Lifespan developmental changes in neural substrates and functional connectivity for visual semantic processing.

Human learning and cognitive functions change with age and experience, with late-developed complex cognitive functions, particularly those served by the prefrontal cortex, showing more age-dependent variance. Reading as a complex process of constructing meaning from print uses the left prefrontal cortex and may show a similar aging pattern. In this study, we delineated the lifespan developmental changes in the neural substrates and functional connectivity for visual semantic processing from childhood (age 6) to late adulthood (age 74). Different from previous studies that reported aging as a form of activation or neuronal changes, we examined additionally how the functional connectivity networks changed with age. A cohort of 122 Chinese participants performed semantic and font-size judgment tasks during functional magnetic resonance imaging. Although a common left-lateralized neural system including the left mid-inferior prefrontal cortex was recruited across all participants, the effect of age, or reading experience, is evident as 2 contrastive developmental patterns: a declining trend in activation strength and extent and an increasing trend in functional connections of the network. This study suggests that visual semantic processing is not prone to cognitive decline, and that continuous reading until old age helps strengthen the functional connections of reading-related brain regions.

Myeloarchitectonic plasticity in elite golf players' brains.

Human neuroimaging studies have demonstrated that exercise influences the cortical structural plasticity as indexed by gray or white matter volume. It remains elusive, however, whether exercise affects cortical changes at the finer-grained myelination structure level. To answer this question, we scanned 28 elite golf players in comparison with control participants, using a novel neuroimaging technique-quantitative magnetic resonance imaging (qMRI). The data showed myeloarchitectonic plasticity in the left temporal pole of the golf players: the microstructure of this brain region of the golf players was better proliferated than that of control participants. In addition, this myeloarchitectonic plasticity was positively related to golfing proficiency. Our study has manifested that myeloarchitectonic plasticity could be induced by exercise, and thus, shed light on the potential benefits of exercise on brain health and cognitive enhancement.

Myeloarchitectonic Asymmetries of Language Regions in the Human Brain.

One prominent theory in neuroscience and psychology assumes that cortical regions for language are left hemisphere lateralized in the human brain. In the current study, we used a novel technique, quantitative magnetic resonance imaging (qMRI), to examine interhemispheric asymmetries in language regions in terms of macromolecular tissue volume (MTV) and quantitative longitudinal relaxation time (T1) maps in the living human brain. These two measures are known to reflect cortical myeloarchitecture from the microstructural perspective. One hundred and fifteen adults (55 male, 60 female) were examined for their myeloarchitectonic asymmetries of language regions. We found that the cortical myeloarchitecture of inferior frontal areas including the pars opercularis, pars triangularis, and pars orbitalis is left lateralized, while that of the middle temporal gyrus, Heschl's gyrus, and planum temporale is right lateralized. Moreover, the leftward lateralization of myelination structure is significantly correlated with language skills measured by phonemic and speech tone awareness. This study reveals for the first time a mixed pattern of myeloarchitectonic asymmetries, which calls for a general theory to accommodate the full complexity of principles underlying human hemispheric specialization.

Optogenetic fMRI interrogation of brain-wide central vestibular pathways.

Blood oxygen level-dependent functional MRI (fMRI) constitutes a powerful neuroimaging technology to map brain-wide functions in response to specific sensory or cognitive tasks. However, fMRI mapping of the vestibular system, which is pivotal for our sense of balance, poses significant challenges. Physical constraints limit a subject's ability to perform motion- and balance-related tasks inside the scanner, and current stimulation techniques within the scanner are nonspecific to delineate complex vestibular nucleus (VN) pathways. Using fMRI, we examined brain-wide neural activity patterns elicited by optogenetically stimulating excitatory neurons of a major vestibular nucleus, the ipsilateral medial VN (MVN). We demonstrated robust optogenetically evoked fMRI activations bilaterally at sensorimotor cortices and their associated thalamic nuclei (auditory, visual, somatosensory, and motor), high-order cortices (cingulate, retrosplenial, temporal association, and parietal), and hippocampal formations (dentate gyrus, entorhinal cortex, and subiculum). We then examined the modulatory effects of the vestibular system on sensory processing using auditory and visual stimulation in combination with optogenetic excitation of the MVN. We found enhanced responses to sound in the auditory cortex, thalamus, and inferior colliculus ipsilateral to the stimulated MVN. In the visual pathway, we observed enhanced responses to visual stimuli in the ipsilateral visual cortex, thalamus, and contralateral superior colliculus. Taken together, our imaging findings reveal multiple brain-wide central vestibular pathways. We demonstrate large-scale modulatory effects of the vestibular system on sensory processing.

