The transition from vision to language: Distinct patterns of functional connectivity for subregions of the visual word form area.

Reading entails transforming visual symbols to sound and meaning. This process depends on specialized circuitry in the visual cortex, the visual word form area (VWFA). Recent findings suggest that this text-selective cortex comprises at least two distinct subregions: the more posterior VWFA-1 is sensitive to visual features, while the more anterior VWFA-2 processes higher level language information. Here, we explore whether these two subregions also exhibit different patterns of functional connectivity. To this end, we capitalize on two complementary datasets: Using the Natural Scenes Dataset (NSD), we identify text-selective responses in high-quality 7T adult data (N = 8), and investigate functional connectivity patterns of VWFA-1 and VWFA-2 at the individual level. We then turn to the Healthy Brain Network (HBN) database to assess whether these patterns replicate in a large developmental sample (N = 224; age 6-20 years), and whether they relate to reading development. In both datasets, we find that VWFA-1 is primarily correlated with bilateral visual regions. In contrast, VWFA-2 is more strongly correlated with language regions in the frontal and lateral parietal lobes, particularly the bilateral inferior frontal gyrus. Critically, these patterns do not generalize to adjacent face-selective regions, suggesting a specific relationship between VWFA-2 and the frontal language network. No correlations were observed between functional connectivity and reading ability. Together, our findings support the distinction between subregions of the VWFA, and suggest that functional connectivity patterns in the ventral temporal cortex are consistent over a wide range of reading skills.

A general role for ventral white matter pathways in morphological processing: Going beyond reading.

The ability to recognize the structural components of words, known as morphological processing, was recently associated with the bilateral ventral white matter pathways, across different writing systems. However, it remains unclear whether these associations are specific to the context of reading. To shed light on this question, in the current study we investigated whether the ventral pathways are associated with morphological processing in an oral word production task that does not involve reading. Forty-five participants completed a morpheme-based fluency task in Hebrew, as well as diffusion MRI (dMRI) scans. We used probabilistic tractography to segment the major ventral and dorsal white matter pathways, and assessed the correlations between their microstructural properties and performance on the morpheme-based fluency task. We found significant correlations between morpheme-based fluency and properties of the bilateral ventral tracts, suggesting that the involvement of these tracts in morphological processing extends beyond the reading modality. In addition, significant correlations were found in the frontal aslant tract (FAT), a dorsal tract associated with oral fluency and speech production. Together, our findings emphasize that neurocognitive associations reflect both the cognitive construct under investigation as well as the task used for its assessment. Lastly, to elucidate the biological factors underlying these correlations, we incorporated the composite hindered and restricted model of diffusion (CHARMED) framework, measured in independent scans. We found that only some of our findings could be attributed to variation in a CHARMED-based estimate of fiber density. Further, we were able to uncover additional correlations that could not be detected using traditional dMRI indices. In sum, our results show that the involvement of the ventral tracts in morphological processing extends to the production domain, and demonstrate the added value of including sensitive structural measurements in neurocognitive investigations.

Age-Dependent White Matter Characteristics of the Cerebellar Peduncles from Infancy Through Adolescence.

Cerebellum-cerebrum connections are essential for many motor and cognitive functions and cerebellar disorders are prevalent in childhood. The middle (MCP), inferior (ICP), and superior cerebellar peduncles (SCP) are the major white matter pathways that permit communication between the cerebellum and the cerebrum. Knowledge about the microstructural properties of these cerebellar peduncles across childhood is limited. Here, we report on a diffusion magnetic resonance imaging tractography study to describe age-dependent characteristics of the cerebellar peduncles in a cross-sectional sample of infants, children, and adolescents from newborn to 17 years of age (N = 113). Scans were collected as part of clinical care; participants were restricted to those whose scans showed no abnormal findings and whose history and exam had no risk factors for cerebellar abnormalities. A novel automated tractography protocol was applied. Results showed that mean tract-FA increased, while mean tract-MD decreased from infancy to adolescence in all peduncles. Rapid changes were observed in both diffusion measures in the first 24 months of life, followed by gradual change at older ages. The shape of the tract profiles was similar across ages for all peduncles. These data are the first to characterize the variability of diffusion properties both across and within cerebellar white matter pathways that occur from birth through later adolescence. The data represent a rich normative data set against which white matter alterations seen in children with posterior fossa conditions can be compared. Ultimately, the data will facilitate the identification of sensitive biomarkers of cerebellar abnormalities.

Separate parts of occipito-temporal white matter fibers are associated with recognition of faces and places.

