Altering the Brain Circuits for Reading Through Intervention:A Magnetic Source Imaging Study

Panagiotis G. SimosUniversity of Texas, Health Science Center—Houston

Jack M. FletcherUniversity of Houston

Shirin Sarkari and Rebecca L. BillingsleyUniversity of Texas, Health Science Center—Houston

Carolyn DentonUniversity of Texas at Austin

Andrew C. PapanicolaouUniversity of Texas, Health Science Center—Houston

Intervention-related changes in spatiotemporal profiles of regional brain activation were examined bywhole-head magnetoencephalography in 15 children with severe reading difficulties who had failed toshow adequate progress to quality reading instruction during Grade 1. Intensive intervention initiallyfocused on phonological decoding skills (for 8 weeks) and, during the subsequent 8 weeks, on rapid wordrecognition ability. Clinically significant improvement in reading skills was noted in 8 children whoshowed “normalizing” changes in their spatiotemporal profiles of regional brain activity (increasedduration of activity in the left temporoparietal region and a shift in the relative timing of activity intemporoparietal and inferior frontal regions). Seven children who demonstrated “compensatory” changesin brain activity (increased duration of activity in the right temporoparietal region and frontal areas,bilaterally) did not show adequate response to intervention. Nonimpaired readers did not show systematicchanges in brain activity across visits.

Keywords: Magnetoencephalography, functional brain imaging, dyslexia, phonology, training

Supplemental material: http://dx.doi.org/10.1037/0894-4105.21.4.485.supp

Developmental reading disability is most frequently manifestedas a persistent difficulty in acquiring key component skills thatnormally ensure accurate and fluent word recognition. These skillsinclude phonological processing of spoken language, graphemicanalysis, familiarity with the alphabetic principle, phonologicaldecoding, and memory of word forms. This difficulty is typicallyresistant to regular classroom instruction, yet intensive tutoring orsmall group instruction has been shown to be very effective inimproving reading skills (Lyon, Fletcher, Fuchs, & Chlabra, 2006).

There have been several reports of neurophysiological indices ofimpaired auditory and visual (print) processing among childrenand adults with (or at risk for) dyslexia (Breznitz, 2003; Heleniuset al., 2002; Molfese et al., 2006). A large number of studiesutilizing a variety of brain imaging techniques have demonstrated

evidence of reduced engagement of posterior left-hemisphere re-gions in children with word-level reading disabilities (RDs), alongwith evidence of increased involvement of frontal lobe and pos-terior right hemisphere regions (see reviews in Alexander &Slinger-Constant, 2004; Moats, 2004; Noble & McCandliss, 2005;S. E. Shaywitz & Shaywitz, 2004). Given that these differencesappear to be present early during the reading acquisition process,often in spite of adequate classroom reading instruction (Simos,Fletcher, Sarkari, et al., 2005), it is imperative to assess whetherthe aberrant developmental trajectory of the brain mechanism forreading can be altered in RD.

Studies using hemodynamic measures of brain activity in readingtasks before and after brief interventions report both “normalizing”and “compensatory” changes (Aylward et al., 2003; Eden et al., 2004;B. A. Shaywitz et al., 2004; Temple, Deutsch, & Poldrack, 2003). Itis important to note that these terms are henceforth used to describethe status of the brain mechanism responsible for reading rather thanthe phenomenon for which this mechanism is responsible (see Templeet al., 2003). In this framework, normalizing changes were consideredto be those that appeared to “restore” the functionality of brain circuitsfor reading to resemble that observed in typical readers without ahistory of dyslexia, consisting mainly of increased temporoparietalactivity. Compensatory changes are considered to be those indicativeof the institution of alternate circuits for reading, consisting mainly ofincreased hemodynamic responsivity in right temporoparietal andinferior frontal regions.

Although these findings provide very useful insights into thetype of functional brain reorganization that takes place in responseto systematic reading instruction, they provide little information

Panagiotis G. Simos, Shirin Sarkari, Rebecca L. Billingsley, and AndrewC. Papanicolaou, Department of Neurosurgery, Vivian L. Smith Institute ofNeurologic Research, University of Texas, Health Science Center—Hous-ton; Jack M. Fletcher, Department of Psychology, University of Houston;Carolyn Denton, Department of Special Education, University of Texas atAustin.

This work was supported by Major Instrumentation Grant BCS-0116150from the National Science Foundation and Grant RO1 HD38346 from theNational Institute of Child Health and Development to Andrew C. Papa-nicolaou and Interagency Education Research Initiative GrantREC-9979968 to Jack M. Fletcher.

Correspondence concerning this article should be addressed to Panagio-tis G. Simos, who is now at the Department of Psychology, University ofCrete, Rethymno, Crete, Greece. E-mail: psimos@psy.soc.uoc.gr

Neuropsychology Copyright 2007 by the American Psychological Association2007, Vol. 21, No. 4, 485–496 0894-4105/07/$12.00 DOI: 10.1037/0894-4105.21.4.485

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regarding the relative timing of neurophysiological activity. Thisactivity takes place within the first few hundred millisecondsfollowing the presentation of a printed stimulus leading up to thepoint when a verbal or manual response is produced by theparticipant. This issue has been addressed in two recent studieswith magnetoencephalography (MEG), a method that possessesadequate spatial and temporal resolution and accuracy to meet theaforementioned goal.

