Cortical and Subcortical Mechanisms of Orthographic Word-form Learning.

We examined the initial stages of orthographic learning in real time as literate adults learned spellings for spoken pseudowords during fMRI scanning. Participants were required to learn and store orthographic word forms because the pseudoword spellings were not uniquely predictable from sound to letter mappings. With eight learning trials per word form, we observed changes in the brain's response as learning was taking place. Accuracy was evaluated during learning, immediately after scanning, and 1 week later. We found evidence of two distinct learning systems-hippocampal and neocortical-operating during orthographic learning, consistent with the predictions of dual systems theories of learning/memory such as the complementary learning systems framework [McClelland, J. L., McNaughton, B. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. The bilateral hippocampus and the visual word form area (VWFA) showed significant BOLD response changes over learning, with the former exhibiting a rising pattern and the latter exhibiting a falling pattern. Moreover, greater BOLD signal increase in the hippocampus was associated with better postscan recall. In addition, we identified two distinct bilateral brain networks that mirrored the rising and falling patterns of the hippocampus and VWFA. Functional connectivity analysis revealed that regions within each network were internally synchronized. These novel findings highlight, for the first time, the relevance of multiple learning systems in orthographic learning and provide a paradigm that can be used to address critical gaps in our understanding of the neural bases of orthographic learning in general and orthographic word-form learning specifically.

The right hemisphere's capacity for language: evidence from primary progressive aphasia.

The role of the right hemisphere (RH) in core language processes is still a matter of intense debate. Most of the relevant evidence has come from studies of gray matter, with relatively little research on RH white matter (WM) connectivity. Using Diffusion Tensor Imaging-based tractography, the current work examined the role of the two hemispheres in language processing in 33 individuals with Primary Progressive Aphasia (PPA), aiming to better characterize the contribution of the RH to language processing in the context of left hemisphere (LH) damage. The findings confirm the impact of PPA on the integrity of the WM language tracts in the LH. Additionally, an examination of the relationship between tract integrity and language behaviors provides robust evidence of the involvement of the WM language tracts of both hemispheres in language processing in PPA. Importantly, this study provides novel evidence of a unique contribution of the RH to language processing (i.e. a contribution independent from that of the language-dominant LH). Finally, we provide evidence that the RH contribution is specific to language processing rather than being domain general. These findings allow us to better characterize the role of RH in language processing, particularly in the context of LH damage.

Reading Braille by Touch Recruits Posterior Parietal Cortex.

Blind readers use a tactile reading system consisting of raised dot arrays: braille/⠃⠗⠇. How do human brains implement reading by touch? The current study looked for signatures of reading-specific orthographic processes in braille, separate from low-level somatosensory responses and semantic processes. Of specific interest were responses in posterior parietal cortices (PPCs), because of their role in high-level tactile perception. Congenitally blind, proficient braille readers read real words and pseudowords by touch while undergoing fMRI. We leveraged the system of contractions in English braille, where one braille cell can represent multiple English print letters (e.g., "ing" ⠬, "one" ⠐⠕), making it possible to separate physical and orthographic word length. All words in the study consisted of four braille cells, but their corresponding Roman letter spellings varied from four to seven letters (e.g., "con-c-er-t" ⠒⠉⠻⠞. contracted: four cells; uncontracted: seven letters). We found that the bilateral supramarginal gyrus in the PPC increased its activity as the uncontracted word length increased. By contrast, in the hand region of primary somatosensory cortex (S1), activity increased as a function of a low-level somatosensory feature: dot-number per word. The PPC also showed greater response to pseudowords than real words and distinguished between real and pseudowords in multivariate-pattern analysis. Parieto-occipital, early visual and ventral occipito-temporal, as well as prefrontal cortices also showed sensitivity to the real-versus-pseudoword distinction. We conclude that PPC is involved in orthographic processing for braille, that is, braille character and word recognition, possibly because of braille's tactile modality.

