Biology subjects

Price, C. J.

Publications and source records attributed to Price, C. J..

17 recordsLinked to original sources

bioRxiv2026

Reorganisation of Functional Connectivity Gradients in Post-Stroke Aphasia

Aphasia after stroke arises from focal damage to language-relevant cortex but is accompanied by widespread alterations in functional connectivity. In 60 stroke survivors, we related principal component-derived language scores to both lesion location and stroke-related changes in resting-state functional organisation, combining structural lesion-symptom mapping with a gradient-based approach. Structural lesion-symptom mapping identifies which damaged regions are associated with specific language impairments but does not capture how surviving cortex is reconfigured within the brains large-scale architecture. In contrast, lesion-gradient mapping characterises whole-brain connectivity gradients - data-driven axes that summarise the principal patterns of variation in cortical connectivity - and quantifies how behavioural variation relates to displacement of structurally intact regions along these intrinsic axes. Stroke was associated with altered positioning of cortical regions along the gradient separating default mode and control networks. Notably, the position of the left inferior frontal gyrus along this axis predicted dissociable language outcomes: displacement toward default mode connectivity patterns was associated with better speech but poorer writing performance. This opposing behavioural profile suggests that inferior frontal cortex contributes to language through flexible large-scale coupling, with distinct coupling regimes differentially supporting spoken and written production. These findings indicate that gradient-based mapping provides a mechanistic link between focal tissue damage and distributed behavioural consequences by revealing systematic reorganisation of macroscale functional architecture beyond the lesion site.

neuroscience↗

bioRxiv2026

Mitochondrial activity directs nutrient uptake and patterning in human gastrula models.

How a uniform field of cells responds to inductive cues to form distinct, spatially organised, lineages is a question of much interest. In human gastruloids, a BMP4 signalling gradient directs the self-organization of embryonic stem cells (hESCs) into the three germ-layers. But what regulates differential responses to BMP4 is poorly understood. Here we demonstrate that mitochondrial activity is key, as by directing nutrient uptake it determines the threshold of BMP signalling. We show that decreased mitochondrial activity stimulates fatty acid uptake via macropinocytosis and subsequent {beta}-oxidation and that this increases the BMP4 response. However, we also find that disease causing mitochondrial DNA mutations impair dynamic switching between glucose and fatty acid utilisation, causing hESCs to be unable to spatially organise the mesoderm, endoderm and ectoderm layers in gastruloids. These results suggest that the correct interpretation of morphogen gradients during gastrulation emerges through the crosstalk of signalling inputs and nutrient utilisation.

developmental biology↗

bioRxiv2025

Reading ability in both deaf and hearing adults is linked to neural representations of abstract phonology derived from visual speech

Reading is central to academic and vocational success. Some deaf children face reading challenges due to limited access to spoken or signed language. Robust phonological representations are key to reading development in hearing children. Spoken language phonology may be one of many contributors to reading development in deaf children. Indeed, speechreading ability correlates with reading skill in both deaf and hearing individuals, suggesting it is linked to reading development regardless of hearing status. Further support for this hypothesis would be provided by evidence that similar neural representations of speech phonology are evoked by visual speech and other language forms (auditory speech and text), and that these neural representations are related to reading proficiency. We used fMRI and Representational Similarity Analysis (RSA) to identify shared neural representations of spoken language phonological structure. A group of deaf adult participants (N=22), with a mixture of sign language and spoken language backgrounds and reading abilities, were presented with single lexical items as visual speech and dynamic text (cursive text, revealed letter-by-letter to promote a phonological reading strategy). Adult hearing participants (N=25) were presented with the same words, but as visual speech and auditory speech. Shared neural representations of phonological structure of English words were found in each group in the superior and middle temporal cortex (STC/MTC) and these abstract representations were more similar across different language forms in better readers. Our data provide neurobiological evidence of the contribution of visual speech to abstract phonological representations of spoken language, that relate to reading proficiency, in both deaf and hearing adults. Significance StatementReading is an essential skill, yet some deaf children face reading challenges due to reduced access to signed or spoken language. In hearing children, successful reading depends on abstract phonological representations, but whether spoken language phonology relates to reading in deaf individuals remains unclear. Using fMRI and RSA, we show that deaf and hearing adults recruit neural representations of phonology that are shared by visual speech and other language forms (visual/auditory speech in hearing; visual speech/dynamic text in deaf) in the superior and middle temporal cortex. Critically, greater cross-modal alignment of neural representations of phonological structure was associated with better reading in both groups. These findings provide neurobiological evidence that visual speech contributes to phonological representations that relate to reading, regardless of hearing status.