In the earlier study conducted with MEG (Simos et al., 2002), 8children with severe RD 7–17 years of age were tested before andafter an 8-week intensive intervention program that focused on thedevelopment of phonological awareness and decoding skills (Phono-Graphix; McGuiness, McGuiness, & McGuiness, 1996). All childrenwho had severe reading difficulties showed a clinically significantimprovement in reading skills, scoring within the average range onstandardized measures of phonological decoding. Neurophysiologicalchanges were also dramatic, consisting primarily of normalizingtrends, so that children with RD did not differ from controls in thedegree of left temporoparietal activity at the end of the study period.However, the type of whole-head magnetometer device used in thatstudy may not have been sufficiently sensitive to reveal (a) compen-satory changes, especially those involving increased activity in infe-rior frontal regions, and (b) the detailed temporal progression of brainactivity among active regions. Moreover, the limited sample did notpermit examination of systematic individual differences in the patternof change in brain activity.

In the second study, spatiotemporal profiles of brain activity wereobtained during performance of a reading task involving high-fre-quency words before and after intensive reading intervention. Partic-ipants were 15 Grade 2 children who had failed to show adequateprogress in basic reading skills in response to supplemental instructionduring Grade 1 (Simos et al., 2007). Before the intervention, brainactivity was detected primarily in ventral and lateral extrastriate areas,in the posterior portion of the middle temporal gyrus (Brodmann’sarea [BA] 21), and in the inferior frontal and premotor regions,bilaterally. Across three visits, the duration of magnetic activity inBA 21 increased linearly. Moreover, systematic changes were de-tected in the onset latency of regional activity that were essentiallynormalizing: There was an increase in onset latency in premotorregions and a decrease in the onset of activity in BA 21 and extra-striate areas, establishing the temporal progression of activity that istypical of nonimpaired readers.

The present study extends these magnetic source imaging (MSI)results by examining a sample of children who were demonstrablyinadequate responders to effective reading intervention. Thesechildren received a more comprehensive two-stage interventionfocusing during the first 8 weeks on phonological decoding skillsand during the subsequent 8 weeks on rapid word recognition, andallowing for two post-intervention scans. A state-of-the-art neuro-magnetometer was used, affording greater sensitivity in examiningtemporal as well as regional anatomical features of task-specificactivation profiles. We examined individual differences in re-sponse to intervention as a function of the specific changes that thespatiotemporal profile of brain activation had undergone, hypoth-esizing specifically that profiles associated with a positive responseto intervention would resemble those of typically achieving read-ers and that profiles for inadequate responders would show lesschange and parallel those observed in children and adults with RD.

Method

Participants

This study involved a group of children who had been identifiedas at-risk for reading difficulties at the end of kindergarten andreceived a Grade 1 intervention (reported in Mathes et al., 2005).They were selected from the population of six non–Title 1 schoolsin a large urban school district in Texas. These schools wereselected because of evidence indicating that they had adequatecore reading programs. The risk status of all children in kinder-garten in these schools was evaluated with the teacher-adminis-tered Texas Primary Reading Inventory (TPRI; Fletcher et al.,2002). Those children who were identified as at risk on the basisof the screening section from the TPRI received additional stan-dardized assessments of word recognition and text reading toeliminate potential false positives, as the TPRI was designed tominimize the risk of missing children who might have readingproblems, with the expected consequence of higher rates of falsepositives.

The 298 at-risk students were randomly assigned to three read-ing interventions in Grade 1 (Mathes et al., 2005) consisting of (a)enhanced classroom reading instruction in which classroom teach-ers were receiving extensive professional development in readinginstruction, with monitoring of oral reading fluency (n � 114) or(b) one of two different daily small-group supplemental interven-tions (n � 92 each) for 40 min a day over 30 weeks. In anevaluation of these reading interventions, Mathes et al. (2005)reported that students who received either of the two supplementalinterventions performed significantly better on several measures ofreading achievement at the end of Grade 1, as compared withstudents who were at risk but only received enhanced classroominstruction. Across all three interventions, 7% of the participantshad scores below the 31st percentile on measures of word decod-ing, which was less than 2% of the student population. Thesestudents, who represented inadequate responders to reading in-struction that was effective for most participants, were the focus ofanother intervention in Grades 2 and 3 (Denton, Fletcher, Anthony,& Francis, 2006). Both accuracy and fluency criteria were used todetermine eligibility for the intervention study on the basis ofgrade-level benchmarks (Basic Reading Composite � 30th per-centile; reading fluency on a progress monitoring fluencyprobe � 40 words per minute). The 27 students who met theinclusion criteria received a 16-week intervention package thatwas entirely different than the intervention they had receivedduring Grade 1 in both content and intensity. During the first 8weeks, intervention focused on the development of decoding skills(based on the Phono-Graphix program; McGuiness et al., 1996)and was provided for 2 hr per day for 8 weeks. During the next 8weeks, intervention varied by providing instruction aimed at thedevelopment of efficient word recognition skills. This secondprogram was based on the Read Naturally program (Ihnot, Mast-off, Gavin, & Hendrickson, 2001) and involved 1 hr of dailyinstruction. A subset of these students volunteered for a MEGimaging study, which took place before the 16-week interventionand after each of the two intervention phases, with 15 studentsproviding adequate MEG recordings at all three time points. Of theother 12 students, most had dental work that precluded participa-tion, and one did not return for all the recording sessions. Hence-

486 SIMOS ET AL.

forth, the term intervention refers to the 16-week interventionprogram which is the primary focus of this study. The effects of thesupplemental instruction during Grade 1 are described in detailelsewhere (Mathes et al., 2005; Simos et al., 2005).

