The English Sublexical Toolkit: Methods for indexing sound-spelling consistency.

This work introduces the English Sublexical Toolkit, a suite of tools that utilizes an experience-dependent learning framework of sublexical knowledge to extract regularities from the English lexicon. The Toolkit quantifies the empirical regularity of sublexical units in both the reading and spelling directions (i.e., grapheme-to-phoneme and phoneme-to-grapheme) and at multiple grain sizes (i.e., phoneme/grapheme and onset/rime unit size). It can extract multiple experience-dependent regularity indices for words or pseudowords, including both frequency indices (e.g., grapheme frequency) and conditional probability indices (e.g., grapheme-to-phoneme probability). These tools provide (1) superior estimates of the regularities that better reflect the complexity of the sublexical system relative to previously published indices and (2) completely novel indices of sublexical units such as phonographeme frequency (i.e., combined units of individual phonemes and graphemes that are independent of processing direction). We demonstrate that measures from the toolkit explain significant amounts of variance in empirical data (naming of real words and lexical decision), and either outperform or are comparable to the best available consistency measures. The flexibility of the toolkit is further demonstrated by its ability to readily index the probability of different pseudowords pronunciations, and we report that the measures account for the majority of variance in these empirically observed probabilities. Overall, this work provides a framework and resources that can be flexibly used to identify optimal corpus-based consistency measures that help explain reading/spelling behaviors for real and pseudowords.

Hippocampal functional connectivity mediates the association between cardiorespiratory fitness and cognitive function in healthy young adults.

OBJECTIVE: Higher cardiorespiratory fitness (CRF) induces neuroprotective effects in the hippocampus, a key brain region for memory and learning. We investigated the association between CRF and functional connectivity (FC) of the hippocampus in healthy young adults. We also examined the association between hippocampal FC and neurocognitive function. Lastly, we tested whether hippocampal FC mediates the association between 2-Min Walk Test (2MWT) and neurocognitive function. METHODS: 913 young adults (28.7 ± 3.7 years) from the Human Connectome Project were included in the analyses. The 2MWT performance result was used as a proxy for cardiovascular endurance. Fluid and crystalized composite neurocognitive scores were used to assess cognition. Resting-state functional MRI data were processed to measure hippocampal FC. Linear regression was used to examine the association between 2MWT, hippocampal FC, and neurocognitive outcomes after controlling for age, sex, years of education, body mass index, systolic blood pressure, and gait speed. RESULTS: Better 2MWT performance was associated with greater FC between the anterior hippocampus and right posterior cingulate and left middle temporal gyrus. No associations between 2MWT and posterior hippocampal FC, whole hippocampal FC, and caudate FC (control region) were observed. Greater anterior hippocampal FC was associated with better crystalized cognition scores. Lastly, greater FC between the anterior hippocampus and right posterior cingulate mediated the association between better 2MWT scores and higher crystalized cognition scores. CONCLUSIONS: Anterior hippocampal FC may be one underlying neurophysiological mechanism that promotes the association between 2MWT performance and crystalized composite cognitive function in healthy young adults.

Emotional processing and positive affect after acute exercise in healthy older adults.

The well-elucidated improvement of mood immediately after exercise in older adults presumably involves adaptations in emotion-processing brain networks. However, little is known about effects of acute exercise on appetitive and aversive emotion-related network recruitment in older adults. The purpose of this study was to determine the effect of acute exercise, compared to a seated rest control condition, on pleasant and unpleasant emotion-related regional activation in healthy older adults. Functional MRI data were acquired from 32 active older adults during blocked presentations of pleasant, neutral and unpleasant images from the International Affective Pictures System. fMRI data were collected after participants completed 30 min of moderate to vigorous intensity cycling or seated rest, performed in a counterbalanced order across separate days in a within-subject design. The findings suggest three ways that emotional processing in the brain may be different immediately after exercise (relative to immediately after rest): First, reduced demands on emotional regulation during pleasant emotional processing as indicated by lower precuneus activation for pleasant stimuli; second, reduced processing of negative emotional stimuli in visual association areas as indicated by lower activation for unpleasant stimuli in the bilateral fusiform and ITG; third, an increased recruitment in activation associated with regulating/inhibiting unpleasant emotional processing in the bilateral medial superior frontal gyrus (dorsomedial prefrontal cortex), angular gyri, supramarginal gyri, left cerebellar crus I/II and a portion of right dorsolateral prefrontal cortex. Overall, these findings support that acute exercise in active older adults alters activation in key emotional processing and regulating brain regions.

