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1.  Segregation of Lexical and Sub-Lexical Reading Processes in the Left Perisylvian Cortex 
PLoS ONE  2012;7(11):e50665.
A fundamental issue in cognitive neuroscience is the existence of two major, sub-lexical and lexical, reading processes and their possible segregation in the left posterior perisylvian cortex. Using cortical electrostimulation mapping, we identified the cortical areas involved on reading either orthographically irregular words (lexical, “direct” process) or pronounceable pseudowords (sublexical, “indirect” process) in 14 right-handed neurosurgical patients while video-recording behavioral effects. Intraoperative neuronavigation system and Montreal Neurological Institute (MNI) stereotactic coordinates were used to identify the localization of stimulation sites. Fifty-one reading interference areas were found that affected either words (14 areas), or pseudo-words (11 areas), or both (26 areas). Forty-one (80%) corresponded to the impairment of the phonological level of reading processes. Reading processes involved discrete, highly localized perisylvian cortical areas with individual variability. MNI coordinates throughout the group exhibited a clear segregation according to the tested reading route; specific pseudo-word reading interferences were concentrated in a restricted inferior and anterior subpart of the left supramarginal gyrus (barycentre x = −68.1; y = −25.9; z = 30.2; Brodmann’s area 40) while specific word reading areas were located almost exclusively alongside the left superior temporal gyrus. Although half of the reading interferences found were nonspecific, the finding of specific lexical or sublexical interferences is new evidence that lexical and sublexical processes of reading could be partially supported by distinct cortical sub-regions despite their anatomical proximity. These data are in line with many brain activation studies that showed that left superior temporal and inferior parietal regions had a crucial role respectively in word and pseudoword reading and were core regions for dyslexia.
doi:10.1371/journal.pone.0050665
PMCID: PMC3511309  PMID: 23226349
2.  Reading the dyslexic brain: multiple dysfunctional routes revealed by a new meta-analysis of PET and fMRI activation studies 
Developmental dyslexia has been the focus of much functional anatomical research. The main trust of this work is that typical developmental dyslexics have a dysfunction of the phonological and orthography to phonology conversion systems, in which the left occipito-temporal cortex has a crucial role. It remains to be seen whether there is a systematic co-occurrence of dysfunctional patterns of different functional systems perhaps converging on the same brain regions associated with the reading deficit. Such evidence would be relevant for theories like, for example, the magnocellular/attentional or the motor/cerebellar ones, which postulate a more basic and anatomically distributed disorder in dyslexia. We addressed this issue with a meta-analysis of all the imaging literature published until September 2013 using a combination of hierarchical clustering and activation likelihood estimation methods. The clustering analysis on 2360 peaks identified 193 clusters, 92 of which proved spatially significant. Following binomial tests on the clusters, we found left hemispheric network specific for normal controls (i.e., of reduced involvement in dyslexics) including the left inferior frontal, premotor, supramarginal cortices and the left infero-temporal and fusiform regions: these were preferentially associated with reading and the visual-to-phonology processes. There was also a more dorsal left fronto-parietal network: these clusters included peaks from tasks involving phonological manipulation, but also motoric or visuo-spatial perception/attention. No cluster was identified in area V5 for no task, nor cerebellar clusters showed a reduced association with dyslexics. We conclude that the examined literature demonstrates a specific lack of activation of the left occipito-temporal cortex in dyslexia particularly for reading and reading-like behaviors and for visuo-phonological tasks. Additional deficits of motor and attentional systems relevant for reading may be associated with altered functionality of dorsal left fronto-parietal cortex.
doi:10.3389/fnhum.2014.00830
PMCID: PMC4227573  PMID: 25426043
developmental dyslexia; meta-analysis; fMRI; PET; ALE; hierarchical clustering
3.  Reading without the left ventral occipito-temporal cortex 
Neuropsychologia  2012;50-360(14):3621-3635.
The left ventral occipito-temporal cortex (LvOT) is thought to be essential for the rapid parallel letter processing that is required for skilled reading. Here we investigate whether rapid written word identification in skilled readers can be supported by neural pathways that do not involve LvOT. Hypotheses were derived from a stroke patient who acquired dyslexia following extensive LvOT damage. The patient followed a reading trajectory typical of that associated with pure alexia, re-gaining the ability to read aloud many words with declining performance as the length of words increased. Using functional MRI and dynamic causal modelling (DCM), we found that, when short (three to five letter) familiar words were read successfully, visual inputs to the patient’s occipital cortex were connected to left motor and premotor regions via activity in a central part of the left superior temporal sulcus (STS). The patient analysis therefore implied a left hemisphere “reading-without-LvOT” pathway that involved STS. We then investigated whether the same reading-without-LvOT pathway could be identified in 29 skilled readers and whether there was inter-subject variability in the degree to which skilled reading engaged LvOT. We found that functional connectivity in the reading-without-LvOT pathway was strongest in individuals who had the weakest functional connectivity in the LvOT pathway. This observation validates the findings of our patient’s case study. Our findings highlight the contribution of a left hemisphere reading pathway that is activated during the rapid identification of short familiar written words, particularly when LvOT is not involved. Preservation and use of this pathway may explain how patients are still able to read short words accurately when LvOT has been damaged.