Table 1 displays group scores on the Sight Word andPseudoword Efficiency subtests of the Test of Word ReadingEfficiency (TOWRE; Form A; Torgesen, Wagner, & Rashotte,1999) and the Word Attack and Letter–Word Identificationsubtests of the Woodcock–Johnson III Psychoeducational Battery(Woodcock, McGrew, & Mather, 2001), collected independentlyof the intervention study. Baseline scores prior to interventionindicate group mean performance that was at least one standarddeviation below average on untimed measures of word andpseudoword reading accuracy, with particularly low performanceon oral reading efficiency.

Individual differences in response to intervention were assessedon a group basis with change in standard score on the BasicReading Composite between baseline and last visit as an index (a10-point difference cutoff was used, representing the medianamount of change). This measure was used because few studentsachieved grade-level fluency benchmarks and because it is gener-ally more stable than scores on either Word Attack or Letter–WordIdentification subtests alone. Among the sample, 8 children wereclassified as responders, demonstrating a mean improvement onthe Basic Reading Composite of 15 � 3 points, and 7 wereclassified as nonresponders, improving by only 4 � 3 points.Although Table 1 shows that the responder and nonrespondergroups were not comparable at baseline on reading measures (seeTable 1), which is not surprising given that they differed inresponder status at the end of the study, their brain activationprofiles were similar, as described in greater detail below.

A second group of 10 non–reading impaired children who hadnever experienced difficulties in learning to read were tested on threeoccasions over a 6-month period on the same activation tasks toensure that any changes observed over time in the RD group were notdue to confounding factors such as maturation, repeated exposure tothe stimuli, or habituation to the testing procedures. The RD groupincluded 6 boys and 9 girls ages 93–116 months (M � 105 months),with 10 children of African American descent, 2 Hispanic children,and 3 Caucasian children. Most were in Grade 3 (n � 8), with 5 inGrade 2, and 2 retained in Grade 1. Among the participants, 12 hadpreviously received enhanced classroom instruction, whereas 3 had

received both enhanced classroom instruction and a supplementalintervention. There were 7 boys and 3 girls in the non–readingimpaired group, ages 94–122 months (M � 103 months), with 2 ofAfrican American descent, 5 Hispanic children, and 3 Caucasianchildren. All children spoke English as their primary language. Sta-tistical comparisons for age, gender, and ethnicity were not signifi-cant, but the samples are small. Although the groups were comparablein age, the non–reading impaired group tended to have more girls andmore Hispanic than African-American children. We have not ob-served effects of ethnicity or gender in previous MEG studies ofreading.

Procedure

MSI scans were acquired while children performed apseudoword reading task, with three-letter pronounceable non-words (e.g., lan) subtending 2.0o of visual angle. The printedstimuli were projected centrally for 1,500 ms, one at a time (witha randomly varied interstimulus interval of 3–4 s) through an LCDprojector (Sharp Model XG-E690U) on a back-projection screenlocated approximately 60 cm in front of the participant. Thechildren were instructed to read the “made-up” words as soon asthey disappeared from the screen to avoid contamination of theMEG data segments by movement-related magnetic artifacts.Stimuli for each task were arranged randomly into four blocksof 25 items. The stimuli for the activation task were initiallychosen in order to ensure relatively high performance level for allparticipants and prevent floor effects by RD children at baselinewhile still requiring phonological decoding processes.

MSI scans were obtained with a whole-head neuromagneto-meter array (4-D Neuroimaging, Magnes WH3600), which con-sisted of 248 first-order axial gradiometer coils, housed in a mag-netically shielded chamber and arranged to cover the entire headsurface. The methods used for signal processing, source localiza-tion, and precise co-registration with the patient’s structural MRIscans are described in detail elsewhere (Simos et al., 1999).Briefly, the magnetic flux measurements were filtered with abandpass filter between 0.1 and 20 Hz and digitized at 250 Hz. Thesingle-trial event-related field segments (ERFs) in response to50–70 stimulus presentations were averaged after excluding thosecontaining eye movement or other myogenic or mechanical arti-facts. The resulting averaged ERFs, in all cases, consisted of an

Table 1Standardized Measures of Reading Skill at the First and Last MagnetoencephalographyRecording Sessions

Measure

Responders(n � 8)

Non-responders(n � 7)

Averagereaders

(n � 10)

Baseline 3rd visit Baseline 3rd visit Baseline

M (SD) M (SD) M (SD) M (SD) M (SD)

WJ-III Letter-Word Identification 73 (7) 80 (8) 80 (3) 83 (3) 103 (9)WJ-III Word Attack 76 (8) 96 (8) 85 (2) 91 (4) 108 (13)TOWRE Words 81 (4) 92 (4) 75 (6) 80 (7) 104 (6)TOWRE Pseudowords 83 (4) 90 (4) 74 (5) 77 (6) 103 (6)

Note. WJ-III � Woodcock-Johnson III Achievement Battery; TOWRE � Test of Word Reading Efficiency.

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early portion (typically between 30- and 150-ms post-stimulusonset) and a late portion (typically between 150 and 1,000 mspost-stimulus onset). To identify the intracranial origin of ERFs,we analyzed the magnetic flux distribution that had been recordedsimultaneously over the entire head surface at successive points (4ms apart), thus preserving the temporal information that is inherentin the MEG methodology.

The analysis consisted of the application of a mathematicalmodel that considered the intracranial activity sources (sets ofactive neurons) as equivalent to physical current dipoles embeddedin a spherical conductor approximating the local skull curvature(Sarvas, 1987) and was intended to provide estimates of thelocation and strength of these sources, the activity of which hadproduced the recorded magnetic flux at each time point. Occasion-ally, two distinct dipolar distributions were visually identified at asingle time point over a given hemisphere. In those instances,source estimation was performed independently with data from asubset of magnetic sensors covering both extrema of each dipolardistribution. In order to avoid localization errors produced bysmearing of the magnetic flux from one source by the flux inducedby the other source, we retained two simultaneous source solutionsonly if the corresponding dipoles were at least 5 cm apart. Withthis method, no more than two sources, located in different ana-tomical regions, can be computed in each hemisphere at each 4-mstime bin. Therefore, a maximum number of (970 ms /4 ms) � 2sources � 484 sources could be computed for each hemisphereduring each epoch for the time period included in the analysis.

