Biology subjects

DeMarco, A. T.

Publications and source records attributed to DeMarco, A. T..

11 recordsLinked to original sources

bioRxiv2026

Dispelling the Plateau Assumption: Case-Based Evidence for Language Recovery in Chronic-Post Stroke Aphasia

ObjectiveRecovery from post-stroke aphasia is traditionally thought to plateau within a year after stroke. As such, no studies have characterized long-term recovery using comprehensive behavioral assessment and longitudinal functional MRI. We sought to characterize behavioral and neuroplastic changes over nearly six years in a patient with chronic post-stroke aphasia. MethodsA patient with chronic left hemisphere stroke underwent behavioral assessment and task-based fMRI at 9, 22, 33 and 71 months after stroke. Testing assessed auditory comprehension, semantic and phonological processing, naming, reading, spelling, motor speech, and executive function. Task-related activation during an adaptive semantic matching paradigm was quantified within language and semantic regions of interest. ResultsBehavior improved across multiple language domains. WAB-R Aphasia Quotient increased from 49.2 to 69.2, along with the large gains in word finding, connected speech, reading and spelling, whereas auditory comprehension remained relatively stable. fMRI demonstrated progressively increasing activation within left-hemisphere language regions, reaching normative range by the final assessment, along with increasing activation in semantic/executive regions. DiscussionRecovery of language production abilities can continue for years after stroke, supported by neuroplastic changes in the brain. Neurologists should inform stroke survivors that aphasia recovery can continue indefinitely after stroke.

neuroscience↗

bioRxiv2026

Meaning for reading pseudowords: errors reveal semantic influences on pseudoword reading after stroke

Impaired reading, i.e., alexia, is common after left hemisphere stroke. The most common deficit in alexia is a difficulty reading aloud pronounceable novel words, also called pseudowords. While semantic and phonological processes both subserve reading real words, pseudoword reading deficits in alexia are typically ascribed to phonological deficits alone. Some theories, however, suggest that pseudoword reading relies in part on lexical-semantic knowledge, such that semantic deficits could also contribute to poor pseudoword reading in alexia. Leveraging a large sample of left-hemisphere stroke survivors, we examine the cognitive and neural substrates of pseudoword reading accuracy and two error types: lexicalization errors, where a pseudoword is incorrectly read as a real word, and nonword errors, where a pseudoword is read as an incorrect nonword. 76 left-hemisphere stroke survivors read 60 pseudowords aloud, and performed two pseudoword repetition tasks to assess phonological processing and two picture naming tasks to assess mappings between lexical semantics and phonology. Regression models assessed how pseudoword repetition and naming related to overall accuracy and rates of lexicalization and nonword errors in pseudoword reading. Voxel-based and connectome lesion-symptom mapping localized the neural territory responsible for these errors. Pseudoword repetition and naming independently related to pseudoword reading accuracy. Pseudoword repetition but not naming deficits predicted higher rates of lexicalization errors, while naming but not pseudoword repetition deficits predicted higher rates of nonword errors. Greater nonword error rate also predicted smaller imageability effects in real word reading (t(71)=-3.2, p=0.002). Lexicalization errors were associated with lesions to and disconnections of the left putamen and basal ganglia. Nonword errors were associated with lesions to the superior and middle temporal gyri, as well as broad temporo-parietal disconnections, overlapping with previous lesion-mapping results implicating these regions in semantic contributions to word reading. These results suggest that lexicalization errors result from impaired planning and execution of novel motor plans, causing a reliance on the well-learned motor plans associated with lexical items. In contrast, greater rates of nonword errors, relative to lexicalization errors, occur when semantic contributions to reading are impaired. Overall, these findings demonstrate that semantic processes are involved in reading pseudowords, at least in stroke alexia. These findings support connectionist accounts of reading in which damage in the direct orthography to phonology route for reading leads to greater reliance on semantic representations, even for pseudowords, suggesting a reinterpretation of pseudoword reading as a pure measure of phonological deficits in reading.

neuroscience↗

bioRxiv2026

Simulating the spectrum, not the syndrome: Large scale individualized modeling of oral reading in stroke aphasia

