Lateralized and Region-Specific Thalamic Processing of Lexical Status during Reading Aloud.

To explore whether the thalamus participates in lexical status (word vs nonword) processing during spoken word production, we recorded local field potentials from the ventral lateral thalamus in 11 essential tremor patients (three females) undergoing thalamic deep-brain stimulation lead implantation during a visually cued word and nonword reading-aloud task. We observed task-related beta (12-30 Hz) activity decreases that were preferentially time locked to stimulus presentation, and broadband gamma (70-150 Hz) activity increases, which are thought to index increased multiunit spiking activity, occurring shortly before and predominantly time locked to speech onset. We further found that thalamic beta activity decreases bilaterally were greater when nonwords were read, demonstrating bilateral sensitivity to lexical status that likely reflects the tracking of task effort; in contrast, greater nonword-related increases in broadband gamma activity were observed only on the left, demonstrating lateralization of thalamic broadband gamma selectivity for lexical status. In addition, this lateralized lexicality effect on broadband gamma activity was strongest in more anterior thalamic locations, regions which are more likely to receive basal ganglia than cerebellar afferents and have extensive connections with prefrontal cortex including Brodmann's areas 44 and 45, regions consistently associated with grapheme-to-phoneme conversions. These results demonstrate active thalamic participation in reading aloud and provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.SIGNIFICANCE STATEMENT Despite the corticocentric focus of most experimental work and accompanying models, there is increasing recognition of the role of subcortical structures in speech and language. Using local field potential recordings in neurosurgical patients, we demonstrated that the thalamus participates in lexical status (word vs nonword) processing during spoken word production, in a lateralized and region-specific manner. These results provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.

Representations within the Intraparietal Sulcus Distinguish Numerical Tasks and Formats.

How does our brain understand the number five when it is written as an Arabic numeral, and when presented as five fingers held up? Four facets have been implicated in adult numerical processing: semantic, visual, manual, and phonological/verbal. Here, we ask how the brain represents each, using a combination of tasks and stimuli. We collected fMRI data from adult participants while they completed our novel "four number code" paradigm. In this paradigm, participants viewed one of two stimulus types to tap into the visual and manual number codes, respectively. Concurrently, they completed one of two tasks to tap into the semantic and phonological/verbal number codes, respectively. Classification analyses revealed that neural codes representing distinctions between the number comparison and phonological tasks were generalizable across format (e.g., Arabic numerals to hands) within intraparietal sulcus (IPS), angular gyrus, and precentral gyrus. Neural codes representing distinctions between formats were generalizable across tasks within visual areas such as fusiform gyrus and calcarine sulcus, as well as within IPS. Our results identify the neural facets of numerical processing within a single paradigm and suggest that IPS is sensitive to distinctions between semantic and phonological/verbal, as well as visual and manual, facets of number representations.

Multiple adjoining word- and face-selective regions in ventral temporal cortex exhibit distinct dynamics.

The map of category-selectivity in human ventral temporal cortex (VTC) provides organizational constraints to models of object recognition. One important principle is lateral-medial response biases to stimuli that are typically viewed in the center or periphery of the visual field. However, little is known about the relative temporal dynamics and location of regions that respond preferentially to stimulus classes that are centrally viewed, like the face- and word-processing networks. Here, word- and face-selective regions within VTC were mapped using intracranial recordings from 36 patients. Partially overlapping, but also anatomically dissociable patches of face- and word-selectivity were found in VTC. In addition to canonical word-selective regions along the left posterior occipitotemporal sulcus, selectivity was also located medial and anterior to face-selective regions on the fusiform gyrus at the group level and within individual male and female subjects. These regions were replicated using 7 Tesla fMRI in healthy subjects. Left hemisphere word-selective regions preceded right hemisphere responses by 125 ms, potentially reflecting the left hemisphere bias for language; with no hemispheric difference in face-selective response latency. Word-selective regions along the posterior fusiform responded first, then spread medially and laterally, then anteriorally. Face-selective responses were first seen in posterior fusiform regions bilaterally, then proceeded anteriorally from there. For both words and faces, the relative delay between regions was longer than would be predicted by purely feedforward models of visual processing. The distinct time-courses of responses across these regions, and between hemispheres, suggest a complex and dynamic functional circuit supports face and word perception.SIGNIFICANCE STATEMENT:Representations of visual objects in the human brain have been shown to be organized by several principles, including whether those objects tend to be viewed centrally or peripherally in the visual field. However, it remains unclear how regions that process objects that are viewed centrally, like words and faces, are organized relative to one another. Here, invasive and non-invasive neuroimaging suggests there is a mosaic of regions in ventral temporal cortex that respond selectively to either words or faces. These regions display differences in the strength and timing of their responses, both within and between brain hemispheres, suggesting they play different roles in perception. These results illuminate extended, bilateral, and dynamic brain pathways that support face perception and reading.