The location estimates of each “dipolar” source were specified withreference to a Cartesian coordinate system and anchored on threefiducial points on the head (the nasion and the external meatus of eachear). The same fiducial points were marked with vitamin pills, thusenabling precise registration of the location of each dipolar source onthe participants’ high-resolution, T1-weighted MRI scans. Activitysources were found in a significant proportion of participants duringat least one visit (80/150 hemispheres [25 participants � 3 visits � 2hemispheres], binomial test p � .05) in the following areas: posteriorportion of the superior temporal gyrus (BA 22), supramarginal gyrus(BA 40), angular gyrus (BA 39), inferior frontal gyrus (BA 44/45),premotor cortex (BA 6), ventral occipitotemporal cortex (BA 37),lateral occipitotemporal cortex (BA 19), middle temporal gyrus (BA21), and mesial temporal cortex (hippocampus and parahippocampalgyrus). Activity sources in mesial temporal cortices may reflect theinvolvement of short-term memory processes associated with therequirement for brief maintenance of the phonological/articulatoryrepresentation of the pseudoword stimuli before producing a (de-layed) response.

Spatiotemporal profiles of brain magnetic activity were quanti-fied by two complementary variables that were analyzed sepa-rately. One was the number of dipolar sources that were consis-tently localized in a particular area for longer than 12 ms at a time.Activity sources meeting this criterion were consistently identified,across participants, in the nine areas listed above. This measurewas used as an index for the total duration of neurophysiologicalactivity that takes place during stimulus processing and prior to theinitiation of an overt behavioral response (pronunciation of theword). In the context of large-scale studies with both neurologi-cally intact volunteers and patients, this measure has been found tobe the most reliable and valid index of the degree of regionalcerebral activation that is specific to various language functions

(Maestu et al., 2002; Papanicolaou et al., 2004; Szymanski et al.,2001). For the purposes of the parametric analyses, the data werenormalized separately for each participant on the basis of the totalnumber of activity sources found anywhere in the brain for a givenrecording session. This was done to control for potential fluctua-tions in the signal-to-noise ratio of MEG recordings across ses-sions, which could affect the likelihood of obtaining satisfactorydipole fits. The second measure used in the present study reflectedthe onset of regional activity in each area, in milliseconds afterstimulus onset.

Data on the number of activity sources (or total duration ofregional activity) were submitted to a multivariate analysis ofvariance (MANOVA) with visit (3) and hemisphere (2) as thewithin-subject variables and group (responder, nonresponder, andnon–reading impaired) as the between-subjects variable. Data fromeach of the nine consistently active regions were treated as differ-ent, yet potentially intercorrelated, measures. Conversely, regionaldifferences in the onset of brain activity reflect the relative timingof engagement of different areas that serve as components of thebrain mechanism supporting the cognitive function exemplified bythe experimental task. In order to preserve this information in theanalyses, onset latency data was initially submitted to an analysisof variance (ANOVA) that included area (with nine levels), visit(1st, 2nd, 3rd), and hemisphere (left, right) as the within-subjectvariables. Group was again used as the between-subjects variable,as described above.

In the second set of analyses, the temporal progression ofregional activity at each visit was examined, first by ranking the 18anatomical locations where activity sources were found consis-tently (nine regions � two hemispheres) according to the meanonset latency of activity in each region. Next, a series of depen-dent-sample t tests were computed between anatomical areas thatfirst became active in close succession, in order to test the hypoth-esis that regional onset latency differences were statistically sig-nificant. In order to control for Type I error for multiple compar-isons, we evaluated all tests at an alpha of .001. This procedurewas performed separately for each visit and for each of the threegroups of participants.

Results

Performance on standardized tests. Significant interactions be-tween visit and RD subgroup (responder vs. nonresponder) werefound for Word Identification scores, F(1, 13) � 49.17, p � .0001,and Word Attack scores, F(1, 13) � 31.30, p � .0001, indicatinggreater improvement for responders across visits. The two sub-groups differed only on Word Attack scores at baseline, F(1,13) � 6.57, p � .024. Subgroup did not mediate the degree ofimprovement on word and pseudoword reading efficiency mea-sures; main effects of visit: F(1, 13) � 60.18, p � .0001 and F(1,13) � 22.29, p � .0001, respectively. As the effects of theintervention at the behavioral level were essentially identical tothose observed in the larger intervention study, the reader isreferred to Denton et al. (2006) for more details.

In-Scanner Task Performance

On average, children showed significant gains in decoding ac-curacy across the three visits, as indicated by main effects and

488 SIMOS ET AL.

linear trends, F(1, 13) � 5.24, p � .019 (see Figure 1). There wereno main effects or interactions with RD subgroup.

Brain Activation Profiles at Baseline

At baseline the typical spatiotemporal brain activation profilefor the group of impaired readers involved early activity in lateraland ventral occipitotemporal areas in both hemispheres. Extrastri-ate activity was followed by magnetic sources in inferior frontal,angular, and superior temporal regions in the right hemisphere;sources in the left supramarginal gyrus in the left hemisphere; andmagnetic activity in middle and mesial temporal cortices, bilater-ally. On average, the degree of activity was bilaterally symmetricin all areas (including BA 22). For BA 22, in particular, 13 of 15participants showed predominantly right hemisphere or bilaterallysymmetric activity. There were no notable differences betweenresponders and nonresponders at baseline.