A central finding of functional MRI studies is the highly selective response of distinct brain areas in the occipital temporal cortex to faces and places. However, little is known about the association of white matter fibers with the processing of these object categories. In the current study we used DTI-based tractography to reconstruct two main fibers that connect the occipital lobe with the anterior temporal lobe (inferior longitudinal fasciculus-ILF) and with the frontal lobe (inferior fronto-occipital fasciculus-IFOF) in normal individuals. In addition to MRI scans subjects performed face, scene and body recognition tasks outside the scanner. Results show that recognition of faces and scenes were selectively associated with separate parts of the ILF. In particular, face recognition was highly associated with the fractional anisotropy (FA) of the anterior part of the ILF in the right hemisphere. In contrast, scene recognition was strongly correlated with the FA of the posterior and middle but not the anterior part of the ILF bilaterally. Our findings provide the first demonstration that faces and places are not only associated with distinct brain areas but also with separate parts of white matter fibers.

The Contributions of the Cerebellar Peduncles and the Frontal Aslant Tract in Mediating Speech Fluency.

Fluent speech production is a complex task that spans multiple processes, from conceptual framing and lexical access, through phonological encoding, to articulatory control. For the most part, imaging studies portraying the neural correlates of speech fluency tend to examine clinical populations sustaining speech impairments and focus on either lexical access or articulatory control, but not both. Here, we evaluated the contribution of the cerebellar peduncles to speech fluency by measuring the different components of the process in a sample of 45 neurotypical adults. Participants underwent an unstructured interview to assess their natural speaking rate and articulation rate, and completed timed semantic and phonemic fluency tasks to assess their verbal fluency. Diffusion magnetic resonance imaging with probabilistic tractography was used to segment the bilateral cerebellar peduncles (CPs) and frontal aslant tract (FAT), previously associated with speech production in clinical populations. Our results demonstrate distinct patterns of white matter associations with different fluency components. Specifically, verbal fluency is associated with the right superior CP, whereas speaking rate is associated with the right middle CP and bilateral FAT. No association is found with articulation rate in these pathways, in contrast to previous findings in persons who stutter. Our findings support the contribution of the cerebellum to aspects of speech production that go beyond articulatory control, such as lexical access, pragmatic or syntactic generation. Further, we demonstrate that distinct cerebellar pathways dissociate different components of speech fluency in neurotypical speakers.

Fast and reliable quantitative measures of white matter development with magnetic resonance fingerprinting.

Developmental cognitive neuroscience aims to shed light on evolving relationships between brain structure and cognitive development. To this end, quantitative methods that reliably measure individual differences in brain tissue properties are fundamental. Standard qualitative MRI sequences are influenced by scan parameters and hardware-related biases, and also lack physical units, making the analysis of individual differences problematic. In contrast, quantitative MRI can measure physical properties of the tissue but with the cost of long scan durations and sensitivity to motion. This poses a critical limitation for studying young children. Here, we examine the reliability and validity of an efficient quantitative multiparameter mapping method - Magnetic Resonance Fingerprinting (MRF) - in children scanned longitudinally. We focus on T1 values in white matter, since quantitative T1 values are known to primarily reflect myelin content, a key factor in brain development. Forty-nine children aged 8-13y (mean 10.3y ±1.4) completed two scanning sessions 2-4 months apart. In each session, two 2-minute 3D-MRF scans at 1mm isotropic resolution were collected to evaluate the effect of scan duration on image quality and scan-rescan reliability. A separate calibration scan was used to measure B0 inhomogeneity and correct for bias. We examined the impact of scan time and B0 inhomogeneity correction on scan-rescan reliability of values in white matter, by comparing single 2-min and combined two 2-min scans, with and without B0-correction. Whole-brain voxel-based reliability analysis showed that combining two 2-min MRF scans improved reliability (pearson's r=0.87) compared with a single 2-min scan (r=0.84), while B0-correction had no effect on reliability in white matter (r=0.86 and 0.83 4-min vs 2-min). Using diffusion tractography, we delineated MRF-derived T1 profiles along major white matter fiber tracts and found similar or higher reliability for T1 from MRF compared to diffusion parameters (based on a 10-minute dMRI scan). Lastly, we found that T1 values in multiple white matter tracts were significantly correlated with age. In sum, MRF-derived T1 values were highly reliable in a longitudinal sample of children and replicated known age effects. Reliability in white matter was improved by longer scan duration but was not affected by B0-correction, making it a quick and straightforward scan to collect. We propose that MRF provides a promising avenue for acquiring quantitative brain metrics in children and patient populations where scan time and motion are of particular concern.