Neutral auditory words immediately followed by painful electric shock may show reduced next-day recollection.

In this study, we investigated the effect of experimentally delivered acute pain on memory. Twenty-five participants participated in experimental sessions on consecutive days. The first session involved a categorization task to encourage memory encoding. There were two conditions, presented in randomized order, in which participants listened to a series of words, which were repeated three times. In one condition, one-third of the word items were immediately followed by a painful electrical shock. This word-shock pairing was consistent across repetition and the pain-paired items were presented unpredictably. In the other condition, all word items were not associated with pain. Response times over these repeated presentations were assessed for differences. Explicit memory was tested the following day, employing a Remember-Know assessment of word recognition, with no shocks employed. We found evidence that recollection may be reduced for pain-paired words, as the proportion of correct Remember responses (out of total correct responses) was significantly lower. There were no significant reductions in memory for non-pain items that followed painful stimulation after a period of several seconds. Consistent with the experience of pain consuming working memory resources, we theorize that painful shocks interrupt memory encoding for the immediately preceding experimental items, due to a shift in attention away from the word item.

Role of the striatum in incidental learning of sound categories.

Humans are born as "universal listeners" without a bias toward any particular language. However, over the first year of life, infants' perception is shaped by learning native speech categories. Acoustically different sounds-such as the same word produced by different speakers-come to be treated as functionally equivalent. In natural environments, these categories often emerge incidentally without overt categorization or explicit feedback. However, the neural substrates of category learning have been investigated almost exclusively using overt categorization tasks with explicit feedback about categorization decisions. Here, we examined whether the striatum, previously implicated in category learning, contributes to incidental acquisition of sound categories. In the fMRI scanner, participants played a videogame in which sound category exemplars aligned with game actions and events, allowing sound categories to incidentally support successful game play. An experimental group heard nonspeech sound exemplars drawn from coherent category spaces, whereas a control group heard acoustically similar sounds drawn from a less structured space. Although the groups exhibited similar in-game performance, generalization of sound category learning and activation of the posterior striatum were significantly greater in the experimental than control group. Moreover, the experimental group showed brain-behavior relationships related to the generalization of all categories, while in the control group these relationships were restricted to the categories with structured sound distributions. Together, these results demonstrate that the striatum, through its interactions with the left superior temporal sulcus, contributes to incidental acquisition of sound category representations emerging from naturalistic learning environments.

Midazolam and Ketamine Produce Distinct Neural Changes in Memory, Pain, and Fear Networks during Pain.

BACKGROUND: Despite the well-known clinical effects of midazolam and ketamine, including sedation and memory impairment, the neural mechanisms of these distinct drugs in humans are incompletely understood. The authors hypothesized that both drugs would decrease recollection memory, task-related brain activity, and long-range connectivity between components of the brain systems for memory encoding, pain processing, and fear learning. METHODS: In this randomized within-subject crossover study of 26 healthy adults, the authors used behavioral measures and functional magnetic resonance imaging to study these two anesthetics, at sedative doses, in an experimental memory paradigm using periodic pain. The primary outcome, recollection memory performance, was quantified with d' (a difference of z scores between successful recognition versus false identifications). Secondary outcomes were familiarity memory performance, serial task response times, task-related brain responses, and underlying brain connectivity from 17 preselected anatomical seed regions. All measures were determined under saline and steady-state concentrations of the drugs. RESULTS: Recollection memory was reduced under midazolam (median [95% CI], d' = 0.73 [0.43 to 1.02]) compared with saline (d' = 1.78 [1.61 to 1.96]) and ketamine (d' = 1.55 [1.12 to 1.97]; P < 0.0001). Task-related brain activity was detected under saline in areas involved in memory, pain, and fear, particularly the hippocampus, insula, and amygdala. Compared with saline, midazolam increased functional connectivity to 20 brain areas and decreased to 8, from seed regions in the precuneus, posterior cingulate, and left insula. Compared with saline, ketamine decreased connectivity to 17 brain areas and increased to 2, from 8 seed regions including the hippocampus, parahippocampus, amygdala, and anterior and primary somatosensory cortex. CONCLUSIONS: Painful stimulation during light sedation with midazolam, but not ketamine, can be accompanied by increased coherence in brain connectivity, even though details are less likely to be recollected as explicit memories.