Multimodal Neural and Behavioral Data Predict Response to Rehabilitation in Chronic Poststroke Aphasia.

BACKGROUND: Poststroke recovery depends on multiple factors and varies greatly across individuals. Using machine learning models, this study investigated the independent and complementary prognostic role of different patient-related factors in predicting response to language rehabilitation after a stroke. METHODS: Fifty-five individuals with chronic poststroke aphasia underwent a battery of standardized assessments and structural and functional magnetic resonance imaging scans, and received 12 weeks of language treatment. Support vector machine and random forest models were constructed to predict responsiveness to treatment using pretreatment behavioral, demographic, and structural and functional neuroimaging data. RESULTS: The best prediction performance was achieved by a support vector machine model trained on aphasia severity, demographics, measures of anatomic integrity and resting-state functional connectivity (F1=0.94). This model resulted in a significantly superior prediction performance compared with support vector machine models trained on all feature sets (F1=0.82, P<0.001) or a single feature set (F1 range=0.68-0.84, P<0.001). Across random forest models, training on resting-state functional magnetic resonance imaging connectivity data yielded the best F1 score (F1=0.87). CONCLUSIONS: While behavioral, multimodal neuroimaging data and demographic information carry complementary information in predicting response to rehabilitation in chronic poststroke aphasia, functional connectivity of the brain at rest after stroke is a particularly important predictor of responsiveness to treatment, both alone and combined with other patient-related factors.

Pseudoword spelling ability predicts response to word spelling treatment in acquired dysgraphia.

Although rehabilitation of acquired dysgraphia can be quite effective, identifying predictors of responsiveness to treatment is useful for prognosis and individualization of treatment protocols. This study examined whether various features of treatment response were predicted by the integrity of one or more of the central cognitive components of spelling: orthographic long-term memory, orthographic working memory, and phoneme-grapheme conversion. Twenty dysgraphic individuals received 12 weeks of bi-weekly, individualized, lexically-based spelling rehabilitation using a spell-study-spell paradigm. Linear multiple regression modelling examined whether the type and severity of the dysgraphic deficit, assessed before rehabilitation, predicted the magnitude and rate of improvement, generalization to untrained items and maintenance of treatment gains. The results revealed that pseudoword spelling accuracy - indexing the integrity of the phoneme-grapheme conversion system - was the only factor examined that significantly predicted the rate of accuracy gains for trained words as well as the extent of generalization to untrained words. Pre-treatment pseudoword spelling accuracy also predicted retention of gains for trained and untrained words at 3-month follow-up. These findings reveal that the integrity of the phoneme-grapheme conversion system prior to dysgraphia rehabilitation may play a key role in rehabilitation-driven recovery, even when the treatment approach targets lexical rather than pseudoword spelling processes.

Common and distinct neural substrates of sentence production and comprehension.

Functional neuroimaging and lesion-symptom mapping investigations implicate a left frontal-temporal-parietal network for sentence processing. The majority of studies have focused on sentence comprehension, with fewer in the domain of sentence production, which have not fully elucidated overlapping and/or unique brain structures associated with the two domains, particularly for sentences with noncanonical word order. Using voxel-based lesion symptom mapping (VLSM) we examined the relationship between lesions within the left hemisphere language network and both sentence comprehension and production of simple and complex syntactic structures in 76 participants with chronic stroke-induced aphasia. Results revealed shared regions across domains in the anterior and posterior superior temporal gyri (aSTG, pSTG), and the temporal pole (adjusted for verb production/comprehension). Additionally, comprehension was associated with lesions in the anterior and posterior middle temporal gyri (aMTG, pMTG), the MTG temporooccipital regions, SMG/AG, central and parietal operculum, and the insula. Subsequent VLSM analyses (production versus comprehension) revealed critical regions associated with each domain: anterior temporal lesions were associated with production; posterior temporo-parietal lesions were associated with comprehension, implicating important roles for regions within the ventral and dorsal stream processing routes, respectively. Processing of syntactically complex, noncanonical (adjusted for canonical), sentences was associated with damage to the pSTG across domains, with additional damage to the pMTG and IPL associated with impaired sentence comprehension, suggesting that the pSTG is crucial for computing noncanonical sentences across domains and that the pMTG, and IPL are necessary for re-analysis of thematic roles as required for resolution of long-distance dependencies. These findings converge with previous studies and extend our knowledge of the neural mechanisms of sentence comprehension to production, highlighting critical regions associated with both domains, and further address the mechanism engaged for syntactic computation, controlled for the contribution of verb processing.