Computational models are a linchpin in our understanding of the neurocognitive basis of reading. These models can simulate idealized profiles of alexia syndromes, but in reality, individuals with alexia present with a wide range of mixed deficits rather than idealized syndromes. To provide a complete cognitive theory of reading, computational models must be able to account for this individual variation. However, this has never been demonstrated. We test oral reading and non-reading phonological and semantic processing in 83 left-hemisphere stroke survivors. We show that individual alexia profiles can be simulated by applying graded phonology and semantic lesions to an artificial neural network model of reading, creating "matched models" that represent individual stroke survivors. The severity of damage to the semantic and phonological layers of the matched models was highly correlated with directly-measured semantic and phonological processing deficits. However, we also identify systematic ways in which the models fail to simulate the reading performance of their matched stroke survivors. Our results support theories of alexia that rely on process-based deficits, demonstrate the feasibility of large-scale individualized modelling of alexia, and suggest ways to further improve the correspondence of models and human reading behavior.

neuroscience↗

bioRxiv2025

Identifying left and right hemispheres using functional connectivity

Many studies have analyzed what organizational features distinguish the left and right hemispheres of the human brain, with differences typically being found in language areas and in fine motor control (i.e., handedness). In this analysis, we test whether supervised learning can categorize ("fingerprint") an unseen hemisphere as right or left based on functional connectivity. Using data from the Human Connectome Project, we find success to be extremely high (accuracies > .90) in models trained on right-handed participants (Edinburgh Handedness Inventory [EHI] > 0) and in models trained on left-handed participants (EHI [≤] 0). In a second analysis, we test whether the same can be done to identify handedness alongside hemisphere left/right sidedness. While individuals hemispheres are less distinct the more left-handed they are, hemiconnectomes cannot be reliably classified as belonging to a left- or right-handed person. Our approach can inform developmental and post-injury work on hemispheric organization and reorganization.

neuroscience↗

bioRxiv2025

Dissecting the sublexical route for reading: Frontal and parietal networks support learned orthography-to-phonology mappings

Oral reading relies on lexical and sublexical processes with distinct neural mechanisms. Damage within the sublexical system causes phonological alexia, a blanket diagnosis describing acquired deficits in reading unfamiliar words. Improving the precision of alexia diagnosis requires understanding the neurocognitive basis of specific reading subprocesses. This study investigated the neural correlates of sublexical reading in 64 adults with chronic left-hemisphere stroke (LHS), focusing on lesions that impair the use of learned orthography-to-phonology (OP) mappings to read new words. Participants read aloud real words and three types of pseudowords varying in the number of plausible OP mappings at the level of the orthographic body: zero mappings (0M), one mapping (1M), and multiple mappings (MM). LHS participants exhibited phonological reading deficits with an exaggerated lexicality effect compared to 71 neurotypical controls. Across both groups, pseudowords with learned OP mappings were read more accurately than those without. Voxelwise and connectome-based lesion-symptom mapping revealed that relative lexical reading deficits were associated with lateral temporal lesions, while sublexical reading deficits were associated with lesions or disconnections of the left inferior frontal (IFG), supramarginal, and pre/postcentral gyri. Applying learned OP mappings relied on anterior IFG and frontoparietal connections, while resolving multiple plausible OP mappings relied on intraparietal connections. These results underscore the role of learned mutigraphemic OP mappings in sublexical reading, and demonstrate that disruptions of different sublexical reading subprocesses result in subtly different deficit patterns. Dissecting the neurocognitive basis of reading subprocesses may improve the precision of alexia diagnosis and point to new treatments.

neuroscience↗

bioRxiv2025

Meaning for reading: The neurocognitive basis of semantic reading impairment after stroke

