Neuroplasticity.

The capacity to develop neural pathways and adapt to cognitive demands is the essence of neural plasticity. Changes in electrical impulses, chemical signaling, and histology underlie the behavioral aspects of “learning.” Describing the candidate mechanisms of neuroplasticity in detail is beyond the scope of this paper but to illustrate the complexity of processes involved in neuroplasticity we describe some of what is known and refer the reader to several excellent review papers. At the synaptic level, long-term potentiation (LTP) of the postsynaptic neuron in response to repeated presynaptic stimuli is widely believed to be a primary mechanism of long-term memory and learning [34]. LTP can lead to synaptic modifications that result in enhanced signal transmission [35]. Though short-term synaptic modification does not require protein synthesis, long-term synaptic changes seem to require protein synthesis and these long-term changes are considered to be the cellular correlates of learning and memory [36]. Beyond enhancement of synaptic connections through LTP, gray matter structural mechanisms of neuroplasticity include neurogenesis, axon sprouting, dendritic branching (and synaptogenesis), gliogenesis and glial modifications, and angiogenesis [37]. As numerous gene products are believed to be involved in learning and memory and protein synthesis appears to be required for long-term memory storage, regulation of gene expression is likely to be important in learning processes. Epigenetic mechanisms include histone modification [31] and post-transcriptional regulation of gene expression by microRNAs [38]. Clearly, learning and memory are complex events at the cellular and molecular levels. Yet, what does this mean for children with learning disabilities? Perhaps these processes differ for individuals with RD compared to typically achieving peers. An inefficiency in one mechanism of the intricate processes involved in storing and retrieving information could adversely affect learning. Such neurobiological differences could explain why some children absorb new knowledge effortlessly while others not only struggle to grasp new concepts, but may also have great difficulty in retaining and consolidating information.

If a characterizable neurobiological anomaly underlies poor response to instruction, identifying these individuals and developing an appropriate intervention could possibly compensate for the deficiency. To illustrate, a critical molecular process related to long-term memory is the effect that CREB (cAMP response element binding protein) has on genetic transcription. CREB is stimulus-inducible in neurons and involved in long-term memory by influencing protein synthesis [39]. In a mouse study, long term memory was adversely affected by CREB gene disruption, yet interestingly the learning deficit was overcome by increasing the time between the training events [40]. That is, modifying the behavioral training compensated for a molecular deficiency. Perhaps identifying underlying dysfunction in functional activity can lead to a specific intervention. A challenge lies in understanding these differences and addressing them perhaps in a very prescriptive manner. Whatever the deficiencies may be, characterizing those deficiencies through investigative techniques is a step in the process toward targeted remediation.

Functional neuroimaging.

Neuroimaging is a tool that can be used to explore brain activity and can make a valuable contribution to understanding neuroplasticity. Brain activity, as determined by imaging modalities such as fMRI and MEG, not only indirectly reflects the underlying tissue structure and physiology (as neurons must be present and functioning to exhibit activity), but also represents which areas of the brain are actively engaged when presented with stimuli of interest. Numerous studies have used imaging techniques to explore brain activity associated with specific cognitive tasks. A growing number of studies are exploring various aspects of reading to determine how the brain accomplishes the complex task of reading. Further investigations are concerned with how the brain differs in functional activity between skilled readers and readers who struggle.

Neuroimaging in typically achieving readers.

Studies with unimpaired adult readers have revealed a left hemisphere reading network comprised of three areas: a ventral posterior region, a dorsal posterior region, and an anterior region [41]–[44]. The posterior ventral region is located in an inferior occipito-temporal area. This area appears to be involved in visual processing and recognition of words [41], [45]–[48] as even letters and pseudoletters elicit a response in this region [49]. The posterior dorsal region is comprised of the posterior superior temporal gyrus (pSTG), supramarginal gyrus (SMG), and angular gyrus (AG) and appears to be involved in phonological processing, transforming orthographic representations to phonological representations, and semantic processing [41], [47], [50], [51]. The anterior region is located in and around the inferior frontal gyrus (IFG). The IFG appears to be involved in phonological processing (e.g., [49]) and may be involved in articulatory recoding such that phonological input is converted to speech-gesture articulation output [41], [42] and semantic processing [47]. The studies establishing these regions have largely focused on single word reading. However, studies exploring reading comprehension have found left SMG and AG [52] and bilateral middle temporal gyri (MTG) and STG [53] to be activated by typical readers during comprehension tasks. While imaging studies of reading in children indicate a large amount of overlap with adults in activation, there are some differences. Some evidence indicates that over the course of development, activation in some more dispersed areas attenuates with age while increases with age are more focal, and these changes are largely independent of performance [54], [55]. For example, adults show less activation of left SMG and AG, areas involved in phonological processing [56]. This suggests that children are more actively engaged in using phonology to analyze words as they read, whereas adults have developed such automaticity in word reading that increased use of these phonological processing areas is no longer required. In contrast, adults showed increased activity in frontal and parietal regions thought to be involved in attention and top-down cognitive control [54], [55]. It is important to consider developmental changes in functional activity when reflecting on whether reading difficulties are more related to a delay in development or to dysfunctional reading networks that encourage development of compensatory mechanisms. Another recent finding in functional developmental changes is that sensitivity to visually presented words (i.e. activation response to detecting a word among progressively decreasing visual noise) increases over the school-age years in the L posterior occipito-temporal sulcus [57]. This may imply a more refined usage of an area used in visual word reading.