Highlights
► Word reading can succeed after damage to the left occipito-temporal cortex. ► This is enabled by an alternative pathway via the left superior temporal sulcus. ► Connectivity analysis demonstrated the existence of this pathway in normal readers. ► We hypothesise that this pathway integrates semantics with phonology. ► Our work stresses the importance of mapping alternative degenerate reading pathways.
doi:10.1016/j.neuropsychologia.2012.09.030
PMCID: PMC3524457  PMID: 23017598
Effective connectivity; Alexia; Recovery; Degeneracy; Word reading pathways; Functional MRI
4.  Reading the Wrong Way with the Right Hemisphere 
Brain Sciences  2013;3(3):1060-1075.
Reading is a complex process, drawing on a variety of brain functions in order to link symbols to words and concepts. The three major brain areas linked to reading and phonological analysis include the left temporoparietal region, the left occipitotemporal region and the inferior frontal gyrus. Decreased activation of the left posterior language system in dyslexia is well documented but there is relatively limited attention given to the role of the right hemisphere. The current study investigated differences in right and left hemisphere activation between individuals with dyslexia and non-impaired readers in lexical decision tasks (regular words, irregular words, pseudowords) during functional Magnetic Resonance Imaging (fMRI). Results revealed the expected hypo-activation in the left posterior areas in those with dyslexia but also areas of overactivation in the right hemisphere. During pseudoword decisions, for example, adults with dyslexia showed more right inferior occipital gyrus activation than controls. In general the increased activation of left-hemisphere language areas found in response to both regular and pseudowords was absent in dyslexics. Laterality indices showed that while controls showed left lateralised activation of the temporal lobe during lexical decision making, dyslexic readers showed right activation. Findings will inform theories of reading and will have implications for the design of reading interventions.
doi:10.3390/brainsci3031060
PMCID: PMC4061874  PMID: 24961521
cerebral laterality; dyslexia; fMRI; lexical decision; reading disability; phonological processing
5.  The neural basis of surface dyslexia in semantic dementia 
Brain  2008;132(1):71-86.
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
doi:10.1093/brain/awn300
PMCID: PMC2638692  PMID: 19022856
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI
6.  Visual processing of multiple elements in the dyslexic brain: evidence for a superior parietal dysfunction 
The visual attention (VA) span deficit hypothesis of developmental dyslexia posits that impaired multiple element processing can be responsible for poor reading outcomes. In VA span impaired dyslexic children, poor performance on letter report tasks is associated with reduced parietal activations for multiple letter processing. While this hints towards a non-specific, attention-based dysfunction, it is still unclear whether reduced parietal activity generalizes to other types of stimuli. Furthermore, putative links between reduced parietal activity and reduced ventral occipito-temporal (vOT) in dyslexia have yet to be explored. Using functional magnetic resonance imaging, we measured brain activity in 12 VA span impaired dyslexic adults and 12 adult skilled readers while they carried out a categorization task on single or multiple alphanumeric or non-alphanumeric characters. While healthy readers activated parietal areas more strongly for multiple than single element processing (right-sided for alphanumeric and bilateral for non-alphanumeric), similar stronger multiple element right parietal activations were absent for dyslexic participants. Contrasts between skilled and dyslexic readers revealed significantly reduced right superior parietal lobule (SPL) activity for dyslexic readers regardless of stimuli type. Using a priori anatomically defined regions of interest, we showed that neural activity was reduced for dyslexic participants in both SPL and vOT bilaterally. Finally, we used multiple regressions to test whether SPL activity was related to vOT activity in each group. In the left hemisphere, SPL activity covaried with vOT activity for both normal and dyslexic readers. In contrast, in the right hemisphere, SPL activity covaried with vOT activity only for dyslexic readers. These results bring critical support to the VA interpretation of the VA Span deficit. In addition, they offer a new insight on how deficits in automatic vOT based word recognition could arise in developmental dyslexia.
doi:10.3389/fnhum.2014.00479
PMCID: PMC4083222  PMID: 25071509
developmental dyslexia; visual attention; reading; superior parietal lobes
7.  Reading networks in children with dyslexia compared to children with ocular motility disturbances revealed by fMRI 
Key Points Dyslexia is a neurological disorder with a genetic origin, but the underlying biological and cognitive causes are still being investigated.This study compares the brain activation pattern while reading in Spanish, a semitransparent language, in three groups of children: typically developing readers, dyslexic readers and readers with functional monocular vision.Based on our results Dyslexia would be a neurological disorder not related to vision impairments and would require a multidisciplinary treatment based on improving phonological awareness and language development.