neuroscience↗

bioRxiv2024

Continuous lesion images drive more accurate predictions of outcomes after stroke than binary lesion images

Current medicine cannot confidently predict who will recover from post-stroke impairments. Researchers have sought to bridge this gap by treating the post-stroke prognostic problem as a machine learning problem. Consistent with the observation that these impairments are caused by the brain damage that stroke survivors suffer, information concerning where and how much lesion damage they have suffered conveys useful prognostic information for these models. Much recent research has considered how best to encode this lesion information, to maximise its prognostic value. Here, we consider an encoding that, while not novel, has never before been formally examined in this context: continuous lesion images, which encode continuous evidence for the presence of a lesion, both within and beyond what might otherwise be considered the boundary of a binary lesion image. Current state of the art models employ information derived from binary lesion images. Here, we show that those models are significantly improved (i.e., with smaller Mean Squared Error between predicted and empirical outcome scores) when using continuous lesion images to predict a wide range of cognitive and language outcomes from a very large sample of stroke patients. We use further model comparisons to locate the predictive advantage to the provision of continuous lesion evidence beyond the boundary of binary lesion images. The continuous lesion images thus provide a straightforward way to incorporate details of both lesioned and non-lesioned tissue when predicting outcomes after stroke.

neuroscience↗

bioRxiv2023

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

Human pluripotent stem cell (hPSC)-derived cardiomyocytes have emerged as powerful tools for disease modelling and cell therapy. The production of cardiomyocytes from hPSCs typically requires expanding large numbers of hPSCs and maintaining them in culture for extended periods of time. This in turn predisposes hPSCs to the acquisition of non-random genetic changes, including recurrent gains of chromosome 1q. Here, we show that gain of chromosome 1q in hPSCs affects both the efficiency of differentiation to cardiomyocytes and phenotype of the differentiated cells. Mechanistically, we show that aberrant activation of the Wnt signalling pathway underpins the skewed differentiation of variant 1q hPSCs. Collectively, our data demonstrates that the presence of genetically variant cells in cultures is a significant concern for production of hPSC-derived cardiomyocytes for research or clinical applications. Further, our results suggest new approaches for removing genetically variant cells for future clinical applications.

cell biology↗

bioRxiv2023

Cytogenetic resource enables mechanistic resolution of changing trends in human pluripotent stem cell aberrations linked to feeder-free culture

Since the first derivation of human pluripotent stem cells (hPSCs), the number of culture conditions has steadily increased, making hPSC culture more facile. Nonetheless, there remains the persistent issue of culture-acquired genetic changes, hampering the reproducibility of hPSC research and jeopardising their clinical use. Here, we utilised comprehensive karyotyping datasets from over 20,000 hPSC cultures sampled under different conditions to ascertain association of genetic changes with specific culture regimens. We found condition-dependent patterns of aberrations, with higher prevalence of chromosome 1q gains in recent years, associated with increased use of contemporary, feeder-free cultures. Mechanistically, we show the context-dependent selection of 1q variants is mainly driven by MDM4, a gene amplified in many cancers, located on chromosome 1q. To facilitate reproducibility of hPSC research and their safe clinical utility, we provide a unique hPSC karyotype resource for informing the risk assessment of genetic aberrations and developing strategies to suppress their occurrence.