A Lifespan fMRI Study of Neurodevelopment Associated with Reading Chinese.

We used functional magnetic resonance imaging (fMRI) to map the neural systems involved in reading Chinese in 125 participants 6-74 years old to examine two theoretical issues: how brain structure and function are related in the context of the lifetime neural development of human cognition and whether the neural network for reading is universal or different across languages. Our findings showed that a common network of left frontal and occipital regions typically involved in reading Chinese was recruited across all participants. Crucially, activation in left mid-inferior frontal regions, fusiform and striate-extrastriate sites, premotor cortex, right inferior frontal gyrus, bilateral insula, and supplementary motor area all showed linearly decreasing changes with age. These findings differ from previous findings on alphabetic reading development and suggest that early readers at age 6-7 are already using the same cortical network to process printed words as adults, though the connections among these regions are modulated by reading proficiency, and cortical regions for reading are tuned by experience toward reduced and more focused activation. This fMRI study has demonstrated, for the first time, the neurodevelopment of reading across the lifespan and suggests that learning experience, instead of pre-existing brain structures, determines reading acquisition.

Sex Differences in Functional Brain Networks for Language.

Men and women process language differently, but how the brain functions to support this difference is poorly understood. A few studies reported sex influences on brain activation for language, whereas others failed to detect the difference at the functional level. Recent advances of brain network analysis have shown great promise in picking up brain connectivity differences between sexes, leading us to hypothesize that the functional connections among distinct brain regions for language may differ in males and females. To test this hypothesis, we scanned 58 participants' brain activities (28 males and 30 females) in a semantic decision task using functional magnetic resonance imaging. We found marked sex differences in dynamic interactions among language regions, as well as in functional segregation and integration of brain networks during language processing. The brain network differences were further supported by a machine learning analysis that accurately discriminated males from females using the multivariate patterns of functional connectivity. The sex-specific functional brain connectivity may constitute an essential neural basis for the long-held notion that men and women process language in different ways. Our finding also provides important implications for sex differences in the prevalence of language disorders, such as dyslexia and stuttering.

IFNAR1 gene mutation may contribute to developmental stuttering in the Chinese population.

BACKGROUND: Developmental stuttering is the most common form of stuttering without apparent neurogenic or psychogenic impairment. Recently, whole-exome sequencing (WES) has been suggested to be a promising approach to study Mendelian disorders. METHODS: Here, we describe an application of WES to identify a gene potentially responsible for persistent developmental stuttering (PDS) by sequencing DNA samples from 10 independent PDS families and 11 sporadic cases. Sanger sequencing was performed for verification with samples obtained from 73 additional patients with sporadic cases. RESULTS: We first searched for cosegregating variants/candidate genes in a Chinese family (Family 0) by sequencing DNA obtained from 3 affected members and 3 controls. Next, we sequenced DNA samples obtained from 9 additional Chinese families (Families 1-9) with stuttering to verify the identified candidate genes. Intriguingly, we found that two missense variants (Leu552Pro and Lys428Gln) of interferon-alpha/beta receptor 1 (IFNAR1) cosegregated with stuttering in three independent families (Families 0, 5 and 9). Moreover, we found two additional mutations (Gly301Glu and Pro335del) in the IFNAR1 gene in 4 patients with sporadic cases by using WES or Sanger sequencing. Further receptor mutagenesis and cell signaling studies revealed that these IFNAR1 variants may impair the activity of type I IFN signaling. CONCLUSION: Our data indicate that IFNAR1 might be a potential pathogenic gene of PDS in the Chinese population.