Neuroimaging of reading disabilities.

Over the past two decades, numerous studies have reported differences in brain function during reading tasks for people with reading problems relative to controls with typical reading achievement and several narrative reviews have highlighted the commonalities among studies [41], [43], [58]–[61]. The functional differences between RD and typical readers are generally characterized by reduced activity in L hemisphere regions for RD. Reviews of the literature have indicated that RD involves a dysfunction of the aforementioned three-region reading network: general underactivation of L temporo-parietal region (including STG) and ventral occipito-temporal (including lateral extrastriate, fusiform, and inferior temporal gyrus) and overactivation of the L IFG. This overactivation of the L IFG has been presumed to be due to compensatory articulatory effort and evidence that contradicts this portion of the accepted model has recently emerged [62]. Though less consistent than reduced left hemisphere activation, some studies have also reported increased right hemisphere activation that may signify compensatory activity for people with RD during reading tasks [51], [63]–[66] and this compensatory activity may develop as early as second grade [67]. Adding further complexity, there is evidence that, at times, typical readers exhibit less brain activation in reading areas than do readers with RD. Rimrodt et al [64] found that adolescents with RD activated more than typical readers in the left middle and superior temporal gyri when reading incongruent sentences, perhaps suggesting more effortful processing of nonmeaningful sentences. Pugh et al [68] found through manipulating stimuli that for non-impaired adolescent readers, factors that make the word easier to process were associated with relatively reduced activation. However, for readers with RD facilitative factors were associated with increased activation in the same areas, “suggesting that the LH reading circuitry in adolescent RD is poorly trained but not wholly disrupted” [68]. Less activation may at times be reflective of knowledge consolidation. If cognitive processing is less effortful, then the resulting efficiency may mean less functional activity. Though evidence is limited, some studies have shown that typically achieving novice performers can exhibit increased activation, yet following training or practice, decreased activation is observed [28], [69], [70].

While the value of the narrative reviews cannot be discounted, meta-analysis provides a statistical approach to synthesizing across studies. In a meta-analysis of adults with reading disabilities compared to controls, reduced activation was reported for L hemisphere ventral occipitotemporal cortex, inferior parietal cortex, STG, IFG, and thalamus [71]. Another recent meta-analysis, which included both children and adults with reading disabilities, identified underactivation in the L hemisphere inferior parietal, superior temporal, middle and inferior temporal, and fusiform regions and also reported underactivation in the L IFG that coincided with overactivation in the primary motor cortex and anterior insula [72]. In a meta-analysis that compared adults with RD and children with RD, showed similar results except that temporoparietal underactivation was seen only for adults with RD, not for children with RD [73].These meta-analyses are consistent with the literature reviews in identifying a dysfunctionally underactivating left hemisphere network in RD. However, the meta-analyses indicate the presence of underactivation of the L IFG in RD rather than the overactivation assumed in the narrative reviews [62]. The meta-analysis would appear to constitute a consensus across studies, yet appropriate caution should be used when interpreting meta-analyses. Due to the necessary requirement of coordinates of activation to perform functional meta-analysis, not all relevant studies may be included in the analysis. Hence, both the meta-analytic approach and the narrative literature review provide insight into understanding differences between typical readers and those with RD.

Inclusion criteria.

To obtain studies that examined brain activity associated with reading intervention, six inclusion criteria were stipulated. First, only peer-reviewed, primary research studies were included. Second, only studies with at least some participants designated as having reading difficulties, reading disabilities, dyslexia, or at-risk status for reading difficulties were included. For studies that used imaging to predict future reading scores, the designation of reading difficulties could be determined at posttest. Case studies were excluded. Third, the reading difficulty must have been idiopathic in nature and not the result of head trauma, stroke, or illness. Fourth, the studies were required to describe reading-related instruction that occurred during the experiment. Though the intended focus was upon intervention, studies in which participants received regular (business-as-usual) instruction rather than implementing an intervention were not excluded. Fifth, the studies were required to include neuroimaging in the modalities of either fMRI or MEG and the experimental design must associate the imaging with the reading instruction. Sixth, the functional imaging task must have been a reading task or a task of reading-related skill (e.g., letter sound matched to visual letter).