Basal forebrain functional connectivity as a mediator of associations between cardiorespiratory fitness and cognition in healthy older women.

Age-related cholinergic dysfunction within the basal forebrain (BF) is one of the key hallmarks for age-related cognitive decline. Given that higher cardiorespiratory fitness (CRF) induces neuroprotective effects that may differ by sex, we investigated the moderating effects of sex on the associations between CRF, BF cholinergic function, and cognitive function in older adults. 176 older adults (68.5 years) were included from the Nathan Kline Institute Rockland Sample. Functional connectivity (rsFC) of the BF subregions including the medial septal nucleus/diagonal band of Broca (MS/DB) and nucleus basalis of Meynert (NBM) were computed from resting-sate functional MRI. Modified Astrand-Ryhming submaximal cycle ergometer protocol was used to estimate CRF. Trail making task and inhibition performance during the color word interference test from the Delis-Kaplan Executive Function System and Rey Auditory Verbal Learning Test were used to examine cognitive function. Linear regression models were used to assess the associations between CRF, BF rsFC, and cognitive performance after controlling for age, sex, and years of education. Subsequently, we measured the associations between the variables in men and women separately to investigate the sex differences. There was an association between higher CRF and greater rsFC between the NBM and right middle frontal gyrus in older men and women. There were significant associations between CRF, NBM rsFC, and trail making task number-letter switching performance only in women. In women, greater NBM rsFC mediated the association between higher CRF and better trail making task number-letter switching performance. These findings provide evidence that greater NBM rsFC, particularly in older women, may be an underlying neural mechanism for the relationship between higher CRF and better executive function.

Pseudoword spelling: insights into sublexical representations and lexical interactions.

ABSTRACTIn this work we introduce a new tool for measuring English spelling-sound consistency, the PG Toolkit, which we use to conduct detailed analyses of pseudoword spellings that provide new insights into the nature of sublexical and lexical representations. There are several key findings: first, sound-spelling consistency measured at two different "grain sizes", phonographeme and onset/rime, each explained unique variance in pseudoword spelling. Second, lexical skill was more related to pseudoword accuracy at the onset/rime level than at the phonographeme level, and individuals who chose more consistent mappings to spell pseudowords tended to have better lexical skill. Finally, no unique contribution of consistency in the reading direction ("feedback") was found after controlling for consistency in the spelling direction. Taken together, the results validate the various measures provided by the PG Toolkit and establish new evidence that supports an interpretation of sublexical processes as operations over hierarchically-structured representations.

Neurite dispersion and density mediates the relationship between cardiorespiratory fitness and cognition in healthy younger adults.

Growing evidence suggests physical activity and cardiorespiratory fitness are associated with better cognition across the lifespan. However, the neurobiological underpinnings relating fitness and cognition remain unclear, particularly in healthy younger adults. Using a well-established and popular multi-compartment diffusion modeling approach, called Neurite Orientation and Dispersion and Density Imaging (NODDI), we investigated the relationship between physical fitness (measured via a 2-min walk test), cognition (fluid and crystallized), and gray and white matter microstructure, in a large sample (n = 816) of healthy younger adults (ages 22-35 years) from the human connectome project (HCP). Concurrent with previous literature, we found that fitness was positively associated with both fluid and crystallized cognition. Furthermore, we found that physical fitness was negatively associated with white matter orientation dispersion index (ODIWM) around the cerebellar peduncle and was negatively associated with widespread cortical and subcortical gray matter neurite density index (NDIGM). Lower ODIWM of the cerebral peduncle was associated with better fluid cognitive performance, while lower NDIGM was associated with better crystallized cognition. Finally, we found that while ODIWM partially mediated the relationship between fitness and fluid cognition, NDIGM partially mediated the relationship between fitness and crystallized cognition. This study is the first to explore the relationship between physical fitness and white and gray matter microstructure measures using NODDI. Our findings suggest that in addition to improved cognitive performance, higher physical fitness may be associated with lower white matter tract dispersion and lower neurite density in the cortical and subcortical gray matter of healthy younger adults.

