Chemical linguistics: Reading the modified proteome.

In this issue of Molecular Cell, Lin et al. (2021) develop a tri-functional amino acid probe for the discovery and characterization of protein domains that sense or "read" protein post-translational modifications, a chemical tool that can facilitate our understanding of how signaling networks act at the molecular level.

Saccades are locked to the phase of alpha oscillations during natural reading.

We saccade 3 to 5 times per second when reading. However, little is known about the neuronal mechanisms coordinating the oculomotor and visual systems during such rapid processing. Here, we ask if brain oscillations play a role in the temporal coordination of the visuomotor integration. We simultaneously acquired MEG and eye-tracking data while participants read sentences silently. Every sentence was embedded with a target word of either high or low lexical frequency. Our key finding demonstrated that saccade onsets were locked to the phase of alpha oscillations (8 to 13 Hz), and in particular, for saccades towards low frequency words. Source modelling demonstrated that the alpha oscillations to which the saccades were locked, were generated in the right-visual motor cortex (BA 7). Our findings suggest that the alpha oscillations serve to time the processing between the oculomotor and visual systems during natural reading, and that this coordination becomes more pronounced for demanding words.

Predictive Brain Activity Shows Congruent Semantic Specificity in Language Comprehension and Production.

Sentence fragments strongly predicting a specific subsequent meaningful word elicit larger preword slow waves, prediction potentials (PPs), than unpredictive contexts. To test the current predictive processing models, 128-channel EEG data were collected from both sexes to examine whether (1) different semantic PPs are elicited in language comprehension and production and (2) whether these PPs originate from the same specific "prediction area(s)" or rather from widely distributed category-specific neuronal circuits reflecting the meaning of the predicted item. Slow waves larger after predictable than unpredictable contexts were present both before subjects heard the sentence-final word in the comprehension experiment and before they pronounced the sentence-final word in the production experiment. Crucially, cortical sources underlying the semantic PP were distributed across several cortical areas and differed between the semantic categories of the expected words. In both production and comprehension, the anticipation of animal words was reflected by sources in posterior visual areas, whereas predictable tool words were preceded by sources in the frontocentral sensorimotor cortex. For both modalities, PP size increased with higher cloze probability, thus further confirming that it reflects semantic prediction, and with shorter latencies with which participants completed sentence fragments. These results sit well with theories viewing distributed semantic category-specific circuits as the mechanistic basis of semantic prediction in the two modalities.

Cortical asymmetries at different spatial hierarchies relate to phonological processing ability.

The ability to map speech sounds to corresponding letters is critical for establishing proficient reading. People vary in this phonological processing ability, which has been hypothesized to result from variation in hemispheric asymmetries within brain regions that support language. A cerebral lateralization hypothesis predicts that more asymmetric brain structures facilitate the development of foundational reading skills like phonological processing. That is, structural asymmetries are predicted to linearly increase with ability. In contrast, a canalization hypothesis predicts that asymmetries constrain behavioral performance within a normal range. That is, structural asymmetries are predicted to quadratically relate to phonological processing, with average phonological processing occurring in people with the most asymmetric structures. These predictions were examined in relatively large samples of children (N = 424) and adults (N = 300), using a topological asymmetry analysis of T1-weighted brain images and a decoding measure of phonological processing. There was limited evidence of structural asymmetry and phonological decoding associations in classic language-related brain regions. However, and in modest support of the cerebral lateralization hypothesis, small to medium effect sizes were observed where phonological decoding accuracy increased with the magnitude of the largest structural asymmetry across left hemisphere cortical regions, but not right hemisphere cortical regions, for both the adult and pediatric samples. In support of the canalization hypothesis, small to medium effect sizes were observed where phonological decoding in the normal range was associated with increased asymmetries in specific cortical regions for both the adult and pediatric samples, which included performance monitoring and motor planning brain regions that contribute to oral and written language functions. Thus, the relevance of each hypothesis to phonological decoding may depend on the scale of brain organization.

Cracking the neural code for word recognition in convolutional neural networks.