Subthalamic Nucleus and Sensorimotor Cortex Activity During Speech Production.

The sensorimotor cortex is somatotopically organized to represent the vocal tract articulators such as lips, tongue, larynx, and jaw. How speech and articulatory features are encoded at the subcortical level, however, remains largely unknown. We analyzed LFP recordings from the subthalamic nucleus (STN) and simultaneous electrocorticography recordings from the sensorimotor cortex of 11 human subjects (1 female) with Parkinson's disease during implantation of deep-brain stimulation (DBS) electrodes while they read aloud three-phoneme words. The initial phonemes involved either articulation primarily with the tongue (coronal consonants) or the lips (labial consonants). We observed significant increases in high-gamma (60-150 Hz) power in both the STN and the sensorimotor cortex that began before speech onset and persisted for the duration of speech articulation. As expected from previous reports, in the sensorimotor cortex, the primary articulators involved in the production of the initial consonants were topographically represented by high-gamma activity. We found that STN high-gamma activity also demonstrated specificity for the primary articulator, although no clear topography was observed. In general, subthalamic high-gamma activity varied along the ventral-dorsal trajectory of the electrodes, with greater high-gamma power recorded in the dorsal locations of the STN. Interestingly, the majority of significant articulator-discriminative activity in the STN occurred before that in sensorimotor cortex. These results demonstrate that articulator-specific speech information is contained within high-gamma activity of the STN, but with different spatial and temporal organization compared with similar information encoded in the sensorimotor cortex.SIGNIFICANCE STATEMENT Clinical and electrophysiological evidence suggest that the subthalamic nucleus (STN) is involved in speech; however, this important basal ganglia node is ignored in current models of speech production. We previously showed that STN neurons differentially encode early and late aspects of speech production, but no previous studies have examined subthalamic functional organization for speech articulators. Using simultaneous LFP recordings from the sensorimotor cortex and the STN in patients with Parkinson's disease undergoing deep-brain stimulation surgery, we discovered that STN high-gamma activity tracks speech production at the level of vocal tract articulators before the onset of vocalization and often before related cortical encoding.

Abstract inference of unchosen option values.

Reinforcement learning research has pursued a persistent question: Does reward feedback prompt inferences that transcend simple associations? Reversal learning data suggest an affirmative answer: When the positive stimulus (S+) becomes the negative stimulus (S-), trained humans rapidly switch to choosing the former S-. The operations supporting such inferences remain ambiguous. Do participants identify transitions between stimulus-specific contexts (i.e., A+B- and A-B+), or deduce values by learning the abstract contingency structure? Across two experiments, we probed humans' use of abstract rules to infer the values of unchosen alternatives. In Experiment 1, 37 participants attempted a task that originally demonstrated monkeys' difficulty with this form of inference. We presented modified discrimination problems in which the initially chosen stimulus (abstract inference group) or unchosen stimulus (control group) was replaced with a novel stimulus of identical status on Trial 2. In the abstract inference condition, accurate performance can be achieved by applying the consistent contingency structure (but not memory of stimulus-specific reward associations) to infer to the unchosen stimulus' value. The abstract inference group learned to make accurate choices, but only after committing substantially more errors than were observed among control participants-suggesting that unchosen value inferences are infrequently drawn in standard discrimination scenarios. In Experiment 2, 17 participants completed abstract inference problems that had been modified to be suitable for fMRI investigations. Behavioral results both corroborated the Experiment 1 trends and further revealed marked individual differences in explicit awareness of the novel stimulus values.

Subthalamic Nucleus Neurons Differentially Encode Early and Late Aspects of Speech Production.