Developmental dyslexia is a neurological disorder the underlying biological and cognitive causes of which are still being investigated, a key point, because the findings will determine the best therapeutic approach to use. Using functional magnetic resonance imaging, we studied the brain activation pattern while reading in the language-related cortical areas from the two reading routes, phonological and orthographic, and the strength of their association with reading scores in 66 Spanish-speaking children aged 9–12 years divided into three groups: typically developing readers (controls), dyslexic readers and readers with monocular vision due to ocular motility disorders but with normal reading development, to assess whether (or not) the neuronal network for reading in children with dyslexia has similarities with that in children with impaired binocular vision due to ocular motility disorders. We found that Spanish-speaking children with dyslexia have a brain circuit for reading that differs from that in children with monocular vision. Individuals with dyslexia tend to hypoactivate some of the language-related areas in the left hemisphere engaged by the phonological route, especially the visual word form area and left Wernicke's area, and try to compensate this deficit by activating language-related areas related to the orthographic route, such as the anterior part of the visual word form area and the posterior part of both middle temporal gyri. That is, they seem to compensate for impairment in the phonological route through orthographic routes of both hemispheres. Our results suggest that ocular motility disturbances do not play a causal role in dyslexia. Dyslexia seems to be a neurological disorder that is unrelated to vision impairments and requires early recognition and multidisciplinary treatment, based on improving phonological awareness and language development, to achieve the best possible outcome.
doi:10.3389/fnhum.2014.00936
PMCID: PMC4237045  PMID: 25477808
developmental dyslexia; fMRI; ocular motility disorders; paradigm; pseudoword
8.  Neural substrates related to auditory working memory comparisons in dyslexia: An fMRI study 
Adult readers with developmental phonological dyslexia exhibit significant difficulty comparing pseudowords and pure tones in auditory working memory (AWM). This suggests deficient AWM skills for adults diagnosed with dyslexia. Despite behavioral differences, it is unknown whether neural substrates of AWM differ between adults diagnosed with dyslexia and normal readers. Prior neuroimaging of adults diagnosed with dyslexia and normal readers, and post-mortem findings of neural structural anomalies in adults diagnosed with dyslexia support the hypothesis of atypical neural activity in temporoparietal and inferior frontal regions during AWM tasks in adults diagnosed with dyslexia. We used fMRI during two binaural AWM tasks (pseudowords or pure tones comparisons) in adults diagnosed with dyslexia (n = 11) and normal readers (n = 11). For both AWM tasks, adults diagnosed with dyslexia exhibited greater activity in left posterior superior temporal (BA 22) and inferior parietal regions (BA 40) than normal readers. Comparing neural activity between groups and between stimuli contrasts (pseudowords vs. tones), adults diagnosed with dyslexia showed greater primary auditory cortex activity (BA 42; tones > pseudowords) than normal readers. Thus, greater activity in primary auditory, posterior superior temporal, and inferior parietal cortices during linguistic and non-linguistic AWM tasks for adults diagnosed with dyslexia compared to normal readers indicate differences in neural substrates of AWM comparison tasks.
doi:10.1017/S1355617708080867
PMCID: PMC3010865  PMID: 18577292
Reading; Language; Linguistics; Adult; Cognition; Speech
9.  Brain Bases of Reading Fluency in Typical Reading and Impaired Fluency in Dyslexia 
PLoS ONE  2014;9(7):e100552.
Although the neural systems supporting single word reading are well studied, there are limited direct comparisons between typical and dyslexic readers of the neural correlates of reading fluency. Reading fluency deficits are a persistent behavioral marker of dyslexia into adulthood. The current study identified the neural correlates of fluent reading in typical and dyslexic adult readers, using sentences presented in a word-by-word format in which single words were presented sequentially at fixed rates. Sentences were presented at slow, medium, and fast rates, and participants were asked to decide whether each sentence did or did not make sense semantically. As presentation rates increased, participants became less accurate and slower at making judgments, with comprehension accuracy decreasing disproportionately for dyslexic readers. In-scanner performance on the sentence task correlated significantly with standardized clinical measures of both reading fluency and phonological awareness. Both typical readers and readers with dyslexia exhibited widespread, bilateral increases in activation that corresponded to increases in presentation rate. Typical readers exhibited significantly larger gains in activation as a function of faster presentation rates than readers with dyslexia in several areas, including left prefrontal and left superior temporal regions associated with semantic retrieval and semantic and phonological representations. Group differences were more extensive when behavioral differences between conditions were equated across groups. These findings suggest a brain basis for impaired reading fluency in dyslexia, specifically a failure of brain regions involved in semantic retrieval and semantic and phonological representations to become fully engaged for comprehension at rapid reading rates.
doi:10.1371/journal.pone.0100552
PMCID: PMC4109933  PMID: 25058010
10.  Sensitivity to Orthographic Familiarity in the Occipito-Temporal Region 
NeuroImage  2007;39(4):1988-2001.