Differential associations of regional cerebellar volume with gait speed and working memory.

The relationship between gait speed and working memory is well-understood in older adults. However, it remains to be determined whether this relationship also exists in younger adults; and there is little known regarding the possible neural mechanism underlying the association between gait speed and working memory. The aims of this study are to determine if there is: (1) an association between gait speed and working memory performance; and (2) a mediating role of cerebellar subregion volume in the correlation between gait speed and working memory in healthy younger adults. 1054 younger adults (28.7 ± 3.6 years) from the Human Connectome Project were included in the analyses. A four-meter gait test was used to assess gait speed. The 2-back task was used to measure working memory performance [accuracy and response time (RT)]. T1-weighted structural MRI data (obtained using Siemens 3 T MRI scanner) was used to assess cerebellar subregion volumes. Linear regression and mediation analysis were used to examine the relationships between the variables after controlling for age, sex, and education. There was no association between gait speed and 2-back working memory performance in younger adults. Greater Crus I and whole cerebellar volumes were associated with better 2-back working memory accuracy. Greater VIIIa volume was associated with faster gait speed. Greater Crus 1 and VIIIa volumes were also associated with higher fluid cognition. The present study suggests that specific subregions of the cerebellar volumes are distinctively associated with gait speed and working memory performance in healthy younger adults.

Microstructural Plasticity in the Hippocampus of Healthy Older Adults after Acute Exercise.

INTRODUCTION: The hippocampus experiences structural and functional decline with age and is a critical region for memory and many cognitive processes. Exercise is beneficial for the aging brain and shows preferential benefits for hippocampal volume, activation, and memory-related cognitive processes. However, research thus far has primarily focused on the effects of exercise on long-term volumetric changes in the hippocampus using structural magnetic resonance imaging. Critically, microstructural alterations within the hippocampus over short time intervals are associated with neuroplasticity and cognitive changes that do not alter its volume but are still functionally relevant. However, it is not yet known if microstructural neuroplasticity occurs in the hippocampus in response to a single session of exercise. METHODS: We used a within-subject design to determine if a 30-min bout of moderate-intensity aerobic exercise altered bilateral hippocampal diffusion tensor imaging measures in healthy older adults (n = 30) compared with a seated rest control condition. RESULTS: Significantly lower fractional anisotropy and higher mean diffusivity were found after exercise relative to seated rest within the bilateral hippocampus, and this effect was driven by higher radial diffusivity. No significant differences in axial diffusivity were observed. CONCLUSIONS: These findings suggest that a single exercise session can lead to microstructural alterations in the hippocampus of healthy older adults. These differences may be associated with changes in the extracellular space and glial, synaptic, and dendritic processes within the hippocampus. Repeated microstructural alterations resulting from acute bouts of exercise may accumulate and precede larger volumetric and functional improvements in the hippocampus.

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.

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.

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.

Shared orthographic neuronal representations for spelling and reading.