Searches.

Two search strategies were employed to identify relevant studies and these searches were current as of January 2013. First, searches were conducted using two electronic databases, PubMed and Web of Science. The Web of Science search input was (TS = ((reading disability OR dyslexia OR reading difficulty) AND (neuroimaging OR fMRI OR brain activation) AND (reading intervention OR reading instruction OR reading treatment))) AND Document Types = (Article). The PubMed search input was (((“reading”[MeSH Terms] OR “reading”[All Fields]) AND disability[All Fields]) OR (“reading”[MeSH Terms] OR “reading”[All Fields]) AND difficulty[All Fields]) OR (“dyslexia”[MeSH Terms] OR “dyslexia”[All Fields]) AND ((“neuroimaging”[MeSH Terms] OR “neuroimaging”[All Fields]) OR (“magnetic resonance imaging”[MeSH Terms] OR (“magnetic”[All Fields] AND “resonance”[All Fields] AND “imaging”[All Fields]) OR “magnetic resonance imaging”[All Fields] OR “fmri”[All Fields]) OR ((“brain”[MeSH Terms] OR “brain”[All Fields]) AND activation[All Fields])) AND (((“reading”[MeSH Terms] OR “reading”[All Fields]) AND (“Intervention”[Journal] OR “Interv Sch Clin”[Journal] OR “intervention”[All Fields])) OR ((“reading”[MeSH Terms] OR “reading”[All Fields]) AND (“teaching”[MeSH Terms] OR “teaching”[All Fields] OR “instruction”[All Fields]))). The Web of Science search yielded 75 articles. The PubMed search yielded 49 articles. The resulting 124 articles were examined and those that did not meet criteria were systematically eliminated (Fig 1) [94]. Next, using references from studies that met inclusion criteria, additional studies were considered. Additionally, Google Scholar searches were performed to locate papers that have cited some of the studies that met inclusion criteria.

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Figure 1. Systematic review flow diagram.

(PRISMA template; Moher, Liberati, Tetzlaff, Altman, & The PRISMA Group, 2009).

https://doi.org/10.1371/journal.pone.0083668.g001

IFG.

The IFG was found to be associated with intervention across multiple studies. Following reading intervention, previously underactivating L IFG in RD more closely resembled controls [98], [102], [105] with one study showing underactivation of at-risk children shifting to overactivation following intervention [100]. Interestingly, Richards & Berninger [106] found that children with RD showed higher functional connectivity than controls for the L IFG as related to R and L supplemental motor areas and L precentral gyrus as well as R superior frontal gyrus. Following intervention, no difference was observed between children with RD and controls. An additional functional connectivity study [107] similarly found that L and R inferior frontal connectivity was the same following treatment for RD as compared to controls, but in somewhat of a contrast, found that nonresponders to intervention showed less functional connectivity than did responders. Hoeft et al [108] found that activity in the pars triangularis of the L IFG was positively correlated with reading gains, whereas L IFG/Insula activity was negatively correlated. To summarize, it seems that L IFG involvement may be that of underactivation prior to intervention relative to controls, followed by normalization after treatment; however, there is not complete consensus among the studies in this review.

The right IFG is also prominent in findings related to intervention. Prior to treatment, at-risk children showed underactivation in R IFG [100]. Activation increases in R IFG were seen following intervention [63], [69], [98] and at follow-up [102] and considered to be normalized to the level of controls [99]. Prior to treatment, higher R IFG activity predicted higher reading gains for children with RD [108]. Following treatment, responders exhibited greater R IFG activation than did nonresponders and controls [103]. Nonresponders showed increased duration of activity in bilateral frontal areas [66], and exhibited less functional connectivity between left and right inferior frontal regions than did responders and controls [107].

Additional frontal areas.