The involvement of the left hemisphere occipito-temporal (OT) junction in reading has been established, yet there is current controversy over the region’s specificity for reading and the nature of its role in the reading process. Recent neuroimaging findings suggest that the region is sensitive to orthographic familiarity (Kronbichler et al., 2007), and the present study tested that hypothesis. Using fMRI, the OT region and other regions in the reading network were localized in 28 adult, right-handed participants. The BOLD signal in these regions was measured during a phonological judgment task (i.e., “Does it sound like a word?”). Stimuli included words, pseudohomophones (phonologically familiar yet orthographically unfamiliar), and pseudowords (phonologically and orthographically unfamiliar) that were matched on lexical properties including sublexical orthography. Relative to baseline, BOLD signal in the OT region was greater for pseudohomophones than for words, suggesting that the region is sensitive to orthographic familiarity at the whole-word level. Further contrasts of orthographic frequency within the word condition revealed increased BOLD signal for low- than high-frequency words. Specialization in the OT area for recognition of frequent letter strings may support the development of reading expertise. Additionally, BOLD signal in the OT region correlates positively with reading efficiency, supporting the idea that this region is a skill zone for reading printed words. BOLD signal in the IFG and STG correlate negatively with reading efficiency, indicating that processing effort in these classic phonological regions is inversely related to reading efficiency.
doi:10.1016/j.neuroimage.2007.10.044
PMCID: PMC2267437  PMID: 18180168
11.  The locus of impairment in English developmental letter position dyslexia 
Many children with reading difficulties display phonological deficits and struggle to acquire non-lexical reading skills. However, not all children with reading difficulties have these problems, such as children with selective letter position dyslexia (LPD), who make excessive migration errors (such as reading slime as “smile”). Previous research has explored three possible loci for the deficit – the phonological output buffer, the orthographic input lexicon, and the orthographic-visual analysis stage of reading. While there is compelling evidence against a phonological output buffer and orthographic input lexicon deficit account of English LPD, the evidence in support of an orthographic-visual analysis deficit is currently limited. In this multiple single-case study with three English-speaking children with developmental LPD, we aimed to both replicate and extend previous findings regarding the locus of impairment in English LPD. First, we ruled out a phonological output buffer and an orthographic input lexicon deficit by administering tasks that directly assess phonological processing and lexical guessing. We then went on to directly assess whether or not children with LPD have an orthographic-visual analysis deficit by modifying two tasks that have previously been used to localize processing at this level: a same-different decision task and a non-word reading task. The results from these tasks indicate that LPD is most likely caused by a deficit specific to the coding of letter positions at the orthographic-visual analysis stage of reading. These findings provide further evidence for the heterogeneity of dyslexia and its underlying causes.
doi:10.3389/fnhum.2014.00356
PMCID: PMC4042363  PMID: 24917802
phonological output deficit; orthographic input lexicon deficit; orthographic-visual analysis deficit; migration errors; substitution errors; developmental dyslexia
12.  A Dual-Route Perspective on Poor Reading in a Regular Orthography: An fMRI Study 
This study examined functional brain abnormalities in dyslexic German readers who – due to the regularity of German in the reading direction – do not exhibit the reading accuracy problem of English dyslexic readers, but suffer primarily from a reading speed problem. The in-scanner task required phonological lexical decisions (i.e., Does xxx sound like an existing word?) and presented familiar and unfamiliar letter strings of existing phonological words (e.g., Taxi-Taksi) together with nonwords (e.g., Tazi). Dyslexic readers exhibited the same response latency pattern (words < pseudohomophones < nonwords) as nonimpaired readers, but latencies to all item types were much prolonged. The imaging results were suggestive for a different neural organization of reading processes in dyslexic readers. Specifically, dyslexic readers, in response to lexical route processes, exhibited underactivation in a left ventral occipitotemporal region which presumably is engaged by visual-orthographic whole word recognition. This region was also insensitive to the increased visual-orthographic processing demands of the sublexical route. Reduced engagement in response to sublexical route processes was also found in a left inferior parietal region, presumably engaged by attentional processes, and in a left inferior frontal region, presumably engaged by phonological processes. In contrast to this reduced engagement of the optimal left hemisphere reading network (ventral OT, inferior parietal, inferior frontal), our dyslexic readers exhibited increased engagement of visual occipital regions and of regions presumably engaged by silent articulatory processes (premotor/motor cortex and subcortical caudate and putamen).