Diagnosis of alexia has historically focused on syndromes, such as surface alexia, which capture discrete patterns of reading deficits observed in some patients, but do not describe the breadth of reading deficits observed in practice. Aphasia research has recently shifted focus to language process impairments rather than syndromic classifications. A similar shift in focus to reading process impairments may improve our diagnostic approach to alexia. Behavioural evidence suggests that semantic processing influences reading aloud, and that semantic deficits in the context of semantic dementia underlie surface alexia. Because stroke rarely causes loss of semantic knowledge and surface alexia as a syndromic diagnosis is unusual after stroke, semantic reading deficits in stroke alexia have not previously been examined systematically. Semantic reading deficits in stroke may not relate to semantic deficits per se, but rather an inability to use semantics to support reading. Imageability, the degree to which a word brings to mind an image, is one index of semantic influences on reading. High imageability words are read more quickly by healthy persons and more accurately following brain damage. Here, we test if deficits of semantic reading after stroke, as indexed by reduced imageability effects, result from semantic or post-semantic processes. Examining nonverbal semantic processing, semantics-phonology mapping, and semantic control in a sample of 56 left-hemisphere stroke survivors, only semantics-phonology mappings predicted the reading advantage for high imageability words over low imageability words. Support vector regression voxel-based lesion symptom mapping revealed that damage along the superior temporal sulcus and underlying white matter, extending into both the middle and superior temporal gyri, reduced the advantage of high imageability over low imageability words during reading, reflecting an inability to use semantics to support reading. A similar cluster related to impairments in semantics-phonology mapping. The imageability and semantics-phonology mapping results overlapped in the left posterior superior temporal sulcus. Support vector regression connectome lesion symptom mapping revealed white matter disconnections within a broad temporoparietal network important for both phonological and semantic processing were associated with a reduction of the imageability advantage during reading. These results demonstrate that, irrespective of syndromic classification, semantic reading deficits occur in left-hemisphere stroke survivors as a result of impaired integration of semantic and phonological representations, and that the left posterior superior temporal sulcus underlies this process. Our results clarify the neurobiology of reading aloud, and support the existence of a post-semantic impairment of semantic reading in left-hemisphere stroke survivors.

neuroscience↗

bioRxiv2021

The organization of individually mapped structural and functional semantic networks in aging adults

Language function in the brain, once thought to be highly localized, is now appreciated as relying on a connected but distributed network. The semantic system is of particular interest in the language domain because of its hypothesized integration of information across multiple cortical regions. Previous work in healthy individuals has focused on group-level functional connectivity (FC) analyses of the semantic system, which may obscure interindividual differences driving variance in performance. These studies also overlook the contributions of white matter networks to semantic function. Here, we identified semantic network nodes with a semantic decision fMRI task in 53 typically-aging adults, characterized network organization using structural connectivity (SC), and quantified the segregation and integration of the network using FC. Hub regions were identified in left inferior frontal gyrus. The individualized semantic network was composed of three interacting modules: 1) default-mode module characterized by bilateral medial prefrontal and posterior cingulate regions and also including right-hemisphere homotopes of language regions; 2) left frontal module extending dorsally from inferior frontal gyrus to pre-motor area; and 3) left temporoparietal module extending from temporal pole to inferior parietal lobule. FC within Module3 and integration of the entire network related to a semantic verbal fluency task, but not a matched phonological task. These results support and extend the tri-network semantic model (Xu et al., 2017) and the controlled semantic cognition model (Chiou et al., 2018) of semantic function.

neuroscience↗

bioRxiv2021

Structural Disconnection of the Posterior Medial Frontal Cortex Reduces Speech Error Monitoring

Optimal performance in any task relies on the ability to detect and repair errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production and executive function. Interactions between pMFC and other taskrelevant processors may similarly be critical for error monitoring in other task contexts.

neuroscience↗

bioRxiv2021

Glass Half Full: Preserved Anatomical Bypasses Predict Variance in Language Functions After Stroke

The severity of post-stroke aphasia is related to damage to white matter connections. However, neural signaling can route not only through direct connections, but also along multi-step network paths. When brain networks are damaged by stroke, paths can bypass around the damage to restore communication. The shortest network paths between regions could be the most efficient routes for mediating bypasses. We examined how shortest-path bypasses after left hemisphere strokes were related to language performance. Regions within and outside of the canonical language network could be important in aphasia recovery. Therefore, we innovated methods to measure the influence of bypasses in the whole brain. Distinguishing bypasses from all residual shortest paths is difficult without pre-stroke imaging. We identified bypasses by finding shortest paths in subjects with stroke that were longer than those observed in the average network of the most reliably observed connections in age-matched controls. We tested whether features of those bypasses predicted scores in four orthogonal dimensions of language performance derived from a factor analysis of a battery of language tasks. The features were the length of each bypass in steps, and how many bypasses overlapped on each individual direct connection. We related these bypass features to language factors using grid-search cross-validated Support Vector Regression, a technique that extracts robust relationships in high-dimensional data analysis. We discovered that the length of bypasses reliably predicted variance in lexical production (R2 = .576) and auditory comprehension scores (R2 = .164). Bypass overlaps reliably predicted variance in Lexical Production scores (R2 = .247). The predictive elongation features revealed that bypass efficiency along the dorsal stream and ventral stream were most related to Lexical Production and Auditory Comprehension, respectively. Among the predictive bypass overlaps, increased bypass routing through the right hemisphere putamen was negatively related to lexical production ability.