The transition from vision to language: distinct patterns of functional connectivity for sub-regions of the visual word form area.

Reading entails transforming visual symbols to sound and meaning. This process depends on specialized circuitry in the visual cortex, the Visual Word Form Area (VWFA). Recent findings suggest that this word-selective cortex comprises at least two distinct subregions: the more posterior VWFA-1 is sensitive to visual features, while the more anterior VWFA-2 processes higher level language information. Here, we explore whether these two subregions exhibit different patterns of functional connectivity, and whether these patterns have relevance for reading development. We address these questions using two complementary datasets: Using the Natural Scenes Datasets (NSD; Allen et al, 2022) we identify word-selective responses in high-quality 7T individual adult data (N=8; 6 females), and investigate functional connectivity patterns of VWFA-1 and VWFA-2 at the individual level. We then turn to the Healthy Brain Network (HBN; Alexander et al., 2017) database to assess whether these patterns a) replicate in a large developmental sample (N=224; 98 females, age 5-21y), and b) are related to reading development. In both datasets, we find that VWFA-1 is more strongly correlated with bilateral visual regions including ventral occipitotemporal cortex and posterior parietal cortex. In contrast, VWFA-2 is more strongly correlated with language regions in the frontal and lateral parietal lobes, particularly bilateral inferior frontal gyrus (IFG). Critically, these patterns do not generalize to adjacent face-selective regions, suggesting a unique relationship between VWFA-2 and the frontal language network. While connectivity patterns increased with age, no correlations were observed between functional connectivity and reading ability. Together, our findings support the distinction between subregions of the VWFA, and portray the functional connectivity patterns of the reading circuitry as an intrinsic stable property of the brain.

Anatomy and physiology of word-selective visual cortex: from visual features to lexical processing.

Over the past 2 decades, researchers have tried to uncover how the human brain can extract linguistic information from a sequence of visual symbols. The description of how the brain's visual system processes words and enables reading has improved with the progressive refinement of experimental methodologies and neuroimaging techniques. This review provides a brief overview of this research journey. We start by describing classical models of object recognition in non-human primates, which represent the foundation for many of the early models of visual word recognition in humans. We then review functional neuroimaging studies investigating the word-selective regions in visual cortex. This research led to the differentiation of highly specialized areas, which are involved in the analysis of different aspects of written language. We then consider the corresponding anatomical measurements and provide a description of the main white matter pathways carrying neural signals crucial to word recognition. Finally, in an attempt to integrate structural, functional, and electrophysiological findings, we propose a view of visual word recognition, accounting for spatial and temporal facets of word-selective neural processes. This multi-modal perspective on the neural circuitry of literacy highlights the relevance of a posterior-anterior differentiation in ventral occipitotemporal cortex for visual processing of written language and lexical features. It also highlights unanswered questions that can guide us towards future research directions. Bridging measures of brain structure and function will help us reach a more precise understanding of the transformation from vision to language.

Rapid online assessment of reading ability.

An accurate model of the factors that contribute to individual differences in reading ability depends on data collection in large, diverse and representative samples of research participants. However, that is rarely feasible due to the constraints imposed by standardized measures of reading ability which require test administration by trained clinicians or researchers. Here we explore whether a simple, two-alternative forced choice, time limited lexical decision task (LDT), self-delivered through the web-browser, can serve as an accurate and reliable measure of reading ability. We found that performance on the LDT is highly correlated with scores on standardized measures of reading ability such as the Woodcock-Johnson Letter Word Identification test (r = 0.91, disattenuated r = 0.94). Importantly, the LDT reading ability measure is highly reliable (r = 0.97). After optimizing the list of words and pseudowords based on item response theory, we found that a short experiment with 76 trials (2-3 min) provides a reliable (r = 0.95) measure of reading ability. Thus, the self-administered, Rapid Online Assessment of Reading ability (ROAR) developed here overcomes the constraints of resource-intensive, in-person reading assessment, and provides an efficient and automated tool for effective online research into the mechanisms of reading (dis)ability.

Sensitivity to word structure in adult Hebrew readers is associated with microstructure of the ventral reading pathways.