As expected on the basis of previous MSI studies (Simos,Breier, Fletcher, et al., 2001; Simos et al., 2005), spatiotemporalactivation profiles for the group of nonimpaired readers werenotably different following the early activation of extrastriate areasin the left hemisphere. In this group, activity was next observed inhomologous extrastriate areas in the right hemisphere and tem-poroparietal areas (BA 22, BA 39, BA 40) predominantly in theleft hemisphere, followed by activity in frontal regions (BA 44/45,BA 6) bilaterally. On a group basis, significantly greater activationwas found for non–reading impaired as compared with RD chil-dren in the angular gyrus and ventral occipitotemporal cortices inthe left hemisphere, F(1, 23) � 5.17, p � .03 and F(1, 23) � 5.91,p � .02, respectively. Nonsignificant trends in the same directionwere noted for activity in BA 22 and lateral occipitotemporalcortices bilaterally. Nonsignificant differences in the opposite di-rection (greater activity for the RD group) were found in left BA44/45 and in right BA 40.

Degree (or Duration) of Magnetic Activity

Significant changes across visits were noted for activity intemporoparietal and inferior frontal regions, with notable differ-ences between responders and nonresponders. Responders’ datademonstrated a Visit � Hemisphere interaction for BA 22, F(2,14) � 4.26, p � .036, with a significant simple main effect in theleft hemisphere, F(2, 14) � 9.69, p � .002, but not in the righthemisphere ( p � .05). As shown in Figure 2, the duration ofactivity in the left BA 22 (corrected for changes in total brainactivity) increased linearly over the 4-month period of the study:linear trend across three visits: F(1, 7) � 13.74, p � .009. Plannedtrend analyses revealed similar effects for BA 40, F(1, 7) � 7.54,p � .025, and BA 39, F(1, 7) � 12.83, p � .009, both in the lefthemisphere ( p values for corresponding analyses in the righthemisphere were all � .1)

A Visit � Hemisphere interaction for activity in BA 22 was alsofound for nonresponders, F(2, 12) � 5.81, p � .017, but in this groupfollow-up tests indicated that the quasi-linear increase in the durationof activity apparent in Figure 2 was significant only in the righthemisphere, F(1, 6) � 6.55, p � .043 (left hemisphere: p � .1). Theduration of activity in BA 44/45, bilaterally, showed a trend in thesame direction (increasing activity over time), as indicated by a visitsimple main effect, F(2, 12) � 4.77, p � .034, and significant lineartrends in the left hemisphere, F(1, 6) � 8.40, p � .026, and in the righthemisphere, F(1, 6) � 9.58, p � .021. No effects involving visit werenoted for nonimpaired readers ( p � .1), indicating overall stability ofactivation profiles over time.

Onset Latency of Regional Activity

A nonsignificant tendency for (a) reduced onset latency ofactivity in BA 22 and (b) increased onset latency in BA 44/45 wasnoted for both subgroups of impaired readers. Subsequent analysesperformed on data collapsed across subgroups revealed significantmain effects of visit in BA 22, F(2, 28) � 6.65, p � .004, and BA44/45, F(2, 28) � 5.53, p � .01. Significant quadratic trends inboth cases, F(1, 14) � 9.46, p � .008, and F(1, 14) � 13.22, p �.003, respectively, indicated that changes took place predomi-nantly between the first and second visits (increased latency forfrontal activity and decreased latency for superior temporal activ-ity) as shown in Figure 3.

Perhaps the most conspicuous finding consisted of a change inthe relative timing of regional activity among extrastriate, superiortemporal, and inferior frontal regions. For nonimpaired readers,onset latency data were collapsed across visits given the absence ofnotable differences in the spatiotemporal profiles of activity. Al-though the general outline of the temporal progression of activityduring the first 700 or so milliseconds after stimulus onset has beendescribed in the previous paragraph, a closer view indicated sta-tistically reliable temporal differentiation in the onset of activity(revealed by significant, p � .001, differences in onset latencyoutlined in Table 2) among three sets of brain regions: extrastriate,temporoparietal, and frontal. Specifically, the onset of activity inleft occipitotemporal regions (which, on average, occurred at 150ms) was significantly earlier than the onset of activity in any otherbrain region (including the corresponding regions in the righthemisphere). Activity in the left superior, middle temporal, andangular gyri took place next and significantly earlier than activityin the supramarginal gyrus and frontal regions, bilaterally. Finally,

Figure 1. Pseudoword decoding accuracy inside the magnetic sourceimaging scanner over the course of three visits for the entire group ofchildren with reading difficulties (there were no significant differencesbetween responders and non-responders). Vertical bars indicate the rangeof individual scores, and shaded areas represent the 95% confidenceintervals.

489READING INTERVENTION AND BRAIN ACTIVITY

Figure 2. Average degree of activity (number of consecutive magnetic activity sources) in temporoparietal(Brodmann’s area [BA] 22, BA 39, BA 40) and frontal (BA 44/45) regions recorded at each visit (baseline, 2nd,3rd) for the entire group of impaired readers. Regions are shown for a given subgroup of children with readingdisabilities only if significant simple main effects or linear trends for visit were found (indicated by asterisks).Vertical bars represent standard error of the mean.

490 SIMOS ET AL.

the onset of activity in the left supramarginal gyrus was first notedat approximately the same latency as activity in the left inferiorfrontal gyrus and premotor region but significantly earlier thanactivity in the corresponding regions in the right hemisphere.

