educational testing or encourage a reading tutor? What questions can I ask his teacher that would be helpful? Am I missing a medical disorder?"

Paired-associate learning in attention-deficit/hyperactivity disorder as a function of hyperactivity-impulsivity and oppositional defiant disorder.

A paired-associate learning (PAL) test was administered to 22 community volunteers without disruptive disorders and 197 children (7.5-13.5 years-old) presenting with the inattentive and combined subtypes of attention-deficit/hyperactivity disorder (ADHD) either in combination with or without oppositional defiant disorder (ODD). Participants were screened for learning disorders. In comparison to non-ADHD participants, children with ADHD achieved worse PAL and made errors rated as more acoustically and less semantically similar to the correct paired associates. These deficits were not related to hyperactivity-impulsivity or comorbid ODD. These results suggest that ADHD children are less competent at PAL and use less efficient learning strategies than their non-ADHD peers.

Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks.

CONTEXT: Preclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women. OBJECTIVE: To investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998. SETTING: Community volunteers tested in a hospital setting. PATIENTS: Forty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years). INTERVENTION: Twenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments. MAIN OUTCOME MEASURES: Brain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. RESULTS: Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks. CONCLUSIONS: Estrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.

Quantifying and comparing region-of-interest activation patterns in functional brain MR imaging: methodology considerations.

The general aims of functional brain magnetic resonance imaging (fMRI) studies are to ascertain which areas of the brain are activated during a specific task, the extent of this activation, whether different groups of subjects demonstrate different patterns of activation, and how these groups behave in different tasks. Many steps are involved in answering such questions and if each step is not carefully controlled the results may be influenced. This work has three objectives. Firstly, to present a technique for quantitatively evaluating methods used in functional imaging data analysis. While receiver-operator-characteristic (ROC) analysis has been used effectively to evaluate the ability of post-processing algorithms to detect true activations while rejecting false activations, it is difficult to adapt such a technique for comparisons of methods for quantitating activations. We present a technique based on the ANOVA, between two or more regions of interest (ROIs), subject groups, or activation tasks, over a range of statistical thresholds, which reveals the sensitivity of different activation quantification metrics to noise and other variables. Secondly, we use this technique to compare two methods of quantifying localized brain activation. There are numerous ways of quantifying the amount of activation present in a specific region of the brain in an individual subject. We compare the pixel count approach, which simply counts the number of pixels above an arbitrary statistical threshold, with an approach based on the sum of t-values above the same arbitrary t-value threshold. Finally, we examine the sensitivity of the results from an analysis of variance, to user defined parameters such as threshold and region of interest size. Both simulated and real functional magnetic resonance data are used to demonstrate these techniques.

Functional disruption in the organization of the brain for reading in dyslexia.

Learning to read requires an awareness that spoken words can be decomposed into the phonologic constituents that the alphabetic characters represent. Such phonologic awareness is characteristically lacking in dyslexic readers who, therefore, have difficulty mapping the alphabetic characters onto the spoken word. To find the location and extent of the functional disruption in neural systems that underlies this impairment, we used functional magnetic resonance imaging to compare brain activation patterns in dyslexic and nonimpaired subjects as they performed tasks that made progressively greater demands on phonologic analysis. Brain activation patterns differed significantly between the groups with dyslexic readers showing relative underactivation in posterior regions (Wernicke's area, the angular gyrus, and striate cortex) and relative overactivation in an anterior region (inferior frontal gyrus). These results support a conclusion that the impairment in dyslexia is phonologic in nature and that these brain activation patterns may provide a neural signature for this impairment.

Predicting reading performance from neuroimaging profiles: the cerebral basis of phonological effects in printed word identification.

This study linked 2 experimental paradigms for the analytic study of reading that heretofore have been used separately. Measures on a lexical decision task designed to isolate phonological effects in the identification of printed words were examined in young adults. The results were related to previously obtained measures of brain activation patterns for these participants derived from functional magnetic resonance imaging (fMRI). The fMRI measures were taken as the participants performed tasks that were designed to isolate orthographic, phonological, and lexical-semantic processes in reading. Individual differences in the magnitude of phonological effects in word recognition, as indicated by spelling-to-sound regularity effects on lexical decision latencies and by sensitivity to stimulus length effects, were strongly related to differences in the degree of hemispheric lateralization in 2 cortical regions.

Attention-deficit/hyperactivity disorder.

In this chapter we have reviewed the diagnosis and management of attention deficit disorder, focusing particularly on the role of stimulant therapy in ADHD. Hisorical review suggests that ADHD has roots that extend back almost a century. The definition of ADHD is based on inclusion and exclusion criteria that are established by history and reflect behavioral concerns. Attention-deficit/hyperactivity disorder is a chronic disorder affecting the child's home, school, and community life. The primary symptoms of the disorder manifest a developmental pattern: activity diminishes while attentional deficits persist. Major sources of concern are the secondary and often more resistant problems of learning difficulties, behavioral problems, lack of peer acceptance, and low self-esteem. An often frustrating and perplexing characteristic of the disorder is its marked variability-over time, across situations, and within the same child and similar situations. Educational management represents an important priority and often forms the cornerstone of all other therapies, nonpharmacologic or pharmacologic. Cognitive-behavioral therapies represent the most widely used alternative to pharmacotherapy. Although the effects of CBT alone are disappointing, recent studies suggest that such therapies may provide a useful adjunct to pharmacotherapy and may be helpful when children are tapered off medication. Psychotherapy, or a combination of psychotherapy and medication (termed multimodality therapy), may also be useful. Pharmacotherapy for ADHD originated almost 60 years ago, and at this time the ameliorative effects of medications in ADHD are well established. The general skepticism of experienced clinicians, coupled with a climate where parents are reluctant to medicare children, serves to limit their use except where indicated. Although the effects of stimulants on attention and activity seem well established, effects on cognition, conduct, and social behavior are more controversial. Within recent years, a great deal has been learned about the pharmacokinetics of stimulants in children with ADHD, providing a rational basis for administration. It is also clear that side effects are minimal, the most serious being the possibility of the emergence of tics. Whereas stimulants are clearly the most effective agents, other agents, including antidepressants, may also be effective. Recent advances may now provide an opportunity to better understand the neural and molecular basis for ADHD. Recent advances in imaging technology, particularly fMRI, offer an opportunity to examine the neural basis of ADHD, and advances in genetics may provide clues to its etiology.