Evolutional and developmental anatomical architecture of the left inferior frontal gyrus.

The left inferior frontal gyrus (IFG) including Broca's area is involved in the processing of many language subdomains, and thus, research on the evolutional and human developmental characteristics of the left IFG will shed light on how language emerges and maturates. In this study, we used diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (fMRI) to investigate the evolutional and developmental patterns of the left IFG in humans (age 6-8, age 11-13, and age 16-18 years) and macaques. Tractography-based parcellation was used to define the subcomponents of left IFG and consistently identified four subregions in both humans and macaques. This parcellation scheme for left IFG in human was supported by specific coactivation patterns and functional characterization for each subregion. During evolution and development, we found increased functional balance, amplitude of low frequency fluctuations, functional integration, and functional couplings. We also observed higher fractional anisotropy values, i.e. better myelination of dorsal and ventral white matter language pathways during evolution and development. We assume that the resting-state functional connectivity and task-related coactivation mapping are associated with hierarchical language processing. Our findings have shown the evolutional and human developmental patterns of left IFG, and will contribute to the understanding of how the human language evolves and how atypical language developmental disorders may occur.

The Cortical Maps of Hierarchical Linguistic Structures during Speech Perception.

The hierarchical nature of language requires human brain to internally parse connected-speech and incrementally construct abstract linguistic structures. Recent research revealed multiple neural processing timescales underlying grammar-based configuration of linguistic hierarchies. However, little is known about where in the whole cerebral cortex such temporally scaled neural processes occur. This study used novel magnetoencephalography source imaging techniques combined with a unique language stimulation paradigm to segregate cortical maps synchronized to 3 levels of linguistic units (i.e., words, phrases, and sentences). Notably, distinct ensembles of cortical loci were identified to feature structures at different levels. The superior temporal gyrus was found to be involved in processing all 3 linguistic levels while distinct ensembles of other brain regions were recruited to encode each linguistic level. Neural activities in the right motor cortex only followed the rhythm of monosyllabic words which have clear acoustic boundaries, whereas the left anterior temporal lobe and the left inferior frontal gyrus were selectively recruited in processing phrases or sentences. Our results ground a multi-timescale hierarchical neural processing of speech in neuroanatomical reality with specific sets of cortices responsible for different levels of linguistic units.

Abnormal neural response to phonological working memory demands in persistent developmental stuttering.

Persistent developmental stuttering is a neurological disorder that commonly manifests as a motor problem. Cognitive theories, however, hold that poorly developed cognitive skills are the origins of stuttering. Working memory (WM), a multicomponent cognitive system that mediates information maintenance and manipulation, is known to play an important role in speech production, leading us to postulate that the neurophysiological mechanisms underlying stuttering may be associated with a WM deficit. Using functional magnetic resonance imaging, we aimed to elucidate brain mechanisms in a phonological WM task in adults who stutter and controls. A right-lateralized compensatory mechanism for a deficit in the rehearsal process and neural disconnections associated with the central executive dysfunction were found. Furthermore, the neural abnormalities underlying the phonological WM were independent of memory load. This study demonstrates for the first time the atypical neural responses to phonological WM in PWS, shedding new light on the underlying cause of stuttering.

Cross-language differences in the brain network subserving intelligible speech.

How is language processed in the brain by native speakers of different languages? Is there one brain system for all languages or are different languages subserved by different brain systems? The first view emphasizes commonality, whereas the second emphasizes specificity. We investigated the cortical dynamics involved in processing two very diverse languages: a tonal language (Chinese) and a nontonal language (English). We used functional MRI and dynamic causal modeling analysis to compute and compare brain network models exhaustively with all possible connections among nodes of language regions in temporal and frontal cortex and found that the information flow from the posterior to anterior portions of the temporal cortex was commonly shared by Chinese and English speakers during speech comprehension, whereas the inferior frontal gyrus received neural signals from the left posterior portion of the temporal cortex in English speakers and from the bilateral anterior portion of the temporal cortex in Chinese speakers. Our results revealed that, although speech processing is largely carried out in the common left hemisphere classical language areas (Broca's and Wernicke's areas) and anterior temporal cortex, speech comprehension across different language groups depends on how these brain regions interact with each other. Moreover, the right anterior temporal cortex, which is crucial for tone processing, is equally important as its left homolog, the left anterior temporal cortex, in modulating the cortical dynamics in tone language comprehension. The current study pinpoints the importance of the bilateral anterior temporal cortex in language comprehension that is downplayed or even ignored by popular contemporary models of speech comprehension.