The Effects of Handwriting Experience on Literacy Learning.

Previous research indicates that writing practice may be more beneficial than nonmotor practice for letter learning. Here, we report a training study comparing typing, visual, and writing learning conditions in adults (N = 42). We investigated the behavioral consequences of learning modality on literacy learning and evaluated the nature of the learned letter representations. Specifically, the study addressed three questions. First, are the benefits of handwriting practice due to motor learning per se or to other incidental factors? Second, do the benefits generalize to untrained tasks? And third, does handwriting practice lead to learning and strengthening only of motor representations or of other types of representations as well? Our results clearly show that handwriting compared with nonmotor practice produces faster learning and greater generalization to untrained tasks than previously reported. Furthermore, only handwriting practice leads to learning of both motor and amodal symbolic letter representations.

Reliability of BOLD signals in chronic stroke-induced aphasia.

Investigating the neurobiology of language impairment and treatment in chronic stroke aphasia using fMRI requires an understanding of measurement variability within and between participants. In this multicenter study, we evaluated the scan-rescan reliability of an auditory and visual (written) story comprehension paradigm in stroke participants with aphasia (N = 65) and healthy controls (N = 22). The multi-modal task was conducted twice (~1 week apart) on separate visits upon study enrolment and twice again at completion three months later. A non-language visuomotor task was studied in the aphasia group only, which was conducted once per time point (3 months apart). While participants were asked to make responses during the comprehension task, these in-scanner responses were not recorded. Reliability was assessed using intraclass correlation coefficient (ICC) at both group and individual participant levels. The visual story comprehension condition had higher reliability than the auditory condition in both groups, with participants with aphasia exhibiting lower reliability than controls in both conditions (stroke ICC = .43, healthy ICC = .81). Differences in reliability within the group of participants with aphasia were found to be partially explained by overall language impairment as well as greater head motion. In the participants with aphasia, the visuomotor paradigm was found to have greater reliability than the story comprehension task at equivalent interscan intervals (visuomotor = 0.50, comprehension = 0.34), and its reliability was not associated with language impairment. This work highlights the importance of considering the reliability of fMRI tasks in aphasia research, provides strategies to improve reliability and has potential implications for the field of clinical neuroimaging in general.

High-level Integrative Networks: A Resting-state fMRI Investigation of Reading and Spelling.

Orthographic processing skills (reading and spelling) are evolutionarily recent and mastered late in development, providing an opportunity to investigate how the properties of the neural networks supporting skills of this type compare to those supporting evolutionarily older, well-established "reference" networks. Although there has been extensive research using task-based fMRI to study the neural substrates of reading, there has been very little using resting-state fMRI to examine the properties of orthographic networks. In this investigation using resting-state fMRI, we compare the within-network and across-network coherence properties of reading and spelling networks directly to these properties of reference networks, and we also compare the network properties of the key node of the orthographic networks-the visual word form area-to those of the other nodes of the orthographic and reference networks. Consistent with previous results, we find that orthographic processing networks do not exhibit certain basic network coherence properties displayed by other networks. However, we identify novel distinctive properties of the orthographic processing networks and establish that the visual word form area has unusually high levels of connectivity with a broad range of brain areas. These characteristics form the basis of our proposal that orthographic networks represent a class of "high-level integrative networks" with distinctive properties that allow them to recruit and integrate multiple, lower level processes.