neuroscience↗

bioRxiv2021

Testing the perilesional neuroplastic recruitment hypothesis in aphasia

ObjectiveA prominent theory proposes that neuroplastic recruitment of perilesional tissue supports aphasia recovery, especially when language-capable cortex is spared by smaller lesions. This theory has rarely been tested directly, and findings have been inconclusive. Here, we test the perilesional plasticity hypothesis using two fMRI tasks in two groups of stroke survivors. MethodsTwo cohorts totaling 84 chronic left-hemisphere stroke survivors with prior aphasia diagnosis, and 80 control participants underwent fMRI using either a naming task or a reliable semantic decision task. Individualized perilesional tissue was defined by dilating anatomical lesions, and language regions were defined using meta-analyses. Mixed modeling examined differences in activity between groups. Relationships with lesion size and aphasia severity were examined. ResultsStroke survivors exhibited reduced activity in perilesional language tissue relative to controls in both tasks. Although a few cortical regions exhibited greater activity irrespective of distance from the lesion, or only when distant from the lesion, no regions exhibited increased activity only when near the lesion. Larger lesions were associated with reduced language activity irrespective of distance from the lesion. Using the reliable fMRI task, reduced language activity related to aphasia severity independent of lesion size. InterpretationWe find no evidence for neuroplastic recruitment of perilesional tissue in aphasia beyond its typical role in language. Rather, our findings are consistent with alternative hypotheses that left-hemisphere activation changes during recovery relate to normalization of language network dysfunction and possibly recruitment of alternate cortical processors. These findings clarify left-hemisphere neuroplastic mechanisms supporting language recovery after stroke. Summary for Social Media If AcceptedO_ST_ABSTwitter handleC_ST_ABS@crlgeorgetown What is the current knowledge on the topic?After left-hemisphere stroke, many individuals experience long-term language impairment (aphasia) while others recover their communication abilities. Although there are several hypotheses concerning the kind of brain neuroplasticity that allows some individuals to recover, these mechanisms are not understood in aphasia. What question did this study address?This study tested the perilesional plasticity hypothesis as it relates to aphasia recovery. This predominant theory posits that tissue around the stroke lesion boundary becomes recruited to support recovered language function in post-stroke aphasia. What does this study add to our knowledge?This study clarifies the mechanisms of neuroplasticity in stroke aphasia recovery. The results are not consistent with the conventional perilesional plasticity hypothesis, but rather favor an interpretation that recovery is supported by normalization of language network dysfunction and possibly recruitment of alternate brain regions How might this potentially impact on the practice of neurology?These conclusions will give practicing neurologists a better understanding of how the brain recovers from aphasia after stroke.

neuroscience↗

bioRxiv2018

Functional anomaly mapping reveals local and distant dysfunction caused by brain lesions

The lesion method has been a cornerstone in the endeavor to understand brain-behavior relationships in humans, but has relied on the flawed assumption that anatomically abnormal tissue functions abnormally and anatomically normal tissue functions normally. To address this longstanding problem, we introduce an approach to directly map the degree of functional anomaly throughout the brain in individual patients. These functional anomaly maps identify anatomical lesions and are stable across measurements. Moreover, the maps identify functionally anomalous regions in anatomically normal tissue, providing a direct measure of remote effects of lesions such as diaschisis. Lesion-behavior mapping using these maps replicates classic behavioral localization and identifies relationships between tissue function and behavior distant from the anatomical lesions. This method provides brain-wide maps of the functional effects of focal lesions, which could have wide implications for one of the most important methods in neuroscience.

neuroscience↗