Predictive Brain Mechanisms in Sound-to-Meaning Mapping during Speech Processing.

Spoken language comprehension relies not only on the identification of individual words, but also on the expectations arising from contextual information. A distributed frontotemporal network is known to facilitate the mapping of speech sounds onto their corresponding meanings. However, how prior expectations influence this efficient mapping at the neuroanatomical level, especially in terms of individual words, remains unclear. Using fMRI, we addressed this question in the framework of the dual-stream model by scanning native speakers of Mandarin Chinese, a language highly dependent on context. We found that, within the ventral pathway, the violated expectations elicited stronger activations in the left anterior superior temporal gyrus and the ventral inferior frontal gyrus (IFG) for the phonological-semantic prediction of spoken words. Functional connectivity analysis showed that expectations were mediated by both top-down modulation from the left ventral IFG to the anterior temporal regions and enhanced cross-stream integration through strengthened connections between different subregions of the left IFG. By further investigating the dynamic causality within the dual-stream model, we elucidated how the human brain accomplishes sound-to-meaning mapping for words in a predictive manner. SIGNIFICANCE STATEMENT: In daily communication via spoken language, one of the core processes is understanding the words being used. Effortless and efficient information exchange via speech relies not only on the identification of individual spoken words, but also on the contextual information giving rise to expected meanings. Despite the accumulating evidence for the bottom-up perception of auditory input, it is still not fully understood how the top-down modulation is achieved in the extensive frontotemporal cortical network. Here, we provide a comprehensive description of the neural substrates underlying sound-to-meaning mapping and demonstrate how the dual-stream model functions in the modulation of expectations, allowing for a better understanding of how the human brain accomplishes sound-to-meaning mapping in a predictive manner.

Genetic polymorphism of nonsyndromic cleft lip with or without cleft palate is associated with developmental dyslexia in Chinese school-aged populations.

Developmental dyslexia (DD) is a neurodevelopment disorder characterized by reading disabilities without apparent etiologies. Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a structural craniofacial malformation featured by isolated orofacial abnormalities. Despite substantial phenotypic differences, potential linkage between these two disorders has been suggested as prevalence of DD among NSCL/P patients was much higher than that in general populations. Previous neuroimaging studies observed impaired short-term memory in patients with DD and NSCL/P, respectively. Genetic factors have a fundamental role during neurodevelopment and craniofacial morphogenesis but there lacks of evidence to support the linkage between DD and NSCL/P at genetic level. A recent genome-wide association study in Chinese populations identified a number of genetic polymorphisms associated with NSCL/P. Herein, we selected three risk variants of NSCL/P namely rs8049367, rs4791774 and rs2235371, and performed association analysis with DD in a Chinese population consisting 631 elementary school-aged children with 288 dyslexic cases without NSCL/P and 343 healthy controls. After Bonferroni correction for multiple comparisons, the T allele of rs8049367 showed significant association with DD (OR=1.41, P=0.0085). It is an intergenic variant between CREBBP and ADCY9 located at 16p13.3. The CREBBP gene was reported to have an essential role during memory formation, although ADCY9 was involved in dental development. In future studies, understanding functional effects of rs8049367 on CERBBP and ADCY9 might contribute to explain underlying etiologies shared by DD and NSCL/P.

Localizing Age-Related Changes in Brain Structure Using Voxel-Based Morphometry.