Re-learning to be different: Increased neural differentiation supports post-stroke language recovery.

Identifying the neural changes that support recovery of cognitive functions after a brain lesion is important to advance our understanding of human neuroplasticity, which, in turn, forms the basis for the development of effective treatments. To date, the preponderance of neuroimaging studies has focused on localizing changes in average brain activity associated with functional recovery. Here, we took a novel approach by evaluating whether cognitive recovery in chronic stroke is related to increases in the differentiation of local neural response patterns. This approach is supported by research indicating that, in the intact brain, local neural representations become more differentiated (dissimilar) with learning (Glezer et al., 2015). We acquired fMRI data before and after 21 individuals received approximately 12 weeks of behavioral treatment for written language impairment due to a left-hemisphere stroke. We used Local-Heterogeneity Regression Analysis (Purcell and Rapp, 2018) to measure local neural response differentiation associated with written language processing, assuming that greater heterogeneity in the pattern of activity across adjacent neural areas indicates more well-differentiated neural representations. First, we observed pre to post-treatment increases in local neural differentiation (Local-Hreg) in the ventral occipital-temporal cortex of the left hemisphere. Second, we found that, in this region, higher local neural response differentiation prior to treatment was associated with less severe written language impairment, and that it also predicted greater future responsiveness to treatment. Third, we observed that changes in neural differentiation were systematically related to performance changes for trained and untrained items. Fourth, we did not observe these brain-behavior relationships for mean BOLD responses, only for Local-Hreg. Thus, this is the first investigation to quantify changes in local neural differentiation in the recovery of a cognitive function and the first to demonstrate the clear behavioral relevance of these changes. We conclude that the findings provide strong support for the novel hypothesis that the local re-differentiation of neural representations can play a significant role in functional recovery after brain lesion.

Language processing from the perspective of electrical stimulation mapping.

Electrical Stimulation (ES) is a neurostimulation technique that is used to localize language functions in the brain of people with intractable epilepsy and/or brain tumors. We reviewed 25 ES articles published between 1984 and 2018 and interpreted them from a cognitive neuropsychological perspective. Our aim was to highlight ES as a tool to further our understanding of cognitive models of language. We focused on associations and dissociations between cognitive functions within the framework of two non-neuroanatomically specified models of language. Also, we discussed parallels between the ES and the stroke literatures and showed how ES data can help us to generate hypotheses regarding how language is processed. A good understanding of cognitive models of language is essential to motivate task selection and to tailor surgical procedures, for example, by avoiding testing the same cognitive functions and understanding which functions may be more or less relevant to be tested during surgery.

Local response heterogeneity indexes experience-based neural differentiation in reading.

The ability to read requires learning letter-string representations whose neural codes would be expected to vary depending on the amount of experience that an individual has with reading them. Motivated by sparse coding theories (e.g., Rolls and Tovee, 1995; Olshausen and Field, 1996), recent work has demonstrated that better-learned relative to less well-learned neural representations are associated with more strongly differentiated, locally heterogeneous blood oxygenation level dependent (BOLD) responses (e.g., Jiang et al., 2013). Here we report a novel analysis method we call local heterogeneity regression (Local-Hreg) that quantifies the cross-voxel heterogeneity of BOLD responses, thereby providing a sensitive and methodologically flexible method for quantifying the local neural differentiation of neural representations. In a study of literate adults, we applied Local-Hreg to fMRI data obtained when participants read letter strings that varied in their frequency of occurrence in the written language. Consistent with previous research identifying the left ventral occipitotemporal cortex (vOTC) as a key site for orthographic representation in reading and spelling, we found that the cross-voxel heterogeneity of neural responses in this region varies according to the frequency with which the written letter strings have been experienced. This work provides a novel approach for examining the local differentiation of neural representations, and demonstrates that well-learned words have greater representational differentiation than less well-learned or unfamiliar words.

