Guinevere F. Eden

Meta-Analysis of the Functional Neuroanatomy of Single-Word Reading: Method and Validation

Intersubject variability and subtle differences in experimental design can lead to variable results in studies of cognitive processes such as reading. To accurately identify the neural processes associated with cognition and sensorimotor processing, meta-analytic methods capable of identifying areas of consistent activation among studies are useful. This paper describes a novel approach for combining published neuroimaging results from multiple studies, designed to maximize the quantification of interstudy concordance while minimizing the subjective aspects of meta-analysis. In this method, a localization probability distribution was modeled for each activation focus obtained from 11 PET studies of reading single words aloud, and the union of these distributions was taken to yield an activation likelihood estimate map for the brain. Significance was assessed via permutation analysis of randomly generated sets of foci. Regions of significant concordance were identified in bilateral motor and superior temporal cortices, pre-SMA, left fusiform gyrus, and the cerebellum. These meta-analytic results were validated by comparison with new fMRI data on aloud word reading in normal adult subjects. Excellent correspondence between the two statistical maps was observed, with fMRI maxima lying close to all meta-analysis peaks and statistical values at the peaks identified by the two techniques correlating strongly. This close correspondence between PET meta-analysis and fMRI results also demonstrates the validity of using fMRI for the study of language tasks involving overt speech responses. Advantages of this automated meta-analysis technique include quantification of the level of concordance at all brain locations and the provision for use of a threshold for statistical significance of concordance.

Development of neural mechanisms for reading

The complexities of pediatric brain imaging have precluded studies that trace the neural development of cognitive skills acquired during childhood. Using a task that isolates reading-related brain activity and minimizes confounding performance effects, we carried out a cross-sectional functional magnetic resonance imaging (fMRI) study using subjects whose ages ranged from 6 to 22 years. We found that learning to read is associated with two patterns of change in brain activity: increased activity in left-hemisphere middle temporal and inferior frontal gyri and decreased activity in right inferotemporal cortical areas. Activity in the left-posterior superior temporal sulcus of the youngest readers was associated with the maturation of their phonological processing abilities. These findings inform current reading models and provide strong support for Ortons 1925 theory of reading development.

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Neural Changes following Remediation in Adult Developmental Dyslexia

Brain imaging studies have explored the neural mechanisms of recovery in adults following acquired disorders and, more recently, childhood developmental disorders. However, the neural systems underlying adult rehabilitation of neurobiologically based learning disabilities remain unexplored, despite their high incidence. Here we characterize the differences in brain activity during a phonological manipulation task before and after a behavioral intervention in adults with developmental dyslexia. Phonologically targeted training resulted in performance improvements in tutored compared to nontutored dyslexics, and these gains were associated with signal increases in bilateral parietal and right perisylvian cortices. Our findings demonstrate that behavioral changes in tutored dyslexic adults are associated with (1) increased activity in those left-hemisphere regions engaged by normal readers and (2) compensatory activity in the right perisylvian cortex. Hence, behavioral plasticity in adult developmental dyslexia involves two distinct neural mechanisms, each of which has previously been observed either for remediation of developmental or acquired reading disorders.

A Meta‐analysis of Functional Neuroimaging Studies of Dyslexia

Reading and phonological processing deficits have been the primary focus of neuroimaging studies addressing the neurologic basis of developmental dyslexia, but to date there has been no objective assessment of the consistency of these findings. To address this issue, spatial coordinates reported in the literature were submitted to two parallel activation likelihood estimate (ALE) meta‐analyses. First, a meta‐analysis including 96 foci from nine publications identified regions where typical readers are likely to show greater activation than dyslexics: two left extrastriate areas within BA 37, precuneus, inferior parietal cortex, superior temporal gyrus, thalamus, and left inferior frontal gyrus. Right hemisphere ALE foci representing hypoactivity in dyslexia were found in the fusiform, postcentral, and superior temporal gyri. To identify regions in which dyslexic subjects reliably show greater activation than controls, 75 foci from six papers were entered into a second meta‐analysis. Here ALE results revealed hyperactivity associated with dyslexia in right thalamus and anterior insula. These findings suggest that during the performance of a variety of reading tasks, normal readers activate left‐sided brain areas more than dyslexic readers do, whereas dyslexia is associated with greater right‐sided brain activity. The most robust result was in left extrastriate cortex, where hypoactivity associated with dyslexia was found. However, the ALE maps provided no support for cerebellar dysfunction, nor for hyperactivity in left frontal cortex in dyslexia, suggesting that these findings, unlike those described above, are likely to be more varied in terms of their reproducibility or spatial location.