Learning to read places a strong challenge on the visual system. Years of expertise lead to a remarkable capacity to separate similar letters and encode their relative positions, thus distinguishing words such as FORM and FROM, invariantly over a large range of positions, sizes and fonts. How neural circuits achieve invariant word recognition remains unknown. Here, we address this issue by recycling deep neural network models initially trained for image recognition. We retrain them to recognize written words and then analyze how reading-specialized units emerge and operate across the successive layers. With literacy, a small subset of units becomes specialized for word recognition in the learned script, similar to the visual word form area (VWFA) in the human brain. We show that these units are sensitive to specific letter identities and their ordinal position from the left or the right of a word. The transition from retinotopic to ordinal position coding is achieved by a hierarchy of "space bigram" unit that detect the position of a letter relative to a blank space and that pool across low- and high-frequency-sensitive units from early layers of the network. The proposed scheme provides a plausible neural code for written words in the VWFA, and leads to predictions for reading behavior, error patterns, and the neurophysiology of reading.

Language models outperform cloze predictability in a cognitive model of reading.

Although word predictability is commonly considered an important factor in reading, sophisticated accounts of predictability in theories of reading are lacking. Computational models of reading traditionally use cloze norming as a proxy of word predictability, but what cloze norms precisely capture remains unclear. This study investigates whether large language models (LLMs) can fill this gap. Contextual predictions are implemented via a novel parallel-graded mechanism, where all predicted words at a given position are pre-activated as a function of contextual certainty, which varies dynamically as text processing unfolds. Through reading simulations with OB1-reader, a cognitive model of word recognition and eye-movement control in reading, we compare the model's fit to eye-movement data when using predictability values derived from a cloze task against those derived from LLMs (GPT-2 and LLaMA). Root Mean Square Error between simulated and human eye movements indicates that LLM predictability provides a better fit than cloze. This is the first study to use LLMs to augment a cognitive model of reading with higher-order language processing while proposing a mechanism on the interplay between word predictability and eye movements.

Subtitled speech: the neural mechanisms of ticker-tape synaesthesia.

The acquisition of reading modifies areas of the brain associated with vision and with language, in addition to their connections. These changes enable reciprocal translation between orthography and the sounds and meaning of words. Individual variability in the pre-existing cerebral substrate contributes to the range of eventual reading abilities, extending to atypical developmental patterns, including dyslexia and reading-related synaesthesias. The present study is devoted to the little-studied but highly informative ticker-tape synaesthesia, in which speech perception triggers the vivid and irrepressible perception of words in their written form in the mind's eye. We scanned a group of 17 synaesthetes and 17 matched controls with functional MRI, while they listened to spoken sentences, words, numbers or pseudowords (Experiment 1), viewed images and written words (Experiment 2) or were at rest (Experiment 3). First, we found direct correlates of the ticker-tape synaesthesia phenomenon: during speech perception, as ticker-tape synaesthesia was active, synaesthetes showed over-activation of left perisylvian regions supporting phonology and of the occipitotemporal visual word form area, where orthography is represented. Second, we provided support to the hypothesis that ticker-tape synaesthesia results from atypical relationships between spoken and written language processing: the ticker-tape synaesthesia-related regions overlap closely with cortices activated during reading, and the overlap of speech-related and reading-related areas is larger in synaesthetes than in controls. Furthermore, the regions over-activated in ticker-tape synaesthesia overlap with regions under-activated in dyslexia. Third, during the resting state (i.e. in the absence of current ticker-tape synaesthesia), synaesthetes showed increased functional connectivity between left prefrontal and bilateral occipital regions. This pattern might reflect a lowered threshold for conscious access to visual mental contents and might imply a non-specific predisposition to all synaesthesias with a visual content. These data provide a rich and coherent account of ticker-tape synaesthesia as a non-detrimental developmental condition created by the interaction of reading acquisition with an atypical cerebral substrate.

Dissociation of reading and naming in ventral occipitotemporal cortex.

Lesions in the language-dominant ventral occipitotemporal cortex (vOTC) can result in selective impairment of either reading or naming, resulting in alexia or anomia. Yet, functional imaging studies that show differential activation for naming and reading do not reveal activity exclusively tuned to one of these inputs. To resolve this dissonance in the functional architecture of the vOTC, we used focused stimulation to the vOTC in 49 adult patients during reading and naming, and generated a population-level, probabilistic map to evaluate if reading and naming are clearly dissociable within individuals. Language mapping (50 Hz, 2829 stimulations) was performed during passage reading (216 positive sites) and visual naming (304 positive sites). Within the vOTC, we isolated sites that selectively disrupted reading (24 sites in 11 patients) or naming (27 sites in 12 patients), and those that disrupted both processes (75 sites in 21 patients). The anteromedial vOTC had a higher probability of producing naming disruption, while posterolateral regions resulted in greater reading-specific disruption. Between them lay a multi-modal region where stimulation disrupted both reading and naming. This work provides a comprehensive view of vOTC organization-the existence of a heteromodal cortex critical to both reading and naming, along with a causally dissociable unimodal naming cortex, and a reading-specific visual word form area in the vOTC. Their distinct roles as associative regions may thus relate to their connectivity within the broader language network that is disrupted by stimulation, more than to highly selective tuning properties. Our work also implies that pre-surgical mapping of both reading and naming is essential for patients requiring vOTC resections, as these functions are not co-localized, and such mapping may prevent the occurrence of unexpected deficits.