Developmental dysgraphia: An overview and framework for research.

Developmental deficits in the acquisition of writing skills (developmental dysgraphias) are common and have significant consequences, yet these deficits have received relatively little attention from researchers. We offer a framework for studying developmental dysgraphias (including both spelling and handwriting deficits), arguing that research should be grounded in theories describing normal cognitive writing mechanisms and the acquisition of these mechanisms. We survey the current state of knowledge concerning developmental dysgraphia, discussing potential proximal and distal causes. One conclusion emerging from this discussion is that developmental writing deficits are diverse in their manifestations and causes. We suggest an agenda for research on developmental dysgraphia, and suggest that pursuing this agenda may contribute not only to a better understanding of developmental writing impairment, but also to a better understanding of normal writing mechanisms and their acquisition. Finally, we provide a brief introduction to the subsequent articles in this special issue on developmental dysgraphia.

Do reading and spelling share orthographic representations? Evidence from developmental dysgraphia.

Both spelling and reading depend on knowledge of the spellings of words. Despite this commonality, observed dissociations between spelling and reading in cases of acquired and developmental deficits suggest some degree of independence between the cognitive mechanisms involved in these skills. In this paper, we examine the relationship between spelling and reading in two children with developmental dysgraphia. For both children, we identified significant deficits in spelling that affected the processing of orthographic long-term memory representations of words. We then examined their reading skills for similar difficulties. Even with extensive testing, we found no evidence of a reading deficit for one of the children. We propose that there may be an underlying difficulty that specifically affects the learning of orthographic word representations for spelling. These results lead us to conclude that at least some components of lexical orthographic representation and processing develop with considerable independence in spelling and reading.

Neural bases of orthographic long-term memory and working memory in dysgraphia.

Spelling a word involves the retrieval of information about the word's letters and their order from long-term memory as well as the maintenance and processing of this information by working memory in preparation for serial production by the motor system. While it is known that brain lesions may selectively affect orthographic long-term memory and working memory processes, relatively little is known about the neurotopographic distribution of the substrates that support these cognitive processes, or the lesions that give rise to the distinct forms of dysgraphia that affect these cognitive processes. To examine these issues, this study uses a voxel-based mapping approach to analyse the lesion distribution of 27 individuals with dysgraphia subsequent to stroke, who were identified on the basis of their behavioural profiles alone, as suffering from deficits only affecting either orthographic long-term or working memory, as well as six other individuals with deficits affecting both sets of processes. The findings provide, for the first time, clear evidence of substrates that selectively support orthographic long-term and working memory processes, with orthographic long-term memory deficits centred in either the left posterior inferior frontal region or left ventral temporal cortex, and orthographic working memory deficits primarily arising from lesions of the left parietal cortex centred on the intraparietal sulcus. These findings also contribute to our understanding of the relationship between the neural instantiation of written language processes and spoken language, working memory and other cognitive skills.

Right Hemisphere Grey Matter Volume and Language Functions in Stroke Aphasia.

The role of the right hemisphere (RH) in recovery from aphasia is incompletely understood. The present study quantified RH grey matter (GM) volume in individuals with chronic stroke-induced aphasia and cognitively healthy people using voxel-based morphometry. We compared group differences in GM volume in the entire RH and in RH regions-of-interest. Given that lesion site is a critical source of heterogeneity associated with poststroke language ability, we used voxel-based lesion symptom mapping (VLSM) to examine the relation between lesion site and language performance in the aphasic participants. Finally, using results derived from the VLSM as a covariate, we evaluated the relation between GM volume in the RH and language ability across domains, including comprehension and production processes both at the word and sentence levels and across spoken and written modalities. Between-subject comparisons showed that GM volume in the RH SMA was reduced in the aphasic group compared to the healthy controls. We also found that, for the aphasic group, increased RH volume in the MTG and the SMA was associated with better language comprehension and production scores, respectively. These data suggest that the RH may support functions previously performed by LH regions and have important implications for understanding poststroke reorganization.