Basal ganglia-thalamocortical loops mediate all motor behavior, yet little detail is known about the role of basal ganglia nuclei in speech production. Using intracranial recording during deep brain stimulation surgery in humans with Parkinson's disease, we tested the hypothesis that the firing rate of subthalamic nucleus neurons is modulated in sync with motor execution aspects of speech. Nearly half of 79 unit recordings exhibited firing-rate modulation during a syllable reading task across 12 subjects (male and female). Trial-to-trial timing of changes in subthalamic neuronal activity, relative to cue onset versus production onset, revealed that locking to cue presentation was associated more with units that decreased firing rate, whereas locking to speech onset was associated more with units that increased firing rate. These unique data indicate that subthalamic activity is dynamic during the production of speech, reflecting temporally-dependent inhibition and excitation of separate populations of subthalamic neurons.SIGNIFICANCE STATEMENT The basal ganglia are widely assumed to participate in speech production, yet no prior studies have reported detailed examination of speech-related activity in basal ganglia nuclei. Using microelectrode recordings from the subthalamic nucleus during a single-syllable reading task, in awake humans undergoing deep brain stimulation implantation surgery, we show that the firing rate of subthalamic nucleus neurons is modulated in response to motor execution aspects of speech. These results are the first to establish a role for subthalamic nucleus neurons in encoding of aspects of speech production, and they lay the groundwork for launching a modern subfield to explore basal ganglia function in human speech.

Word inversion sensitivity as a marker of visual word form area lateralization: An application of a novel multivariate measure of laterality.

An area within the ventral occipitotemporal cortex (vOTC), the "visual word form area" (VWFA), typically exhibits a strongly left-lateralized response to orthographic stimuli in skilled readers. While individual variation in VWFA lateralization has been observed, the behavioral significance of laterality differences remains unclear. Here, we test the hypothesis that differences in VWFA lateralization reflect differing preferences for holistic orthographic analysis. To examine this hypothesis, we implemented a new multivariate method that uses machine learning to assess functional lateralization, along with a traditional univariate lateralization method. We related these neural metrics to behavioral indices of holistic orthographic analysis (inversion sensitivity). The multivariate measure successfully detected the lateralization of orthographic processing in the VWFA, and as hypothesized, predicted behavioral differences in holistic orthographic analysis. An exploratory whole brain analysis identified further regions with a relationship between inversion sensitivity and lateralization: one near the junction of the inferior frontal and precentral sulci, and another along the superior temporal gyrus. We conclude that proficient native readers of English exhibit differences in cortical lateralization of the VWFA that have significant implications for reading behavior.

Memory for non-painful auditory items is influenced by whether they are experienced in a context involving painful electrical stimulation.

In this study, we sought to examine the effect of experimentally induced somatic pain on memory. Subjects heard a series of words and made categorization decisions in two different conditions. One condition included painful shocks administered just after presentation of some of the words; the other condition involved no shocks. For the condition that included painful stimulations, every other word was followed by a shock, and subjects were informed to expect this pattern. Word lists were repeated three times within each condition in randomized order, with different category judgments but consistent pain-word pairings. After a brief delay, recognition memory was assessed. Non-pain words from the pain condition were less strongly encoded than non-pain words from the completely pain-free condition. Recognition of pain-paired words was not significantly different than either subgroup of non-pain words. An important accompanying finding is that response times to repeated experimental items were slower for non-pain words from the pain condition, compared to non-pain words from the completely pain-free condition. This demonstrates that the effect of pain on memory may generalize to non-pain items experienced in the same experimental context.

Decoding and disrupting left midfusiform gyrus activity during word reading.

The nature of the visual representation for words has been fiercely debated for over 150 y. We used direct brain stimulation, pre- and postsurgical behavioral measures, and intracranial electroencephalography to provide support for, and elaborate upon, the visual word form hypothesis. This hypothesis states that activity in the left midfusiform gyrus (lmFG) reflects visually organized information about words and word parts. In patients with electrodes placed directly in their lmFG, we found that disrupting lmFG activity through stimulation, and later surgical resection in one of the patients, led to impaired perception of whole words and letters. Furthermore, using machine-learning methods to analyze the electrophysiological data from these electrodes, we found that information contained in early lmFG activity was consistent with an orthographic similarity space. Finally, the lmFG contributed to at least two distinguishable stages of word processing, an early stage that reflects gist-level visual representation sensitive to orthographic statistics, and a later stage that reflects more precise representation sufficient for the individuation of orthographic word forms. These results provide strong support for the visual word form hypothesis and demonstrate that across time the lmFG is involved in multiple stages of orthographic representation.