Skilled readers differ in their sensitivity to morphological word structure, which captures useful regularities in the mapping between written word forms and their meaning. We recently showed that sensitivity to morphological information in adult English readers is associated with the ventral reading pathways, bilaterally. It remains unclear, however, whether this association is specific to the English writing system. To shed light on this question, we investigated whether the associations between the ventral reading pathways and morphological sensitivity to word structure generalize across languages with different orthographies and morphological systems. To this end, we assessed neurocognitive correlations between white matter structural properties and morphological sensitivity in Hebrew, a Semitic language where morphemes are combined in a non-linear manner. We used diffusion MRI (dMRI) to segment ventral and dorsal tracts of interest in a sample of 43 adult Hebrew readers, who also completed a behavioral language assessment battery that included a morphological task. Significant correlations were found between morphological sensitivity and properties of bilateral ventral, but not dorsal, tracts. These correlations remained significant after controlling for measures of vocabulary and word reading, demonstrating their specificity to the morphological task. The current findings in Hebrew show striking similarity to prior findings in English. Our results support the view that morphological information contributes to lexical access along the ventral pathways, across orthographies and morphological systems.

Structural properties of the ventral reading pathways are associated with morphological processing in adult English readers.

Morphological processing, the ability to extract information about word structure, is an essential component of reading. Functional MRI studies have identified several cortical regions involved in morphological processing, but the white matter pathways that support this skill remain unknown. Here, we examine the relationship between behavioral measures of morphological processing and microstructural properties of white matter pathways. Using diffusion MRI (dMRI), we identified the major ventral and dorsal reading pathways in a group of 45 adult English readers. The same participants completed a behavioral battery that included a morphological task and measures of phonological and orthographic processing. We found significant correlations between morphological processing skill and microstructural properties of the ventral, but not dorsal, pathways. These correlations were detected primarily in the left hemisphere, and remained significant after controlling for phonological or orthographic measures, suggesting some level of cognitive specificity. Morphological processing of written words thus appears to rely on ventral pathways, primarily in the left hemisphere. This finding supports the contribution of morphological processing to lexical access and comprehension of complex English words.

Microsaccades are sensitive to word structure: A novel approach to study language processing.

Microsaccades are miniature eye movements that occur involuntarily during fixation. They are typically inhibited following stimulus onset and are released from inhibition about 300 ms post-stimulus. Microsaccade-inhibition is modulated by low level features of visual stimuli, but it is currently unknown whether they are sensitive to higher level, abstract linguistic properties. To address this question, we measured the timing of microsaccades while subjects were presented with written Hebrew words and pronounceable nonwords (pseudowords). We manipulated the underlying structure of pseudowords such that half of them contained real roots while the other half contained invented roots. Importantly, orthographic similarity to real words was equated between the two conditions. Microsaccade onset was significantly slower following real-root compared to invented-root stimuli. Similar results were obtained when considering post-stimulus delay of eye blinks. Moreover, microsaccade-delay was positively and significantly correlated with measures of real-word similarity. These findings demonstrate, for the first time, sensitivity of microsaccades to linguistic structure. Because microsaccades are involuntary and can be measured in the absence of overt response, our results provide initial evidence that they can be used as a novel physiological measure in the study of language processes in healthy and clinical populations.

The Relationship Between Plasma Cytokine Levels and Response to Selective Serotonin Reuptake Inhibitor Treatment in Children and Adolescents with Depression and/or Anxiety Disorders.

OBJECTIVE: In adults there is growing evidence that antidepressant (AD) treatment results in a decline in inflammatory cytokines. This is the first report, to our knowledge, of the relationship between response to selective serotonin reuptake inhibitor (SSRI) treatment for anxiety and/or depression and cytokine levels in children and adolescents. METHODS: Forty-one patients who met Diagnostic and Statistical Manual for Mental Disorders, 4th ed. (DSM-IV) criteria for major depressive disorder (MDD) or anxiety disorders participated in study. Their ages ranged from 9 to 18 (14.12 ± 2.30) years. The patients were treated with fluoxetine for 8 weeks. Plasma concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß were measured by enzyme linked immunosorbent assays (ELISA) before and after fluoxetine treatment. Clinical response was measured with several scales, including the Children's Depression Rating Scale-Revised (CDRS-R), the Beck Depression Inventory (BDI), and the Screen for Child Anxiety Related Emotional Disorders (SCARED) Results: The overall response rate was 56%. Antidepressant treatment significantly reduced TNF-α levels (p = 0.037), with no significant changes in the levels of IL-6 and IL-1ß. All three proinflammatory cytokines were significantly (p < 0.05) higher in SSRI-refractory than in SSRI-responsive patients. CONCLUSIONS: Higher levels of TNF-α, IL-6, and IL-1ß might predict nonresponse to fluoxetine treatment in children.