Brain connectivity and academic skills in English learners.

English learners (ELs) are a rapidly growing population in schools in the United States with limited experience and proficiency in English. To better understand the path for EL's academic success in school, it is important to understand how EL's brain systems are used for academic learning in English. We studied, in a cohort of Hispanic middle-schoolers (n = 45, 22F) with limited English proficiency and a wide range of reading and math abilities, brain network properties related to academic abilities. We applied a method for localizing brain regions of interest (ROIs) that are group-constrained, yet individually specific, to test how resting state functional connectivity between regions that are important for academic learning (reading, math, and cognitive control regions) are related to academic abilities. ROIs were selected from task localizers probing reading and math skills in the same participants. We found that connectivity across all ROIs, as well as connectivity of just the cognitive control ROIs, were positively related to measures of reading skills but not math skills. This work suggests that cognitive control brain systems have a central role for reading in ELs. Our results also indicate that an individualized approach for localizing brain function may clarify brain-behavior relationships.

Action video games and posterior parietal cortex neuromodulation enhance both attention and reading in adults with developmental dyslexia.

The impact of action video games on reading performance has been already demonstrated in individuals with and without neurodevelopmental disorders. The combination of action video games and posterior parietal cortex neuromodulation by a transcranial random noise stimulation could enhance brain plasticity, improving attentional control and reading skills also in adults with developmental dyslexia. In a double blind randomized controlled trial, 20 young adult nonaction video game players with developmental dyslexia were trained for 15 h with action video games. Half of the participants were stimulated with bilateral transcranial random noise stimulation on the posterior parietal cortex during the action video game training, whereas the others were in the placebo (i.e. sham) condition. Word text reading, pseudowords decoding, and temporal attention (attentional blink), as well as electroencephalographic activity during the attentional blink, were measured before and after the training. The action video game + transcranial random noise stimulation group showed temporal attention, word text reading, and pseudoword decoding enhancements and P300 amplitude brain potential changes. The enhancement in temporal attention performance was related with the efficiency in pseudoword decoding improvement. Our results demonstrate that the combination of action video game training with parietal neuromodulation increases the efficiency of visual attention deployment, probably reshaping goal-directed and stimulus-driven fronto-parietal attentional networks interplay in young adults with neurodevelopmental conditions.

Functional interactions underlying visuospatial orthographic processes in Chinese reading.

As a logographic writing system, Chinese reading involves the processing of visuospatial orthographic (ORT) properties. However, this aspect has received relatively less attention in neuroimaging research, which has tended to emphasize phonological (PHO) and semantic (SEM) aspects in processing Chinese characters. Here, we compared the functional correlates supporting all these three processes in a functional MRI single-character reading study, in which 35 native Chinese adults were asked to make ORT, PHO, and SEM judgments in separate task-specific activation blocks. Our findings revealed increased involvement of the right hemisphere in processing Chinese visuospatial orthography, particularly evident in the right ventral occipito-temporal cortex (vOTC). Additionally, time course analysis revealed that the left superior parietal gyrus (SPG) was initially involved in SEM processing but contributed to the visuospatial processing of words in a later time window. Finally, ORT processing demonstrated stronger recruitment of left vOTC-SPG-middle frontal gyrus (MFG) functional connectivity compared to SEM processing. This functional coupling correlated with reduced regional engagement of the left vOTC and MFG, highlighting that visuospatial ORT processes in reading Chinese rely on functional interactions among key regions rather than local regional processes. In conclusion, these findings underscore visuospatial ORT processes as a distinctive feature of reading logographic characters.

Phonological properties of logographic words modulate brain activation in bilinguals: a comparative study of Chinese characters and Japanese Kanji.