In contrast to nonimpaired readers (Figure 4), a clearly distincttemporal profile of activity was noted at baseline for the entiregroup of impaired readers, with essentially no differences betweenresponders and nonresponders. This profile, which is presentedschematically in Figure 5, featured activity in only 10 brain regions(compared with 16 in the group of nonimpaired readers). Initiallyactivity sources were found in extrastriate cortices (with no reli-able difference between hemispheres) followed by essentially si-multaneous onset of activity in the middle temporal gyrus, bilat-erally, in the right angular, superior temporal, and inferior frontalgyri, and in the left supramarginal gyrus. Significant temporaldifferentiation was found only between extrastriate areas and therest of the active brain regions ( p � .001; see Table 3).

The temporal progression of activity for responders followingintervention (on the third visit) was similar to the profile that wascharacteristic of the group of nonimpaired readers as shown inFigure 6 and Table 4, featuring a reliable temporal differentiationof activity among extrastriate, temporoparietal, and frontal areas.Specifically, initial activation of left hemisphere extrastriate cor-tices was first noted earlier than activity in any other brain region(including corresponding right hemisphere areas). Activity in theleft supramarginal gyrus, the right angular gyrus, and the superiorand middle temporal gyri (in both hemispheres) took place nextand significantly earlier than activity in frontal regions, bilaterally.

Figure 7 and Table 5 reveal a different temporal profile for thegroup of nonresponders. In this group there was (a) lack of a cleartemporal differentiation between hemispheres in the onset of ac-tivity in extrastriate areas, (b) no clear temporal differentiationbetween the onset of activity in left hemisphere temporoparietalareas and the onset of activity in frontal regions, and (c) a signif-

Figure 3. Change in average onset latency of activity (in milliseconds after stimulus onset) across visits(baseline, 2nd, 3rd) in temporoparietal (Brodmann’s area [BA] 22, BA 39, BA 40) and inferior frontal regions(BA 44/45), collapsed across hemispheres. Vertical bars represent standard error of the mean.

Table 2Significant Differences in Mean Onset Latency Among 16 Brain Regions for the Group of Non-Impaired Readers

Brainregion

R L L L R R R L R L R L L R R

19/37 21 39 22 39 21 22 MTL MTL 40 40 44/45 6 44/45 6

L BA 19/37 * * * * * * * * * * * * * * *

R BA 19/37 * * * * * * * *

L BA 21 * * * * * * *

L BA 39 * * * * * * * *

L BA 22 * * * * * * * *

R BA 39 * * * *

R BA 21 * * * *

R BA 22 * * * *

L MTL * * *

R MTL * * *

L BA 40 * *

R BA 40L BA 44/45L BA 6R BA 44/45

Note. R � right hemisphere; L � left hemisphere; BA � Brodmann’s area; MTL � medial temporal lobe. Data were collapsed across all visits.* p � .001.

491READING INTERVENTION AND BRAIN ACTIVITY

icant difference in onset latency between BA 22 in the righthemisphere and BA 6, 44, and 45, in both hemispheres.

Discussion

The data presented here corroborate previous MSI (Simos et al.,2002) and fMRI findings (e.g., Eden et al., 2004; Temple et al., 2003)in showing that completion of an intensive instruction program fo-cusing on the development of phonological awareness and decodingskills is often accompanied by increased neurophysiological activityin temporoparietal cortices in the left hemisphere during performanceof reading tasks that require phonological decoding. The novel findingthat emerged from the present data is that adequate response to thisinstruction is contingent on: (a) increased duration of neurophysio-logical activity in the posterior portion of the superior temporal gyrus,the supramarginal and angular gyri in the left hemisphere, and (b)change in the sequence of regional activity between left temporopa-rietal and frontal regions. For the subgroup of initially impairedreaders who subsequently scored in the average range of standardizedtests of word and pseudoword reading accuracy (responders), thesechanges can be considered as normalizing, rendering the spatiotem-poral activation profiles more similar to the activation profiles ofage-matched children who never experienced difficulties in learningto read. In contrast, for the subgroup of children who showed smalland clinically insignificant improvement in basic reading skills (non-responders), the observed neurophysiological changes indicated in-creased reliance on alternate brain regions to support phonologicaldecoding.

Interestingly, the distinct neurophysiological profiles of re-sponders and nonresponders were obtained while performing aphonological decoding task, the difficulty level of which wastitrated to ensure that both groups would be able to perform atcomparable levels before, during, and after the intervention. Thiscan probably account for the fact that responders showed signifi-

cant improvement on norm-referenced measures of reading accu-racy (involving stimuli of increasing length and complexity),whereas subgroup differences in the rate of improvement on per-formance of the in-scanner task were minimal. This suggests thatneurophysiological differences between the two groups did notreflect different performance levels but rather more basic aspectsof the brain circuits that engage during decoding tasks. Moreover,the fact that neurophysiological changes were observed only in theRD children and not in the control group suggests that they wereassociated with supplemental instruction and were not simply theresult of developmental changes that normally take place duringthe course of regular classroom instruction.