doi:10.1016/j.cortex.2010.06.004
PMCID: PMC3073233  PMID: 20650450
13.  A dual-route perspective on poor reading in a regular orthography: An fMRI study 
This study examined functional brain abnormalities in dyslexic German readers who – due to the regularity of German in the reading direction – do not exhibit the reading accuracy problem of English dyslexic readers, but suffer primarily from a reading speed problem. The in-scanner task required phonological lexical decisions (i.e., Does xxx sound like an existing word?) and presented familiar and unfamiliar letter strings of existing phonological words (e.g., Taxi-Taksi) together with nonwords (e.g., Tazi). Dyslexic readers exhibited the same response latency pattern (words < pseudohomophones < nonwords) as nonimpaired readers, but latencies to all item types were much prolonged. The imaging results were suggestive for a different neural organization of reading processes in dyslexic readers. Specifically, dyslexic readers, in response to lexical route processes, exhibited underactivation in a left ventral occipitotemporal (OT) region which presumably is engaged by visual-orthographic whole word recognition. This region was also insensitive to the increased visual-orthographic processing demands of the sublexical route. Reduced engagement in response to sublexical route processes was also found in a left inferior parietal region, presumably engaged by attentional processes, and in a left inferior frontal region, presumably engaged by phonological processes. In contrast to this reduced engagement of the optimal left hemisphere reading network (ventral OT, inferior parietal, inferior frontal), our dyslexic readers exhibited increased engagement of visual occipital regions and of regions presumably engaged by silent articulatory processes (premotor/motor cortex and subcortical caudate and putamen).
doi:10.1016/j.cortex.2010.06.004
PMCID: PMC3073233  PMID: 20650450
Developmental dyslexia; fMRI; Reading; Phonological lexical decision; Dual-route
14.  Dysfunctional visual word form processing in progressive alexia 
Brain  2013;136(4):1260-1273.
Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the ‘visual word form area’. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.
doi:10.1093/brain/awt034
PMCID: PMC3613714  PMID: 23471694
progressive alexia; letter-by-letter reading; posterior cortical atrophy; logopenic primary progressive aphasia; visual word form system
15.  Fast, visual specialization for reading in English revealed by the topography of the N170 ERP response 
Background
N170 effects associated with visual words may be related to perceptual expertise effects that have been demonstrated for faces and other extensively studied classes of visual stimuli. Although face and other object expertise effects are typically bilateral or right-lateralized, the spatial topography of reading-related N170 effects are often left-lateralized, providing potential insights into the unique aspects of reading-related perceptual expertise.
Methods
Extending previous research in German [1], we use a high-density channel array to characterize the N170 topography for reading-related perceptual expertise in English, a language with inconsistent spelling-to-sound mapping. N170 effects related to overall reading-related expertise are defined by contrasting responses to visual words versus novel symbol strings. By contrasting each of these conditions to pseudowords, we examined how this reading-related N170 effect generalizes to well-ordered novel letter strings.
Results
A sample-by-sample permutation test computed on word versus symbol ERP topographies revealed differences during two time windows corresponding to the N170 and P300 components. Topographic centroid analysis of the word and symbol N170 demonstrated significant differences in both left-right as well as inferior-superior dimensions. Words elicited larger N170 negativities than symbols at inferior occipito-temporal channels, with the maximal effect over left inferior regions often unsampled in conventional electrode montages. Further contrasts produced inferior-superior topographic effects for the pseudoword-symbol comparison and left-lateralized topographic effects for the word-pseudoword comparison.
Conclusion
Fast specialized perception related to reading experience produces an N170 modulation detectable across different EEG systems and different languages. Characterization of such effects may be improved by sampling with greater spatial frequency recordings that sample inferior regions. Unlike in German, reading-related expertise effects in English produced only partial generalization in N170 responses to novel pseudowords. The topographic inferior-superior N170 differences may reflect general perceptual expertise for orthographic strings, as it was found for words and pseudowords across both languages. The topographic left-right N170 difference between words and pseudowords was only found in English, and may suggest that ambiguity in pronunciating novel pseudowords due to inconsistency in spelling-to-sound mapping influences early stages of letter string processing.
doi:10.1186/1744-9081-1-13
PMCID: PMC1208852  PMID: 16091138
16.  Fixation-Related fMRI Analysis in the Domain of Reading Research: Using Self-Paced Eye Movements as Markers for Hemodynamic Brain Responses During Visual Letter String Processing 
Cerebral Cortex (New York, NY)  2013;24(10):2647-2656.