The brain networks for the first (L1) and second (L2) languages are dynamically formed in the bilingual brain. This study delves into the neural mechanisms associated with logographic-logographic bilingualism, where both languages employ visually complex and conceptually rich logographic scripts. Using functional Magnetic Resonance Imaging, we examined the brain activity of Chinese-Japanese bilinguals and Japanese-Chinese bilinguals as they engaged in rhyming tasks with Chinese characters and Japanese Kanji. Results showed that Japanese-Chinese bilinguals processed both languages using common brain areas, demonstrating an assimilation pattern, whereas Chinese-Japanese bilinguals recruited additional neural regions in the left lateral prefrontal cortex for processing Japanese Kanji, reflecting their accommodation to the higher phonological complexity of L2. In addition, Japanese speakers relied more on the phonological processing route, while Chinese speakers favored visual form analysis for both languages, indicating differing neural strategy preferences between the 2 bilingual groups. Moreover, multivariate pattern analysis demonstrated that, despite the considerable neural overlap, each bilingual group formed distinguishable neural representations for each language. These findings highlight the brain's capacity for neural adaptability and specificity when processing complex logographic languages, enriching our understanding of the neural underpinnings supporting bilingual language processing.

Effect of short-term intensive design-based STEM learning on executive function: an fNIRS study of the left-behind children.

Design-based STEM learning is believed to be an effective cross-disciplinary strategy for promoting children's cognitive development. Yet, its impact on executive functions, particularly for disadvantaged children, still need to be explored. This study investigated the effects of short-term intensive design-based STEM learning on executive function among left-behind children. Sixty-one Grade 4 students from a school dedicated to the left-behind children in China were sampled and randomly assigned to an experimental group (10.70 ± 0.47 years old, n = 30) or a control group (10.77 ± 0.43 years old, n = 31). The experimental group underwent a two-week design-based STEM training program, while the control group participated in a 2-week STEM-related reading program. Both groups were assessed with the brain activation from 4 brain regions of interest using functional near-infrared spectroscopy (fNIRS) and behavioral measures during a Stroop task before and after the training. Analysis disclosed: (i) a significant within-group time effect in the experimental group, with posttest brain activation in Brodmann Area 10 and 46 being notably lower during neutral and word conditions; (ii) a significant between-group difference at posttest, with the experimental group showing considerably lower brain activation in Brodmann Area 10 and Brodmann Area 46 than the control group; and (iii) a significant task effect in brain activity among the three conditions of the Stroop task. These findings indicated that this STEM learning effectively enhanced executive function in left-behind children. The discrepancy between the non-significant differences in behavioral performance and the significant ones in brain activation implies a compensatory mechanism in brain activation. This study enriches current theories about the impact of Science, Technology, Engineering, and Mathematics (STEM) learning on children's executive function development, providing biological evidence and valuable insights for educational curriculum design and assessment.

Reading language of the eyes in female depression.

Aberrations in non-verbal social cognition have been reported to coincide with major depressive disorder. Yet little is known about the role of the eyes. To fill this gap, the present study explores whether and, if so, how reading language of the eyes is altered in depression. For this purpose, patients and person-by-person matched typically developing individuals were administered the Emotions in Masked Faces task and Reading the Mind in the Eyes Test, modified, both of which contained a comparable amount of visual information available. For achieving group homogeneity, we set a focus on females as major depressive disorder displays a gender-specific profile. The findings show that facial masks selectively affect inferring emotions: recognition of sadness and anger are more heavily compromised in major depressive disorder as compared with typically developing controls, whereas the recognition of fear, happiness, and neutral expressions remains unhindered. Disgust, the forgotten emotion of psychiatry, is the least recognizable emotion in both groups. On the Reading the Mind in the Eyes Test patients exhibit lower accuracy on positive expressions than their typically developing peers, but do not differ on negative items. In both depressive and typically developing individuals, the ability to recognize emotions behind a mask and performance on the Reading the Mind in the Eyes Test are linked to each other in processing speed, but not recognition accuracy. The outcome provides a blueprint for understanding the complexities of reading language of the eyes within and beyond the COVID-19 pandemic.

Developmental dyslexia susceptibility genes DNAAF4, DCDC2, and NRSN1 are associated with brain function in fluently reading adolescents and young adults.