While the IFG was the most consistently involved region in intervention, other frontal regions emerged in some studies with several studies presenting results in superior frontal (SFG) and middle frontal (MFG) gyri. Prior to intervention, children with RD showed underactivation in R SFG [105] and increases in activation were seen following treatment [98] and at follow-up [69]. Activity in the L SFG was positively correlated in predicting response to intervention [108]. At follow-up to intervention, children with RD showed increased activation in L SFG/cingulate [69]. Prior to intervention, children with RD showed underactivation in L MFG [105] and L MFG activity contributed to whole-brain multivariate patterns that predicted responsiveness to intervention [108]. Pre-treatment activation levels in R MFG negatively correlated with posttest decoding scores [109]. Following intervention, children with RD exhibited increased levels of activation in R MFG [98], [100] whereas adults showed increased activation in R and L MFG [63]. More isolated frontal lobe findings include at-risk children underactivating in bilateral frontal orbital cortex at pre-treatment [100] and responders showing increased dorsolateral prefrontal activation[110].

STG and MTG.

Some consistencies emerged among studies in temporo-parietal areas, particularly in the STG and MTG. Before treatment, participants with RD showed underactivation relative to controls in posterior STG and temporo-parietal cortex that increased or normalized to the level of controls after intervention [98], [100], [102], [111]. Increased L STG activation was evident at follow-up as well [100], [111]. Responders to intervention showed greater activation than nonresponders in L STG prior to treatment [112], [113] and following treatment [114]. Also, responders to treatment showed increased duration of activity in posterior L STG and the L hemisphere sequence of activation changed for responders such that temporoparietal areas activated prior to frontal areas, such that after treatment responders much more closely resembled [66]. In young children considered at-risk for RD, underactivation was seen in the R posterior STG prior to treatment. In adults, increases in R posterior STG/AG activation were seen following treatment [63]. While in one MEG study, responders exhibited bilateral temporal-parietal activation [110], another study showed nonresponders having increased R temporo-parietal activation [66]. Because of the lesser spatial resolution of MEG, these areas are more general than in fMRI.

Though the STG seemed to be the temporo-parietal region with the most consistent findings across studies, the MTG also emerged in findings from several studies. At pre-treatment, relative underactivation of the L MTG was seen, with activation increases observed following treatment [101], [102], [105], [115]. As for responsiveness, higher L MTG activity was predictive of better response to intervention [109], [112] and responders activated more than controls in L MTG/AG following intervention [114]. In addition to the L MTG, increases in activation were also shown for RD in the R MTG following treatment [98], [115]. However, Shaywitz et al [102] found that R MTG activity was higher in RD at pre-treatment than at follow-up and Odegard et al [103] found that after treatment non-responders showed greater activation relative to controls and responders in R MTG. In addition, one study found that responders had increased activity at baseline in R mesial temporal cortex, an area not identified in other studies [112].

Other temporo-parietal areas.

Though less consistent across studies than the STG and MTG findings, activity in other temporo-parietal areas, including inferior temporal gyrus (ITG), inferior parietal lobule, SMG, and AG, was associated with reading intervention in a few studies. In the ITG, children with RD underactivated in the L hemisphere relative to controls at baseline, a difference that was no longer present following treatment [105], a finding in congruence with Gebauer, Fink, Kargl et al [101] that showed increased activation in L ITG for poor spellers/readers at post-intervention. In adults, increases in activation were seen following treatment in R and L inferior parietal lobule and left intraparietal sulcus [63]. At pretreatment, at-risk children underactivated in bilateral SMG, and following treatment activated more than controls in R SMG [100]. Pre intervention L SMG and angular gyrus activity positively correlated with post-intervention fluency gains [113]. Following intervention, responders showed increased activation of L SMG [66] and activated more than controls in L MTG/AG (BA 39). Adults showed increased activity following intervention in R STG/AG (BA 22/39) [63].

Occipital and fusiform.

Children with RD underactivated in the occipital/fusiform region [105] and superior lateral occipital cortex [100] prior to intervention. Baseline activation in the R fusiform and R fusiform/mid occipital gyri positively correlated with later decoding scores [109]. At baseline, children who were responders to intervention showed greater activation than non-responders in L ventral occipitotemporal region [112]. Post treatment L fusiform activation positively correlated with future gains in letter knowledge for young children [116]. Following intervention, increases in activation were seen in adults in the L fusiform gyrus [63] and in children in the L lingual gyrus [98]. Onset latency increased in R lateral occipitotemporal cortex [115]. Of interest, the only region in which children who were on track for typical reading achievement activated more than at-risk children who had received treatment was in the L superior lateral occipital cortex [100]. At a one-year follow-up, increased activation was seen in occipitotemporal regions for children with RD [102].

Pre/postcentral.

Limited evidence indicates possible differences in activity in precentral and postcentral gyri associated with intervention. Following treatment, children considered at-risk for RD showed increased activity relative to controls in L precentral gyrus [100]. Responders exhibited increased onset latency [115] of premotor cortex. Increases were seen in R inferior postcentral gyrus (BA 43) in adults following intervention [63] and in bilateral postcentral gyrus in children at follow-up [69].