The first day is always the hardest: Functional connectivity during cue exposure and the ability to resist smoking in the initial hours of a quit attempt.

Quitting smoking is the single best change in behavior that smokers can make to improve their health and extend their lives. Although most smokers express a strong desire to stop using cigarettes, the vast majority of quit attempts end in relapse. Relapse is particularly likely when smokers encounter cigarette cues. A striking number of relapses occur very quickly, with many occurring within as little as 24h. Characterizing what distinguishes successful quit attempts from unsuccessful ones, particularly just after cessation is initiated, is a research priority. We addressed this significant issue by examining the association between functional connectivity during cigarette cue exposure and smoking behavior during the first 24h of a quit attempt. Functional MRI was used to measure brain activity during cue exposure in nicotine-deprived daily smokers during the first day of a quit attempt. Participants were then given the opportunity to smoke. Using data collected in two parent studies, we identified a subset of participants who chose to smoke and a matched subset who declined (n=38). Smokers who were able to resist smoking displayed significant functional connectivity between the left anterior insula and the dorsolateral prefrontal cortex, whereas there was no such connectivity for those who chose to smoke. Notably, there were no differences in mean levels of activation in brain regions of interest, underscoring the importance of assessing interregional connectivity when investigating the links between cue-related neural responses and overt behavior. To our knowledge, this is the first study to link patterns of functional connectivity and actual cigarette use during the pivotal first hours of attempt to change smoking behavior.

Cerebellum and nonmotor function.

Does the cerebellum influence nonmotor behavior? Recent anatomical studies demonstrate that the output of the cerebellum targets multiple nonmotor areas in the prefrontal and posterior parietal cortex, as well as the cortical motor areas. The projections to different cortical areas originate from distinct output channels within the cerebellar nuclei. The cerebral cortical area that is the main target of each output channel is a major source of input to the channel. Thus, a closed-loop circuit represents the major architectural unit of cerebro-cerebellar interactions. The outputs of these loops provide the cerebellum with the anatomical substrate to influence the control of movement and cognition. Neuroimaging and neuropsychological data supply compelling support for this view. The range of tasks associated with cerebellar activation is remarkable and includes tasks designed to assess attention, executive control, language, working memory, learning, pain, emotion, and addiction. These data, along with the revelations about cerebro-cerebellar circuitry, provide a new framework for exploring the contribution of the cerebellum to diverse aspects of behavior.

Fusiform Gyrus Laterality in Writing Systems with Different Mapping Principles: An Artificial Orthography Training Study.

Writing systems vary in many ways, making it difficult to account for cross-linguistic neural differences. For example, orthographic processing of Chinese characters activates the mid-fusiform gyri (mFG) bilaterally, whereas the processing of English words predominantly activates the left mFG. Because Chinese and English vary in visual processing (holistic vs. analytical) and linguistic mapping principle (morphosyllabic vs. alphabetic), either factor could account for mFG laterality differences. We used artificial orthographies representing English to investigate the effect of mapping principle on mFG lateralization. The fMRI data were compared for two groups that acquired foundational proficiency: one for an alphabetic and one for an alphasyllabic artificial orthography. Greater bilateral mFG activation was observed in the alphasyllabic versus alphabetic group. The degree of bilaterality correlated with reading fluency for the learned orthography in the alphasyllabic but not alphabetic group. The results suggest that writing systems with a syllable-based mapping principle recruit bilateral mFG to support orthographic processing. Implications for individuals with left mFG dysfunction will be discussed.

Evidence for Cerebellar Contributions to Adaptive Plasticity in Speech Perception.

Human speech perception rapidly adapts to maintain comprehension under adverse listening conditions. For example, with exposure listeners can adapt to heavily accented speech produced by a non-native speaker. Outside the domain of speech perception, adaptive changes in sensory and motor processing have been attributed to cerebellar functions. The present functional magnetic resonance imaging study investigates whether adaptation in speech perception also involves the cerebellum. Acoustic stimuli were distorted using a vocoding plus spectral-shift manipulation and presented in a word recognition task. Regions in the cerebellum that showed differences before versus after adaptation were identified, and the relationship between activity during adaptation and subsequent behavioral improvements was examined. These analyses implicated the right Crus I region of the cerebellum in adaptive changes in speech perception. A functional correlation analysis with the right Crus I as a seed region probed for cerebral cortical regions with covarying hemodynamic responses during the adaptation period. The results provided evidence of a functional network between the cerebellum and language-related regions in the temporal and parietal lobes of the cerebral cortex. Consistent with known cerebellar contributions to sensorimotor adaptation, cerebro-cerebellar interactions may support supervised learning mechanisms that rely on sensory prediction error signals in speech perception.