A central question in the study of the neural basis of written language is whether reading and spelling utilize shared orthographic representations. While recent studies employing fMRI to test this question report that the left inferior frontal gyrus (IFG) and ventral occipitotemporal cortex (vOTC) are active during both spelling and reading in the same subjects (Purcell et al., 2011a; Rapp and Lipka, 2011), the spatial resolution of fMRI limits the interpretation of these findings. Specifically, it is unknown if the neurons which encode orthography for reading are also involved in spelling of the same words. Here we address this question by employing an event-related functional magnetic resonance imaging-adaptation (fMRI-A) paradigm designed to examine shared orthographic representations across spelling and reading. First, we identified areas that independently showed adaptation to reading, and adaptation to spelling. Then we identified spatial convergence for these two separate maps via a conjunction analysis. Consistent with previous studies (Purcell et al., 2011a; Rapp and Lipka, 2011), this analysis revealed the left dorsal IFG, vOTC and supplementary motor area. To further validate these observations, we then interrogated these regions using an across-task adaptation technique, and found adaptation across reading and spelling in the left dorsal IFG (BA 44/9). Our final analysis focused specifically on the Visual Word Form Area (VWFA) in the vOTC, whose variability in location among subjects requires the use of subject-specific identification mechanisms (Glezer and Riesenhuber, 2013). Using a functional localizer for reading, we defined the VWFA in each subject, and found adaptation effects for both within the spelling and reading conditions, respectively, as well as across spelling and reading. Because none of these effects were observed during a phonological/semantic control condition, we conclude that the left dorsal IFG and VWFA are involved in accessing the same orthography-specific representations for spelling and reading.

Imaging network level language recovery after left PCA stroke.

PURPOSE: The neural mechanisms that support aphasia recovery are not yet fully understood. Our goal was to evaluate longitudinal changes in naming recovery in participants with posterior cerebral artery (PCA) stroke using a case-by-case analysis. METHODS: Using task based and resting state functional magnetic resonance imaging (fMRI) and detailed language testing, we longitudinally studied the recovery of the naming network in four participants with PCA stroke with naming deficits at the acute (0 week), sub acute (3-5 weeks), and chronic time point (5-7 months) post stroke. Behavioral and imaging analyses (task related and resting state functional connectivity) were carried out to elucidate longitudinal changes in naming recovery. RESULTS: Behavioral and imaging analysis revealed that an improvement in naming accuracy from the acute to the chronic stage was reflected by increased connectivity within and between left and right hemisphere "language" regions. One participant who had persistent moderate naming deficit showed weak and decreasing connectivity longitudinally within and between left and right hemisphere language regions. CONCLUSIONS: These findings emphasize a network view of aphasia recovery, and show that the degree of inter- and intra- hemispheric balance between the language-specific regions is necessary for optimal recovery of naming, at least in participants with PCA stroke.

Beyond the visual word form area: the orthography-semantics interface in spelling and reading.

Lexical orthographic information provides the basis for recovering the meanings of words in reading and for generating correct word spellings in writing. Research has provided evidence that an area of the left ventral temporal cortex, a subregion of what is often referred to as the visual word form area (VWFA), plays a significant role specifically in lexical orthographic processing. The current investigation goes beyond this previous work by examining the neurotopography of the interface of lexical orthography with semantics. We apply a novel lesion mapping approach with three individuals with acquired dysgraphia and dyslexia who suffered lesions to left ventral temporal cortex. To map cognitive processes to their neural substrates, this lesion mapping approach applies similar logical constraints to those used in cognitive neuropsychological research. Using this approach, this investigation: (a) identifies a region anterior to the VWFA that is important in the interface of orthographic information with semantics for reading and spelling; (b) determines that, within this orthography-semantics interface region (OSIR), access to orthography from semantics (spelling) is topographically distinct from access to semantics from orthography (reading); (c) provides evidence that, within this region, there is modality-specific access to and from lexical semantics for both spoken and written modalities, in both word production and comprehension. Overall, this study contributes to our understanding of the neural architecture at the lexical orthography-semantic-phonological interface within left ventral temporal cortex.

Identifying functional reorganization of spelling networks: an individual peak probability comparison approach.