Reading skills and developmental dyslexia, characterized by difficulties in developing reading skills, have been associated with brain anomalies within the language network. Genetic factors contribute to developmental dyslexia risk, but the mechanisms by which these genes influence reading skills remain unclear. In this preregistered study (https://osf.io/7sehx), we explored if developmental dyslexia susceptibility genes DNAAF4, DCDC2, NRSN1, and KIAA0319 are associated with brain function in fluently reading adolescents and young adults. Functional MRI and task performance data were collected during tasks involving written and spoken sentence processing, and DNA sequence variants of developmental dyslexia susceptibility genes previously associated with brain structure anomalies were genotyped. The results revealed that variation in DNAAF4, DCDC2, and NRSN1 is associated with brain activity in key language regions: the left inferior frontal gyrus, middle temporal gyrus, and intraparietal sulcus. Furthermore, NRSN1 was associated with task performance, but KIAA0319 did not yield any significant associations. Our findings suggest that individuals with a genetic predisposition to developmental dyslexia may partly employ compensatory neural and behavioral mechanisms to maintain typical task performance. Our study highlights the relevance of these developmental dyslexia susceptibility genes in language-related brain function, even in individuals without developmental dyslexia, providing valuable insights into the genetic factors influencing language processing.

Both mOTS-words and pOTS-words prefer emoji stimuli over text stimuli during a lexical judgment task.

The visual word form area in the occipitotemporal sulcus (here OTS-words) is crucial for reading and shows a preference for text stimuli. We hypothesized that this text preference may be driven by lexical processing. Hence, we performed three fMRI experiments (n = 15), systematically varying participants' task and stimulus, and separately evaluated middle mOTS-words and posterior pOTS-words. Experiment 1 contrasted text with other visual stimuli to identify both OTS-words subregions. Experiment 2 utilized an fMRI adaptation paradigm, presenting compound words as texts or emojis. In experiment 3, participants performed a lexical or color judgment task on compound words in text or emoji format. In experiment 2, pOTS-words, but not mOTS-words, showed fMRI adaptation for compound words in both formats. In experiment 3, both subregions showed higher responses to compound words in emoji format. Moreover, mOTS-words showed higher responses during the lexical judgment task and a task-stimulus interaction. Multivariate analyses revealed that distributed responses in pOTS-words encode stimulus and distributed responses in mOTS-words encode stimulus and task. Together, our findings suggest that the function of the OTS-words subregions goes beyond the specific visual processing of text and that these regions are flexibly recruited whenever semantic meaning needs to be assigned to visual input.

An executive-functions-based reading training enhances sensory-motor systems integration during reading fluency in children with dyslexia.

The Simple View of Reading model suggests that intact language processing and word decoding lead to proficient reading comprehension, with recent studies pointing at executive functions as an important component contributing to reading proficiency. Here, we aimed to determine the underlying mechanism(s) for these changes. Participants include 120 8- to 12-year-old children (n = 55 with dyslexia, n = 65 typical readers) trained on an executive functions-based reading program, including pre/postfunctional MRI and behavioral data collection. Across groups, improved word reading was related to stronger functional connections within executive functions and sensory networks. In children with dyslexia, faster and more accurate word reading was related to stronger functional connections within and between sensory networks. These results suggest greater synchronization of brain systems after the intervention, consistent with the "neural noise" hypothesis in children with dyslexia and support the consideration of including executive functions as part of the Simple View of Reading model.

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Fast and Slow Rhythms of Naturalistic Reading Revealed by Combined Eye-Tracking and Electroencephalography.

Neural oscillations are thought to support speech and language processing. They may not only inherit acoustic rhythms, but might also impose endogenous rhythms onto processing. In support of this, we here report that human (both male and female) eye movements during naturalistic reading exhibit rhythmic patterns that show frequency-selective coherence with the EEG, in the absence of any stimulation rhythm. Periodicity was observed in two distinct frequency bands: First, word-locked saccades at 4-5 Hz display coherence with whole-head theta-band activity. Second, fixation durations fluctuate rhythmically at ∼1 Hz, in coherence with occipital delta-band activity. This latter effect was additionally phase-locked to sentence endings, suggesting a relationship with the formation of multi-word chunks. Together, eye movements during reading contain rhythmic patterns that occur in synchrony with oscillatory brain activity. This suggests that linguistic processing imposes preferred processing time scales onto reading, largely independent of actual physical rhythms in the stimulus.SIGNIFICANCE STATEMENT The sampling, grouping, and transmission of information are supported by rhythmic brain activity, so-called neural oscillations. In addition to sampling external stimuli, such rhythms may also be endogenous, affecting processing from the inside out. In particular, endogenous rhythms may impose their pace onto language processing. Studying this is challenging because speech contains physical rhythms that mask endogenous activity. To overcome this challenge, we turned to naturalistic reading, where text does not require the reader to sample in a specific rhythm. We observed rhythmic patterns of eye movements that are synchronized to brain activity as recorded with EEG. This rhythmicity is not imposed by the external stimulus, which indicates that rhythmic brain activity may serve as a pacemaker for language processing.