A Flexible and Integrated System for the Remote Acquisition of Neuropsychological Data in Stroke Research.

BACKGROUND: Neuropsychological testing is a central aspect of stroke research because it provides critical information about the cognitive-behavioral status of stroke survivors, as well as the diagnosis and treatment of stroke-related disorders. Standard neuropsychological methods rely upon face-to-face interactions between a patient and researcher, which creates geographic and logistical barriers that impede research progress and treatment advances. INTRODUCTION: To overcome these barriers, we created a flexible and integrated system for the remote acquisition of neuropsychological data (RAND). The system we developed has a secure architecture that permits collaborative videoconferencing. The system supports shared audiovisual feeds that can provide continuous virtual interaction between a participant and researcher throughout a testing session. Shared presentation and computing controls can be used to deliver auditory and visual test items adapted from standard face-to-face materials or execute computer-based assessments. Spoken and manual responses can be acquired, and the components of the session can be recorded for offline data analysis. MATERIALS AND METHODS: To evaluate its feasibility, our RAND system was used to administer a speech-language test battery to 16 stroke survivors with a variety of communication, sensory, and motor impairments. The sessions were initiated virtually without prior face-to-face instruction in the RAND technology or test battery. RESULTS: Neuropsychological data were successfully acquired from all participants, including those with limited technology experience, and those with a communication, sensory, or motor impairment. Furthermore, participants indicated a high level of satisfaction with the RAND system and the remote assessment that it permits. CONCLUSIONS: The results indicate the feasibility of using the RAND system for virtual home-based neuropsychological assessment without prior face-to-face contact between a participant and researcher. Because our RAND system architecture uses off-the-shelf technology and software, it can be duplicated without specialized expertise or equipment. In sum, our RAND system offers a readily available and promising alternative to face-to-face neuropsychological assessment in stroke research.

Learning to read an alphabet of human faces produces left-lateralized training effects in the fusiform gyrus.

Numerous functional neuroimaging studies have shown that most orthographic stimuli, such as printed English words, produce a left-lateralized response within the fusiform gyrus (FG) at a characteristic location termed the visual word form area (VWFA). We developed an experimental alphabet (FaceFont) comprising 35 face-phoneme pairs to disentangle phonological and perceptual influences on the lateralization of orthographic processing within the FG. Using functional imaging, we found that a region in the vicinity of the VWFA responded to FaceFont words more strongly in trained versus untrained participants, whereas no differences were observed in the right FG. The trained response magnitudes in the left FG region correlated with behavioral reading performance, providing strong evidence that the neural tissue recruited by training supported the newly acquired reading skill. These results indicate that the left lateralization of the orthographic processing is not restricted to stimuli with particular visual-perceptual features. Instead, lateralization may occur because the anatomical projections in the vicinity of the VWFA provide a unique interconnection between the visual system and left-lateralized language areas involved in the representation of speech.

Using Artificial Orthographies for Studying Cross-Linguistic Differences in the Cognitive and Neural Profiles of Reading.

Reading and writing are cultural inventions that have become vital skills to master in modern society. Unfortunately, writing systems are not equally learnable and many individuals struggle to become proficient readers. Languages and their writing systems often have co-varying characteristics, due to both psycholinguistic and socio-cultural forces. This makes it difficult to determine the source of cross-linguistic differences in reading and writing. Nonetheless, it is important to make progress on this issue: a more precise understanding of the factors that affect reading disparities should improve reading instruction theory and practice, and the diagnosis and treatment of reading disorders. In this review, we consider the value of artificial orthographies as a tool for unpacking the factors that create cognitive and neural differences in reading acquisition and skill. We do so by focusing on one dimension that differs among writing systems: grain size. Grain size, or the unit of spoken language that is mapped onto a visual graph, is thought to affect learning, but its impact is still not well understood. We review relevant literature about cross-linguistic writing system differences, the benefits of using artificial orthographies as a research tool, and our recent work with an artificial alphasyllabic writing system for English. We conclude that artificial orthographies can be used to elucidate cross-linguistic principles that affect reading and writing.