Intrahemispheric Perfusion in Chronic Stroke-Induced Aphasia.

Stroke-induced alterations in cerebral blood flow (perfusion) may contribute to functional language impairments and recovery in chronic aphasia. Using MRI, we examined perfusion in the right and left hemispheres of 35 aphasic and 16 healthy control participants. Across 76 regions (38 per hemisphere), no significant between-subjects differences were found in the left, whereas blood flow in the right was increased in the aphasic compared to the control participants. Region-of-interest (ROI) analyses showed a varied pattern of hypo- and hyperperfused regions across hemispheres in the aphasic participants; however, there were no significant correlations between perfusion values and language abilities in these regions. These patterns may reflect autoregulatory changes in blood flow following stroke and/or increases in general cognitive effort, rather than maladaptive language processing. We also examined blood flow in perilesional tissue, finding the greatest hypoperfusion close to the lesion (within 0-6 mm), with greater hypoperfusion in this region compared to more distal regions. In addition, hypoperfusion in this region was significantly correlated with language impairment. These findings underscore the need to consider cerebral perfusion as a factor contributing to language deficits in chronic aphasia as well as recovery of language function.

Modality and morphology: what we write may not be what we say.

Written language is an evolutionarily recent human invention; consequently, its neural substrates cannot be determined by the genetic code. How, then, does the brain incorporate skills of this type? One possibility is that written language is dependent on evolutionarily older skills, such as spoken language; another is that dedicated substrates develop with expertise. If written language does depend on spoken language, then acquired deficits of spoken and written language should necessarily co-occur. Alternatively, if at least some substrates are dedicated to written language, such deficits may doubly dissociate. We report on 5 individuals with aphasia, documenting a double dissociation in which the production of affixes (e.g., the -ing in jumping) is disrupted in writing but not speaking or vice versa. The findings reveal that written- and spoken-language systems are considerably independent from the standpoint of morpho-orthographic operations. Understanding this independence of the orthographic system in adults has implications for the education and rehabilitation of people with written-language deficits.

Challenges in the use of treatment to investigate cognition.

The use of data from people with cognitive impairments to inform theories of cognition is an established methodology, particularly in the field of cognitive neuropsychology. However, it is less well known that studies that aim to improve cognitive functioning using treatment can also inform our understanding of cognition. This paper discusses a range of challenges that researchers face when testing theories of cognition and particularly when using treatment as a tool for doing so. It highlights the strengths of treatment methodology for testing causal relations and additionally discusses how generalization of treatment effects can shed light on the nature of cognitive representations and processes. These points are illustrated using examples from the Special Issue of Cognitive Neuropsychology entitled Treatment as a tool for investigating cognition.

The similarity structure of distributed neural responses reveals the multiple representations of letters.

Most cognitive theories of reading and spelling posit modality-specific representations of letter shapes, spoken letter names, and motor plans as well as abstract, amodal letter representations that serve to unify the various modality-specific formats. However, fundamental questions remain regarding the very existence of abstract letter representations, the neuro-topography of the different types of letter representations, and the degree of cortical selectivity for orthographic information. We directly test quantitative models of the similarity/dissimilarity structure of distributed neural representations of letters using Multivariate Pattern Analysis-Representational Similarity Analysis (MVPA-RSA) searchlight methods to analyze the BOLD response recorded from single letter viewing. These analyses reveal a left hemisphere ventral temporal region selectively tuned to abstract letter representations as well as substrates tuned to modality-specific (visual, phonological and motoric) representations of letters. The approaches applied in this research address various shortcomings of previous studies that have investigated these questions and, therefore, the findings we report serve to advance our understanding of the nature and format of the representations that occur within the various sub-regions of the large-scale networks used in reading and spelling.