Previous research has shown that damage to the neural substrates of orthographic processing can lead to functional reorganization during reading (Tsapkini et al., 2011); in this research we ask if the same is true for spelling. To examine the functional reorganization of spelling networks we present a novel three-stage Individual Peak Probability Comparison (IPPC) analysis approach for comparing the activation patterns obtained during fMRI of spelling in a single brain-damaged individual with dysgraphia to those obtained in a set of non-impaired control participants. The first analysis stage characterizes the convergence in activations across non-impaired control participants by applying a technique typically used for characterizing activations across studies: Activation Likelihood Estimate (ALE) (Turkeltaub et al., 2002). This method was used to identify locations that have a high likelihood of yielding activation peaks in the non-impaired participants. The second stage provides a characterization of the degree to which the brain-damaged individual's activations correspond to the group pattern identified in Stage 1. This involves performing a Mahalanobis distance statistics analysis (Tsapkini et al., 2011) that compares each of a control group's peak activation locations to the nearest peak generated by the brain-damaged individual. The third stage evaluates the extent to which the brain-damaged individual's peaks are atypical relative to the range of individual variation among the control participants. This IPPC analysis allows for a quantifiable, statistically sound method for comparing an individual's activation pattern to the patterns observed in a control group and, thus, provides a valuable tool for identifying functional reorganization in a brain-damaged individual with impaired spelling. Furthermore, this approach can be applied more generally to compare any individual's activation pattern with that of a set of other individuals.

Examining the central and peripheral processes of written word production through meta-analysis.

Producing written words requires "central" cognitive processes (such as orthographic long-term and working memory) as well as more peripheral processes responsible for generating the motor actions needed for producing written words in a variety of formats (handwriting, typing, etc.). In recent years, various functional neuroimaging studies have examined the neural substrates underlying the central and peripheral processes of written word production. This study provides the first quantitative meta-analysis of these studies by applying activation likelihood estimation (ALE) methods (Turkeltaub et al., 2002). For alphabet languages, we identified 11 studies (with a total of 17 experimental contrasts) that had been designed to isolate central and/or peripheral processes of word spelling (total number of participants = 146). Three ALE meta-analyses were carried out. One involved the complete set of 17 contrasts; two others were applied to subsets of contrasts to distinguish the neural substrates of central from peripheral processes. These analyses identified a network of brain regions reliably associated with the central and peripheral processes of word spelling. Among the many significant results, is the finding that the regions with the greatest correspondence across studies were in the left inferior temporal/fusiform gyri and left inferior frontal gyrus. Furthermore, although the angular gyrus (AG) has traditionally been identified as a key site within the written word production network, none of the meta-analyses found it to be a consistent site of activation, identifying instead a region just superior/medial to the left AG in the left posterior intraparietal sulcus. These meta-analyses and the discussion of results provide a valuable foundation upon which future studies that examine the neural basis of written word production can build.

A combined fMRI study of typed spelling and reading.

In this study we employed a novel technique to examine the neural basis of written spelling by having subjects touch-type single words on an fMRI compatible QWERTY keyboard. Additionally, in the same group of participants we determined if task-related signal changes associated with typed spelling were also co-localized with or separate from those for reading. Of particular interest were the left inferior frontal gyrus, left inferior parietal lobe as well as an area in the left occipitotemporal cortex termed the Visual Word Form Area (VWFA), each of which have been associated with both spelling and reading. Our results revealed that typed spelling was associated with a left hemisphere network of regions which included the inferior frontal gyrus, intraparietal sulcus, inferior temporal/fusiform gyrus, as well as a region in the superior/middle frontal gyrus, near Exner's area. A conjunction analysis of activation associated with spelling and reading revealed a significant overlap in the left inferior frontal gyrus and occipitotemporal cortex. Interestingly, within the occipitotemporal cortex just lateral and superior to the VWFA we identified an area that was selectively associated with spelling, as revealed by a direct comparison of the two tasks. These results demonstrate that typed spelling activates a predominantly left hemisphere network, a subset of which is functionally relevant to both spelling and reading. Further analysis revealed that the left occipitotemporal cortex contains regions with both conjoint and dissociable patterns of activation for spelling and reading.