Dyslexics are impaired on implicit higher-order sequence learning, but not on implicit spatial context learning.

Developmental dyslexia is characterized by poor reading ability and impairments on a range of tasks including phonological processing and processing of sensory information. Some recent studies have found deficits in implicit sequence learning using the serial reaction time task, but others have not. Other skills, such as global visuo-spatial processing may even be enhanced in dyslexics, although deficits have also been noted. The present study compared dyslexic and non-dyslexic college students on two implicit learning tasks, an alternating serial response time task in which sequential dependencies exist across non-adjacent elements and a spatial context learning task in which the global configuration of a display cues the location of a search target. Previous evidence indicates that these implicit learning tasks are based on different underlying brain systems, fronto-striatal-cerebellar circuits for sequence learning and medial temporal lobe for spatial context learning. Results revealed a double dissociation: dyslexics showed impaired sequence learning, but superior spatial context learning. Consistent with this group difference, there was a significant positive correlation between reading ability (single real and non-word reading) and sequence learning, but a significant negative correlation between these measures and spatial context learning. Tests of explicit knowledge confirmed that learning was implicit for both groups on both tasks. These findings indicate that dyslexic college students are impaired on some kinds of implicit learning, but not on others. The specific nature of their learning deficit is consistent with reports of physiological and anatomical differences for individuals with dyslexia in frontal and cerebellar structures.

Neural Systems Affected in Developmental Dyslexia Revealed by Functional Neuroimaging

Table 1Colocalization of Functional Neuroimaging Studies Investigating Differences between Dyslexics and Controls During Phonological and Visual Motion Processing TasksRhyme JudgmentVisual MotionAuthorRumsey et al.Rumsey et al.Rumsey et al.Paulesu et al.Shaywitz et al.Eden et al.Demb et al.(1992)(1997)(1996)(1996)(1998)*(1996)*(1997)*Response typeDecision makingPronunciationDecision makingDecision makingDecision makingNoneNone(button press)(button press)(button press)(button press)#STMRegion (Brodmann area)MTV/V5(19/37) L+50 −70 +05 C--- CR+52 −75 +08 C--- CInferior parietalSupramarginal(39/40) L--- C−28 −32 +44 C−44 −40 +28 C−46 −44 +24 #CR+52 −22 +28 C+40 −62 +28 C+/−47 +/−45 +/−33 CTemporalSuperior temporal(42/22) L−52 −30 +12 C−44 −22 +04 CR+44 −20 −04 C+/−53 +/−43 +/−11 CMedial temporal(21/37) L--- C−54 −22 −04 C−50 −56 +08 CR+46 −58 −08 CInferior temporal/Fusiform L−42 −28 −16 C−48 −40 −16 CR--- C+50 −34 −20 C+48 −30 −20 COccipitalStriate/extrastriate(17/18) L−10 −92 00 D−24 −84 −04 D+/−08 +/−89 +/−03 CR+/−36 +/−80 +/−05 CFunctional brain imaging studies employing PET or fMRI (*) that have identified differences between dyslexics and controls in the posterior areas of the brain during phonological processing or visual motion processing. “C” and “D” denote which of the two groups (controls or dyslexics, respectively) showed greater activation. Talairach coordinates correspond to distance in millimeters from the anterior commissure (+ corresponds to right hemisphere; − corresponds to left hemisphere). Phonological processing studies represent group data and visual motion studies represent single subject data. STM, short-term memory task.

Utilizing hemodynamic delay and dispersion to detect fMRI signal change without auditory interference: The behavior interleaved gradients technique

A major problem associated with the use of functional magnetic resonance imaging (fMRI) is the attendant gradient noise, which causes undesirable auditory system stimulation. A method is presented here that delays data acquisition to a period immediately after task completion, utilizing the physiological delay and dispersion between neuronal activity and its resulting hemodynamic lag. Subjects performed finger movements with the gradients off, followed by a rest period with the gradients on. This resulted in task‐related signals comparable to those obtained with concurrent task performance and image data acquisition. This behavior interleaved gradients technique may be particularly useful for the studies involving auditory stimulation or overt verbal responses. Magn Reson Med 41:13‐20, 1999.

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 (Brodmanns 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.

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 childrens 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.