The present study investigated the feasibility of using self-paced eye movements during reading (measured by an eye tracker) as markers for calculating hemodynamic brain responses measured by functional magnetic resonance imaging (fMRI). Specifically, we were interested in whether the fixation-related fMRI analysis approach was sensitive enough to detect activation differences between reading material (words and pseudowords) and nonreading material (line and unfamiliar Hebrew strings). Reliable reading-related activation was identified in left hemisphere superior temporal, middle temporal, and occipito-temporal regions including the visual word form area (VWFA). The results of the present study are encouraging insofar as fixation-related analysis could be used in future fMRI studies to clarify some of the inconsistent findings in the literature regarding the VWFA. Our study is the first step in investigating specific visual word recognition processes during self-paced natural sentence reading via simultaneous eye tracking and fMRI, thus aiming at an ecologically valid measurement of reading processes. We provided the proof of concept and methodological framework for the analysis of fixation-related fMRI activation in the domain of reading research.
doi:10.1093/cercor/bht117
PMCID: PMC4153805  PMID: 23645718
cerebrum; functional magnetic resonance imaging; language; visual word form area; visual word recognition
17.  Grey Matter Alterations Co-Localize with Functional Abnormalities in Developmental Dyslexia: An ALE Meta-Analysis 
PLoS ONE  2012;7(8):e43122.
The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions.
doi:10.1371/journal.pone.0043122
PMCID: PMC3423424  PMID: 22916214
18.  Cortical thickness abnormalities associated with dyslexia, independent of remediation status 
NeuroImage : Clinical  2014;7:177-186.
Abnormalities in cortical structure are commonly observed in children with dyslexia in key regions of the “reading network.” Whether alteration in cortical features reflects pathology inherent to dyslexia or environmental influence (e.g., impoverished reading experience) remains unclear. To address this question, we compared MRI-derived metrics of cortical thickness (CT), surface area (SA), gray matter volume (GMV), and their lateralization across three different groups of children with a historical diagnosis of dyslexia, who varied in current reading level. We compared three dyslexia subgroups with: (1) persistent reading and spelling impairment; (2) remediated reading impairment (normal reading scores), and (3) remediated reading and spelling impairments (normal reading and spelling scores); and a control group of (4) typically developing children. All groups were matched for age, gender, handedness, and IQ. We hypothesized that the dyslexia group would show cortical abnormalities in regions of the reading network relative to controls, irrespective of remediation status. Such a finding would support that cortical abnormalities are inherent to dyslexia and are not a consequence of abnormal reading experience. Results revealed increased CT of the left fusiform gyrus in the dyslexia group relative to controls. Similarly, the dyslexia group showed CT increase of the right superior temporal gyrus, extending into the planum temporale, which resulted in a rightward CT asymmetry on lateralization indices. There were no group differences in SA, GMV, or their lateralization. These findings held true regardless of remediation status. Each reading level group showed the same “double hit” of atypically increased left fusiform CT and rightward superior temporal CT asymmetry. Thus, findings provide evidence that a developmental history of dyslexia is associated with CT abnormalities, independent of remediation status.
Highlights
•Rightward superior temporal cortical thickness asymmetry in dyslexia•Increased left fusiform gyrus thickness in dyslexia•Primary effects present across three subgroups with differing reading levels•Cortical thickness findings were independent from volume and surface area.•“Double hit” of left fusiform anomaly and rightward temporal asymmetry in dyslexia
doi:10.1016/j.nicl.2014.11.005
PMCID: PMC4300011  PMID: 25610779
Dyslexia; MRI; Lateralization; Cortical thickness; Surface area; Gray matter volume
19.  Developmental dyslexia: dysfunction of a left hemisphere reading network 
This mini-review summarizes and integrates findings from recent meta-analyses and original neuroimaging studies on functional brain abnormalities in dyslexic readers. Surprisingly, there is little empirical support for the standard neuroanatomical model of developmental dyslexia, which localizes the primary phonological decoding deficit in left temporo-parietal (TP) regions. Rather, recent evidence points to a dysfunction of a left hemisphere reading network, which includes occipito-temporal (OT), inferior frontal, and inferior parietal regions.
doi:10.3389/fnhum.2012.00120
PMCID: PMC3340948  PMID: 22557962
brain; developmental dyslexia; fMRI; meta-analysis; neuroimaging; reading
20.  Dissociations between developmental dyslexias and attention deficits 
Frontiers in Psychology  2015;5:1501.
We examine whether attention deficits underlie developmental dyslexia, or certain types of dyslexia, by presenting double dissociations between the two. We took into account the existence of distinct types of dyslexia and of attention deficits, and focused on dyslexias that may be thought to have an attentional basis: letter position dyslexia (LPD), in which letters migrate within words, attentional dyslexia (AD), in which letters migrate between words, neglect dyslexia, in which letters on one side of the word are omitted or substituted, and surface dyslexia, in which words are read via the sublexical route. We tested 110 children and adults with developmental dyslexia and/or attention deficits, using extensive batteries of reading and attention. For each participant, the existence of dyslexia and the dyslexia type were tested using reading tests that included stimuli sensitive to the various dyslexia types. Attention deficit and its type was established through attention tasks assessing sustained, selective, orienting, and executive attention functioning. Using this procedure, we identified 55 participants who showed a double dissociation between reading and attention: 28 had dyslexia with normal attention and 27 had attention deficits with normal reading. Importantly, each dyslexia with suspected attentional basis dissociated from attention: we found 21 individuals with LPD, 13 AD, 2 neglect dyslexia, and 12 surface dyslexia without attention deficits. Other dyslexia types (vowel dyslexia, phonological dyslexia, visual dyslexia) also dissociated from attention deficits. Examination of 55 additional individuals with both a specific dyslexia and a certain attention deficit found no attention function that was consistently linked with any dyslexia type. Specifically, LPD and AD dissociated from selective attention, neglect dyslexia dissociated from orienting, and surface dyslexia dissociated from sustained and executive attention. These results indicate that visuospatial attention deficits do not underlie these dyslexias.