Aim. We report the dynamic anatomical sequence of human cortical gray matter development from late childhood to young adults using VBM and ROI-based methods. Method. The structural MRI of 91 normal individuals ranging in age from 6 to 26 years was obtained and the GMV for each region was measured. Results. Our results showed that the earliest loss of GMV occurred in left olfactory, right precuneus, caudate, left putamen, pallidum, and left middle temporal gyrus. In addition, the trajectory of maturational and aging showed a linear decline in GMV on both cortical lobes and subcortical regions. The most loss of gray matter was observed in the parietal lobe and basal ganglia, whereas the less loss occurred in the temporal lobe and hippocampus, especially in the left middle temporal pole, which showed no decline until 26 years old. Moreover, the volumes of GM, WM, and CSF were also assessed for linear age effects, showing a significant linear decline in GM with age and a significant linear increase in both WM and CSF with age. Interpretation. Overall, our findings lend support to previous findings of the normal brain development of regional cortex, and they may help in understanding of neurodevelopmental disorders.

Chinese Character and English Word processing in children's ventral occipitotemporal cortex: fMRI evidence for script invariance.

Learning to read is thought to involve the recruitment of left hemisphere ventral occipitotemporal cortex (OTC) by a process of "neuronal recycling", whereby object processing mechanisms are co-opted for reading. Under the same theoretical framework, it has been proposed that the visual word form area (VWFA) within OTC processes orthographic stimuli independent of culture and writing systems, suggesting that it is universally involved in written language. However, this "script invariance" has yet to be demonstrated in monolingual readers of two different writing systems studied under the same experimental conditions. Here, using functional magnetic resonance imaging (fMRI), we examined activity in response to English Words and Chinese Characters in 1st graders in the United States and China, respectively. We examined each group separately and found the readers of English as well as the readers of Chinese to activate the left ventral OTC for their respective native writing systems (using both a whole-brain and a bilateral OTC-restricted analysis). Critically, a conjunction analysis of the two groups revealed significant overlap between them for native writing system processing, located in the VWFA and therefore supporting the hypothesis of script invariance. In the second part of the study, we further examined the left OTC region responsive to each group's native writing system and found that it responded equally to Object stimuli (line drawings) in the Chinese-reading children. In English-reading children, the OTC responded much more to Objects than to English Words. Together, these results support the script invariant role of the VWFA and also support the idea that the areas recruited for character or word processing are rooted in object processing mechanisms of the left OTC.

China's language input system in the digital age affects children's reading development.

Written Chinese as a logographic system was developed over 3,000 y ago. Historically, Chinese children have learned to read by learning to associate the visuo-graphic properties of Chinese characters with lexical meaning, typically through handwriting. In recent years, however, many Chinese children have learned to use electronic communication devices based on the pinyin input method, which associates phonemes and English letters with characters. When children use pinyin to key in letters, their spelling no longer depends on reproducing the visuo-graphic properties of characters that are indispensable to Chinese reading, and, thus, typing in pinyin may conflict with the traditional learning processes for written Chinese. We therefore tested character reading ability and pinyin use by primary school children in three Chinese cites: Beijing (n = 466), Guangzhou (n = 477), and Jining (n = 4,908). Children with severe reading difficulty are defined as those who were normal in nonverbal IQ but two grades (i.e., 2 y) behind in character-reading achievement. We found that the overall incidence rate of severe reading difficulty appears to be much higher than ever reported on Chinese reading. Crucially, we found that children's reading scores were significantly negatively correlated with their use of the pinyin input method, suggesting that pinyin typing on e-devices hinders Chinese reading development. The Chinese language has survived the technological challenges of the digital era, but the benefits of communicating digitally may come with a cost in proficient learning of written Chinese.

Effective connectivity of brain regions related to visual word recognition: An fMRI study of Chinese reading.

Past neuroimaging studies have focused on identifying specialized functional brain systems for processing different components of reading, such as orthography, phonology, and semantics. More recently, a few experiments have been performed to look into the integration and interaction of distributed neural systems for visual word recognition, suggesting that lexical processing in alphabetic languages involves both ventral and dorsal neural pathways originating from the visual cortex. In the present functional magnetic resonance imaging study, we tested the multiple pathways model with Chinese character stimuli and examined how the neural systems interacted in reading Chinese. Using dynamic causal modeling, we demonstrated that visual word recognition in Chinese engages the ventral pathway from the visual cortex to the left ventral occipitotemporal cortex, but not the dorsal pathway from the visual cortex to the left parietal region. The ventral pathway, however, is linked to the superior parietal lobule and the left middle frontal gyrus (MFG) so that a dynamic neural network is formed, with information flowing from the visual cortex to the left ventral occipitotemporal cortex to the parietal lobule and then to the left MFG. The findings suggest that cortical dynamics is constrained by the differences in how visual orthographic symbols in writing systems are linked to spoken language.