Subcortical.

Post-intervention increases in activation were found in adults with RD in the L hippocampal gyrus [63]. Increases in thalamus activity were observed in the left hemisphere following intervention for adults [63], bilaterally for children following intervention [98], and in L hemisphere for children at follow-up [69]. Following treatment, children with RD showed increased activation in L putamen relative to controls [69]. At follow-up in the same study increased activation was seen in L and R insula/putamen.

Insula.

Following treatment, increased activation was seen in R insula/IFG [69], [98] and at follow-up in bilateral insula/putamen [69]. Prior to intervention, bilateral insular activity contributed to predicting response to intervention with a positive correlation for R insula and a negative correlation for L insula [108].

Additional sublobar/medial areas.

Prior to intervention, the R precuneus contributed to prediction of responsiveness [108]. At treatment follow-up, children with RD showed greater activation than controls in R precuneus [69]. Children with RD showed greater activation than controls in R anterior cingulate after treatment [100] and at follow-up [69]. Prior to treatment, L posterior cingulate activation was negatively correlated in whole-brain multivariate patterns predicting responsiveness to intervention [108]. At post-intervention, poor spellers/readers showed increased activation in R posterior cingulate cortex when compared with a no-treatment group [101]. At treatment follow-up, children with RD showed greater activation than controls in R posterior cingulate [69].

Responsiveness to intervention.

In addition to exploring the differences in activity associated with intervention, we were interested in finding predictors of intervention response and differences among responders and nonresponders. Individuals may vary in their neurobiological receptiveness to training or instruction. Exploring these differences may eventually facilitate the targeting of intervention to individual needs. A few studies have begun the investigation of neural predictors of reading improvement in children with RD. Pre-intervention fMRI activity in the R IFG [108] L MTG, L STG, L ventral occipitotemporal, and MEG activity in the R medial temporal cortex [112] predicts response to intervention. Hoeft et al [108] found that brain measures were more predictive of reading gains for adolescents with dyslexia than were behavioral measures, with greater activation in the R IFG during rhyme-judgment predicting greater reading improvement over the next 2 ½ years. Another study of adolescents who struggled with reading showed that brain activity prior to intervention was predictive of behavioral response to a year-long intervention that emphasized vocabulary, comprehension, word study, and fluency. Higher MEG activity in L middle, superior temporal, ventral occipitotemporal regions,and R medial temporal cortex predicted better response as demonstrated by word reading efficiency than was predicted by pre-intervention reading accuracy or fluency measures alone [112]. These areas overlap with the previously discussed posterior areas involved in reading. In general, this suggests that adolescents with neurobiological profiles more closely resembling typically achieving readers are more likely to respond well to intervention.

The studies which looked at differential responsiveness and post-intervention imaging indicated that children who demonstrate behavioral response as evidenced by standardized test scores, exhibited more activation in left middle temporal and posterior superior temporal areas [66], [114] and left inferior parietal region [103] following intervention as compared to children who did not respond to intervention. Nonresponders (a year after intervention) had increased right middle temporal lobe during a letter-sound task [103]. Functional connectivity data indicate that responders and non-impaired readers exhibit connectivity between inferior frontal regions that is absent in nonresponders [107]. Identifying these patterns of responders and nonresponders may provide insight into determining if these children are somehow at an optimal state to grow or unknowingly primed to respond to intervention, so that the lesser responders can be moved into that zone.

Changes: Normalizing or compensatory.

Given that change in functional activity appears to be associated with reading intervention leads to consideration of what the quality or type of change is. That is, does reading intervention lead to readers with RD becoming more like typical readers or does intervention lead to compensatory changes that enhance reading ability? While the limited studies available may not present a definitive answer, they do provide some insight. Several of the studies reviewed provide evidence of normalizing changes [63], [66], [69], [98], [99], [102], [106], [115], including normalized functional connectivity [106]. However, a few studies showed evidence of possible compensatory mechanisms [63], [66], [98]. Interestingly, one study presented evidence that responders to intervention exhibit normalization while nonresponders exhibit compensation [66]. Though the evidence is limited, this may be indicative of differing types or severities of RD (i.e., less severe RD responds better both behaviorally and neurologically to intervention). Alternatively, it is possible that the responders are typical readers who have not previously received adequate instruction and when provided with adequate instruction show the functional activation profile of typical readers. Another study [63] showed adults exhibiting both normalization and compensation, illustrating that not only can adults with RD be remediated but also that the capacity for both normalizing and compensating mechanisms remains intact into adulthood.