Evidence regarding the actual role of alternate regions (righttemporoparietal and inferior frontal cortex) in the brain circuits forreading is mostly indirect. Some brain imaging studies on dyslexiahave reported increased activity in these regions during perfor-mance of a variety of reading tasks (Brunswick, McCrory, Price,Frith, & Frith, 1999; S. E. Shaywitz et al., 1998). Damage to theseregions, however, does not regularly cause deficits in single wordreading. Moreover, MSI studies with more experienced nonim-paired readers, both children and adults, clearly show that activa-tion of inferior frontal cortices occurs at a latency when wordrecognition and lexical access has already taken place (between500–700 ms after stimulus onset; Simos, Breier, Fletcher, et al.,2001; Simos et al., 2007). A plausible explanation for the putativehyperactivation of inferior frontal regions suggests that these areasare involved in the mapping of the sound structure of the printedstimuli via activation of articulatory patterns (S. E. Shaywitz &Shaywitz, 2004). At the psychological level, this process is not asefficient for fluent reading as the more direct mapping of print tosound (either at the word or the subword level), but when the latterprocess is deficient, children with severe reading difficulties mayinadvertently rely on this alternative strategy. Along the same

Figure 5. Reading-impaired children at baseline: Temporal progressionof magnetic activity on schematic views of the lateral surface of the left (L)and right (R) hemispheres. Mean onset latency of activity in each activeregion is shown in milliseconds after stimulus onset. Areas with signifi-cantly different onset latencies are shown in different colors.

Figure 4. Nonimpaired readers (data collapsed across the three visits):Temporal progression of magnetic activity on schematic views of the lateralsurface of the left (L) and right (R) hemispheres. Mean onset latency of activityin each active region is shown in milliseconds after stimulus onset. Areas withsignificantly different onset latencies are shown in different colors.

492 SIMOS ET AL.

lines, increased engagement of right hemisphere temporoparietalregions during reading in children with dyslexia may correspond,at the psychological level, to increased reliance on (visual) per-ceptual processes to compensate for poor phonological decodingskills. It should be noted, however, that increased activation ofinferior frontal regions in children with dyslexia versus controls isnot a universal finding (see, for example, Eden et al., 2004), andthere is some evidence that this activity may serve to compensatefor disrupted posterior brain systems.

In the present study, changes in spatiotemporal profiles of acti-vation were observed during performance of a task that posedsignificant demands on phonological decoding processes(pseudoword reading). Despite the fact that RD children had

received supplemental instruction during Grade 1 (prior to thebaseline scan), their activation profiles showed some of the com-monly observed differences from those of nonimpaired readers,namely, reduced activity in temporoparietal and occipitotemporalregions in the left hemisphere and increased activation of inferiorfrontal cortices.

At the behavioral level, the two-stage intervention influencedboth accuracy and reading efficiency measures (Denton et al.,2006), yet there was a tendency for greater improvement of basicreading skills (word and pseudoword reading accuracy) and read-ing speed during the first 8 weeks of the program, which focusedon phonological decoding skills. At the neurophysiological level,the trajectory of changes in activation during performance of thepseudoword reading task did not appear to be in phase with thetype of intervention. Changes in the duration of activity took placewith similar intensity during the two phases of the program,whereas changes in onset latency were more prominent during thefirst phase of the program. A similar trend was observed in Simoset al. (2007), where the most evident changes in activation patternsduring performance of a sight-word reading task took place duringthe first 8 weeks of the intervention program. These findings mayreflect an essential temporal uncoupling of instruction effects at thepsychological and brain level, a peculiarity of the particular inter-vention programs used in the study, or the effects of individualvariability in response to instruction made more prominent in theresults by the small sample size.

In an earlier MSI study, increased activity and reduced onsetlatency of activation were observed in the middle temporal gyrusand extrastriate (occipitotemporal) areas during performance of atask that posed lesser demands for decoding and increased de-mands for rapid recognition of (mostly familiar) word forms(Simos et al., 2007). This finding is in partial agreement withresults from a large scale functional magnetic resonance imagingstudy comparing children who received intensive intervention fora period of 8 months (focusing on phonological decoding, wordrecognition, and text comprehension skills) with children whoreceived less systematic interventions within the school setting(B. A. Shaywitz, Shaywitz, Blachman, et al., 2004). Persistentchanges in the degree of regional activation observed duringperformance of a cross-modal letter name identification task were

Table 3Significant Differences in Mean Onset Latency Among the Ten Brain Regions Where Activity Was Detected for the Group of ImpairedReaders at Baseline

Brainregion R BA 19/37 L 40 L MTL R 21 R 39 R 44/45 R MTL R 22 L 21

L BA 19/37 * * * * * * * *

R BA 19/37 * * * * * * * *

L BA 40L MTLR BA 21R BA 39R BA 44/45R MTLR BA 22

Note. R � right hemisphere; L � left hemisphere; BA � Brodmann’s area; MTL � medial temporal lobe. Data were collapsed for responders andnon-responders.* p � .001.

Figure 6. Responders post-intervention: Temporal progression of mag-netic activity on schematic views of the lateral surface of the left (L) andright (R) hemispheres. Mean onset latency of activity in each active regionis shown in milliseconds after stimulus onset. Areas with significantlydifferent onset latencies are shown in different colors. The temporal profileof activity was essentially identical for the 2nd and 3rd visits, and data werecollapsed across the two visits.

493READING INTERVENTION AND BRAIN ACTIVITY

found in occipitotemporal and inferior frontal areas. Therefore,data from studies conducted with a variety of cognitive tasks andimaging methods are in agreement with suggestions that specifictask demands (which are in part determined by the nature of theprinted stimuli used) affect the layout and organization of the braincircuit that is engaged to perform each task (Bentin, Kutas, &Hillyard, 1995; Ruz, Wolmetz, Tudela, & McCandliss, 2005).