doi:10.3389/fpsyg.2014.01501
PMCID: PMC4290487  PMID: 25628578
developmental dyslexia; attention; letter position dyslexia; attentional dyslexia; dissociation; neglect dyslexia; surface dyslexia
21.  Developmental dyslexia in Chinese and English populations: dissociating the effect of dyslexia from language differences 
Brain  2010;133(6):1694-1706.
Previous neuroimaging studies have suggested that developmental dyslexia has a different neural basis in Chinese and English populations because of known differences in the processing demands of the Chinese and English writing systems. Here, using functional magnetic resonance imaging, we provide the first direct statistically based investigation into how the effect of dyslexia on brain activation is influenced by the Chinese and English writing systems. Brain activation for semantic decisions on written words was compared in English dyslexics, Chinese dyslexics, English normal readers and Chinese normal readers, while controlling for all other experimental parameters. By investigating the effects of dyslexia and language in one study, we show common activation in Chinese and English dyslexics despite different activation in Chinese versus English normal readers. The effect of dyslexia in both languages was observed as less than normal activation in the left angular gyrus and in left middle frontal, posterior temporal and occipitotemporal regions. Differences in Chinese and English normal reading were observed as increased activation for Chinese relative to English in the left inferior frontal sulcus; and increased activation for English relative to Chinese in the left posterior superior temporal sulcus. These cultural differences were not observed in dyslexics who activated both left inferior frontal sulcus and left posterior superior temporal sulcus, consistent with the use of culturally independent strategies when reading is less efficient. By dissociating the effect of dyslexia from differences in Chinese and English normal reading, our results reconcile brain activation results with a substantial body of behavioural studies showing commonalities in the cognitive manifestation of dyslexia in Chinese and English populations. They also demonstrate the influence of cognitive ability and learning environment on a common neural system for reading.
doi:10.1093/brain/awq106
PMCID: PMC2877905  PMID: 20488886
dyslexia; fMRI; language processing; cognitive impairment; developmental neuroimaging
22.  Reading Disorders in Primary Progressive Aphasia: a behavioral and neuroimaging study 
Neuropsychologia  2009;47(8-9):1893-1900.
Previous neuropsychological studies on acquired dyslexia revealed a double dissociation in reading impairments. Patients with phonological dyslexia have selective difficulty reading pseudo-words, while those with surface dyslexia misread exception words. This double dissociation in reading abilities has often been reported in brain damaged patients, but it has not been consistently shown in patients with neurodegenerative diseases.
In this study, we investigated reading impairments and their anatomical correlates in various neurodegenerative diseases. First, we performed a behavioral analysis to characterize the reading of different word types in primary progressive aphasia (PPA). Then, we conducted a voxel-based morphometry neuroimaging study to map the brain areas in which gray matter volume correlated with accurate reading of exception and pseudo-words.
The results showed a differential pattern of exception and pseudo-word reading abilities in different clinical variants of PPA. Patients with semantic dementia, a disorder characterized by selective loss of semantic memory, revealed a pattern of surface dyslexia, while patients with logopenic/phonological progressive aphasia, defined by phonological loop deficits, showed phonological dyslexia. Neuroimaging results showed that exception word reading accuracy correlated with gray matter volume in the left anterior temporal structures, including the temporal pole, the anterior superior and middle temporal and fusiform gyri, while pseudo-word reading accuracy correlated with left temporoparietal regions, including the posterior superior and middle temporal and fusiform gyri, and the inferior parietal lobule.
These results suggest that exception and pseudo-word reading not only rely upon different language mechanisms selectively damaged in PPA, but also that these processes are sustained by separate brain structures.
doi:10.1016/j.neuropsychologia.2009.02.033
PMCID: PMC2734967  PMID: 19428421
exception words; pseudo-words; neurodegenerative diseases; voxel-based morphometry
23.  Neural Correlates of Letter Reversal in Children and Adults 
PLoS ONE  2014;9(5):e98386.