Neural signatures of lexical tone reading.

Research on how lexical tone is neuroanatomically represented in the human brain is central to our understanding of cortical regions subserving language. Past studies have exclusively focused on tone perception of the spoken language, and little is known as to the lexical tone processing in reading visual words and its associated brain mechanisms. In this study, we performed two experiments to identify neural substrates in Chinese tone reading. First, we used a tone judgment paradigm to investigate tone processing of visually presented Chinese characters. We found that, relative to baseline, tone perception of printed Chinese characters were mediated by strong brain activation in bilateral frontal regions, left inferior parietal lobule, left posterior middle/medial temporal gyrus, left inferior temporal region, bilateral visual systems, and cerebellum. Surprisingly, no activation was found in superior temporal regions, brain sites well known for speech tone processing. In activation likelihood estimation (ALE) meta-analysis to combine results of relevant published studies, we attempted to elucidate whether the left temporal cortex activities identified in Experiment one is consistent with those found in previous studies of auditory lexical tone perception. ALE results showed that only the left superior temporal gyrus and putamen were critical in auditory lexical tone processing. These findings suggest that activation in the superior temporal cortex associated with lexical tone perception is modality-dependent.

Association study of stuttering candidate genes GNPTAB, GNPTG and NAGPA with dyslexia in Chinese population.

BACKGROUND: Dyslexia is a polygenic speech and language disorder characterized by an unexpected difficulty in reading in children and adults despite normal intelligence and schooling. Increasing evidence reveals that different speech and language disorders could share common genetic factors. As previous study reported association of GNPTAB, GNPTG and NAGPA with stuttering, we investigated these genes with dyslexia through association analysis. RESULTS: The study was carried out in an unrelated Chinese cohort with 502 dyslexic individuals and 522 healthy controls. In all, 21 Tag SNPs covering GNPTAB, GNPTG and NAGPA were subjected to genotyping. Association analysis was performed on all SNPs. Significant association of rs17031962 in GNPTAB and rs882294 in NAGPA with developmental dyslexia was identified after FDR correction for multiple comparisons. CONCLUSION: Our results revealed that the stuttering risk genes GNPTAB and NAGPA might also associate with developmental dyslexia in the Chinese population.

Octopus visual system: a functional MRI model for detecting neuronal electric currents without a blood-oxygen-level-dependent confound.

PURPOSE: Despite the efforts that have been devoted to detecting the transient magnetic fields generated by neuronal firing, the conclusion that a functionally relevant signal can be measured with MRI is still controversial. For human studies of neuronal current MRI (nc-MRI), the blood-oxygen-level-dependent (BOLD) effect remains an irresolvable confound. For tissue studies where hemoglobin is removed, natural sensory stimulation is not possible. This study investigates the feasibility of detecting a physiologically induced nc-MRI signal in vivo in a BOLD-free environment. METHODS: The cephalopod mollusc Octopus bimaculoides has vertebrate-like eyes, large optic lobes (OLs), and blood that does not contain hemoglobin. Visually evoked potentials were measured in the octopus retina and OL by electroretinogram and local field potential. nc-MRI scans were conducted at 9.4 Tesla to capture these activities. RESULTS: Electrophysiological recording detected strong responses in the retina and OL in vivo; however, nc-MRI failed to demonstrate any statistically significant signal change with a detection threshold of 0.2° for phase and 0.2% for magnitude. Experiments in a dissected eye-OL preparation yielded similar results. CONCLUSION: These findings in a large hemoglobin-free nervous system suggest that sensory evoked neuronal magnetic fields are too weak for direct detection with current MRI technology.