In comparison with an earlier MSI investigation on the effects ofintensive instruction on the profile of activity associated with theperformance of a phonological decoding task (Simos et al., 2002),

the design of the present study has incorporated a number ofimprovements. First, it included a larger sample of children se-lected to ensure a wider representation of participants based oninitial standardized scores and socioeconomic status (SES) andhome characteristics. The present sample was more uniform withrespect to age and instructional experiences, permitting the exam-ination of individual differences in response to intervention. Sec-ond, on average, children in the present sample had less severe RD(mean Word Attack standard score � 80 � 8.3 vs. 72 � 7.4 in theprevious study). In the present study, only 7 of 15 children scoredbelow the 10th percentile (i.e., had a standard score � 80) on theWord Attack subtest of the Woodcock–Johnson battery. In ourprevious study 6 of 8 children scored in that range. Third, inter-vention was performed at the school by specially trained teachers,and not at a reading clinic, with close supervision and the capa-bility to customize the instructional sequence to fit the student’srate of progress. Fourth, there was a second follow-up approxi-mately 2 months after the initial intervention. During that periodchildren received structured teaching to improve word recognitionand fluency skills. Fifth, we used a different neuromagnetometersensor, which was equipped with 248 first-order gradiometer coils(compared with only 148 magnetometer coils in our previousstudy), which affords significantly improved signal-to-noise ratioand denser coverage of the head surface. The inclusion of a larger,more homogeneous sample of RD children, and the improvedsensitivity of the magnetic scanning device used in the presentstudy (which is crucial for detecting magnetic activity emanatingfrom frontal cortices) may account for the present study’s successin identifying systematic individual variability in intervention-related changes in neurophysiological activity for reading.

In conclusion, the present findings demonstrate that remediationcan be associated with changes in the relative timing of activity inkey brain regions and, often, with quite dramatic changes in thesequence of neurophysiological events that comprise the neuralsignature of the brain mechanism for reading. Successful interven-tion (evidenced in the group of responders) was associated withestablishment of a brain circuit for reading that was structurally

Table 4Significant Differences in Mean Onset Latency Among 16 Brain Regions for the Group of Responders

Brainregion

R R L R L L R R L R R L L L R

19/37 39 22 21 21 40 MTL 22 6 6 40 39 MTL 44/45 44/45

L BA 19/37 * * * * * * * * * * * * * * *

R BA 19/37 * * * * * * *

R BA 39 * * * * * * *

L BA 22 * * * * * * *

R BA 21 * * * * * * *

L BA 21 * * * *

L BA 40 * * * * * * *

R MTL * * * *

R BA 22 * * * *

L BA 6R BA 6R BA 40L BA 39L MTLL BA 44/45

Note. R � right hemisphere; L � left hemisphere; BA � Brodmann’s area; MTL � medial temporal lobe. Data were collapsed across the 2nd and 3rd visits.* p � .001.

Figure 7. Non-responders post-intervention: Temporal progression ofmagnetic activity on schematic views of the lateral surface of the left (L)and right (R) hemispheres. Mean onset latency of activity in each activeregion is shown in milliseconds after stimulus onset. Areas with signifi-cantly different onset latencies are shown in different colors. The temporalprofile of activity was essentially identical for the 2nd and 3rd visits anddata were collapsed across the two visits.

494 SIMOS ET AL.

similar to, and operated like, the brain mechanism characteristic ofnonimpaired readers (normalizing changes at the neurophysiolog-ical level). Conversely, when intervention failed to have a signif-icant impact at the behavioral level, it was associated with neuro-physiological changes suggestive of the establishment of alterna-tive brain circuits for reading (compensatory changes). The natureof intervention-related changes in the profile of regional brainactivation is consistent with the notion that dyslexia is associatedwith a functionally impaired brain circuit for reading, which, inturn, may be caused by inefficient or inadequate neuronal connec-tions between key brain areas that normally participate in thiscircuit (Beaulieu, Plewes, Paulson, et al., 2005; Deutsch et al.,2005; Eckert et al., 2005; Klingberg et al., 2000; Horwitz, Rumsey,& Donohue, 1998; Niogi & McCandliss, 2006; Pugh, Mencl,Shaywitz, et al., 2000; Stanberry et al., 2006). The data presentedhere provide more direct evidence for changes in the relativetiming of neurophysiological activity among various componentsof the brain circuit for reading, indicating substantial changes inthe pattern of functional corticocortical connections that supportthis circuit.

Whereas the relatively small sample of the present study maynot be sufficient to draw definite conclusions regarding the natureof changes in neuronal circuitry in response to systematic instruc-tion, data are consistent with the prevalent notion regarding thepathophysiology of dyslexia (at least at the macroscopic level).Our findings are also clearly indicative of systematic individualdifferences in the type of changes, at the neuronal level, thatappear to reflect a child’s degree of response to intervention. Itshould be emphasized, however, that conclusions based on thepresent findings are necessarily limited to the task used, the brainimaging method used, and the characteristics of the participants.Future investigations, with larger samples of RD children, shouldsystematically examine factors that may influence response tointervention, which may include, but are not limited to, individualreading skill profiles, developmental histories, genetic predisposi-tion, and factors related to the intensity, duration, and content ofthe intervention itself. The role of practices targeting motivation

and self-monitoring ability appears to be a particularly importantbut often overlooked area in intervention research (e.g., Eckerd,Ardoin, Daly, & Martens, 2002; Morgan & Sideridis, 2006). Itshould also be noted that the small numbers of responders andnonresponders in our study did not permit a detailed account of theextent to which the second part of the intervention, focusing on thedevelopment of rapid word recognition skills, contributed to fur-ther changes in brain activation profiles. In future studies non-responders could be randomly assigned to different treatments inorder to assess the relative impact of different components of theintervention program.

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Table 5Significant Differences in Mean Onset Latency Among 16 Brain Regions for the Group of Non-Responders

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Received May 30, 2006Revision received November 17, 2006

Accepted December 11, 2006 �

496 SIMOS ET AL.