Children often make letter reversal errors when first learning to read and write, even for letters whose reversed forms do not appear in normal print. However, the brain basis of such letter reversal in children learning to read is unknown. The present study compared the neuroanatomical correlates (via functional magnetic resonance imaging) and the electrophysiological correlates (via event-related potentials or ERPs) of this phenomenon in children, ages 5–12, relative to young adults. When viewing reversed letters relative to typically oriented letters, adults exhibited widespread occipital, parietal, and temporal lobe activations, including activation in the functionally localized visual word form area (VWFA) in left occipito-temporal cortex. Adults exhibited significantly greater activation than children in all of these regions; children only exhibited such activation in a limited frontal region. Similarly, on the P1 and N170 ERP components, adults exhibited significantly greater differences between typical and reversed letters than children, who failed to exhibit significant differences between typical and reversed letters. These findings indicate that adults distinguish typical and reversed letters in the early stages of specialized brain processing of print, but that children do not recognize this distinction during the early stages of processing. Specialized brain processes responsible for early stages of letter perception that distinguish between typical and reversed letters may develop slowly and remain immature even in older children who no longer produce letter reversals in their writing.
doi:10.1371/journal.pone.0098386
PMCID: PMC4032318  PMID: 24859328
24.  Similar alterations in brain function for phonological and semantic processing to visual characters in Chinese dyslexia 
Neuropsychologia  2012;50(9):2224-2232.
Dyslexia in alphabetic languages has been extensively investigated and suggests a central deficit in orthography to phonology mapping in the left hemisphere. Compared to dyslexia in alphabetic languages, the central deficit for Chinese dyslexia is still unclear. Because of the logographic nature of Chinese characters, some have suggested that Chinese dyslexia should have larger deficits in the semantic system. To investigate this, Chinese children with reading disability (RD) were compared to typically developing (TD) children using functional magnetic resonance imaging (fMRI) on a rhyming judgment task and on a semantic association judgment task. RD children showed less activation for both tasks in right visual (BA18, 19) and left occipito-temporal cortex (BA 37), suggesting a deficit in visuo-orthographic processing. RD children also showed less activation for both tasks in left inferior frontal gyrus (BA44), which additionally showed significant correlations with activation of bilateral visuo-orthographic regions in the RD group, suggesting that the abnormalities in frontal cortex and in posterior visuo-orthographic regions may reflect a deficit in the connection between brain regions. Analyses failed to reveal larger differences between groups for the semantic compared to the rhyming task, suggesting that Chinese dyslexia is similarly impaired in the access to phonology and to semantics from the visual orthography.
doi:10.1016/j.neuropsychologia.2012.05.026
PMCID: PMC3987122  PMID: 22698991
Chinese dyslexia; Orthography; Phonology; Semantics
25.  Not All Reading Disabilities Are Dyslexia: Distinct Neurobiology of Specific Comprehension Deficits 
Brain Connectivity  2013;3(2):199-211.
Abstract
Although an extensive literature exists on the neurobiological correlates of dyslexia (DYS), to date, no studies have examined the neurobiological profile of those who exhibit poor reading comprehension despite intact word-level abilities (specific reading comprehension deficits [S-RCD]). Here we investigated the word-level abilities of S-RCD as compared to typically developing readers (TD) and those with DYS by examining the blood oxygenation-level dependent response to words varying on frequency. Understanding whether S-RCD process words in the same manner as TD, or show alternate pathways to achieve normal word-reading abilities, may provide insights into the origin of this disorder. Results showed that as compared to TD, DYS showed abnormal covariance during word processing with right-hemisphere homologs of the left-hemisphere reading network in conjunction with left occipitotemporal underactivation. In contrast, S-RCD showed an intact neurobiological response to word stimuli in occipitotemporal regions (associated with fast and efficient word processing); however, inferior frontal gyrus (IFG) abnormalities were observed. Specifically, TD showed a higher-percent signal change within right IFG for low-versus-high frequency words as compared to both S-RCD and DYS. Using psychophysiological interaction analyses, a coupling-by-reading group interaction was found in right IFG for DYS, as indicated by a widespread greater covariance between right IFG and right occipitotemporal cortex/visual word-form areas, as well as bilateral medial frontal gyrus, as compared to TD. For S-RCD, the context-dependent functional interaction anomaly was most prominently seen in left IFG, which covaried to a greater extent with hippocampal, parahippocampal, and prefrontal areas than for TD for low- as compared to high-frequency words. Given the greater lexical access demands of low frequency as compared to high-frequency words, these results may suggest specific weaknesses in accessing lexical-semantic representations during word recognition. These novel findings provide foundational insights into the nature of S-RCD, and set the stage for future investigations of this common, but understudied, reading disorder.
doi:10.1089/brain.2012.0116
PMCID: PMC3634135  PMID: 23273430
dyslexia; fMRI; reading comprehension; reading disorder; specific comprehension deficits

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