cell biology↗

bioRxiv2023

Auditory cortex anatomy reflects multilingual phonological experience

This study explores the relationship between the anatomy of the auditory cortex and multilingual experience, shedding light on the complex mechanisms of auditory processing in humans. Integrating previous research on auditory information processing and the impact of bi- and multilingualism on brain structure, we investigate how the morphology of auditory brain regions reflects individuals language experience and, more specifically, their phonological repertoire. Leveraging two distinct samples comprising over 200 participants, each exposed to between 1 and 7 languages encompassing 36 different languages, we explore whether the morphological variability of auditory brain regions reflects individual language experience, specifically focusing on the phonological repertoire. Additionally, we examine the potential influence of typological distances between languages spoken by multilingual individuals on the neural signatures of multilingualism within the auditory cortex. Our findings revealed a relationship between the average thickness of the left and right second transverse temporal gyrus (TTG) and participants language experience. Model comparisons demonstrated that the inclusion of phoneme-level information in the language experience index accounted for the greatest variance in average TTG thickness (bilaterally). The direction of this effect was negative, indicating that a more extensive and more phonologically diverse language experience was associated with thinner cortices in the second TTG. Across two independent datasets, we provide robust evidence linking the degree of language experience and typological distance between languages to cortical thickness in early auditory brain regions. We propose that this phenomenon may reflect experience-driven pruning and neural efficiency, warranting further investigation through longitudinal studies of language acquisition. Moreover, our findings support the notion that experiences with typologically similar languages differ from those with typologically distant languages, offering valuable insights into the intricate relationship between language diversity and brain structure. Our findings also indicate that early auditory regions seem to represent phoneme-level cross-linguistic information, contrary to the most established models of language processing in the brain, which suggest that phonological processing happens in more lateral posterior STG and STS.

neuroscience↗

bioRxiv2022

HDAC6 inhibition partially alleviates mitochondrial trafficking defects and restores motor function in human motor neuron and zebrafish models of Charcot-Marie-Tooth Disease Type 2A

Charcot Marie Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. There are currently no treatments for this debilitating disease. To investigate disease mechanisms and facilitate treatment discovery, here we developed an in vitro model for CMT type 2A by introducing the patient-specific MFN2R94Q mutation into human embryonic stem cells (hESCs). Isogenic mutant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in reduced numbers of mitochondria in distal parts of axons. Importantly, we showed that mitochondrial trafficking defects can be alleviated by treatment with an HDAC6 inhibitor. Chemical and genetic inhibition of HDAC6 also significantly rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a mutation-specific insight into CMT2A disease mechanism and confirms HDAC6 as a promising target for further therapeutic development.

cell biology↗

bioRxiv2022

A Machine Learning Approach Towards the Differentiation Between Interoceptive and Exteroceptive Attention

Interoception, the representation of the bodys internal state, plays a central role in emotion, motivation, and wellbeing. Interoceptive attention is qualitatively different from attention to the external senses and may recruit a distinct neural system, but the neural separability of interoceptive and exteroceptive attention is unclear. We used a machine learning approach to classify neural correlates of interoceptive and exteroceptive attention in a randomized control trial of interoceptive training (MABT). Participants in the training and control groups attended fMRI assessment before and after an 8-week intervention period (N = 44 scans). The imaging paradigm manipulated attention targets (breath vs. visual stimulus) and reporting demands (active reporting vs. passive monitoring). Machine learning models achieved high accuracy in distinguishing between interoceptive and exteroceptive attention using both in-sample and more stringent out-of-sample tests. We then explored the potential of these classifiers in "reading out" mental states in a sustained interoceptive attention task. Participants were classified as maintaining an active reporting state for only [~]90s of each 3-minute sustained attention period. Within this active period, interoceptive training enhanced participants ability to sustain interoceptive attention. These findings demonstrate that interoceptive and exteroceptive attention engage reliable and distinct neural networks; machine learning classifiers trained on this distinction show promise for assessing the stability of interoceptive attention, with implications for the future assessment of mental health and treatment response.

neuroscience↗

bioRxiv2022

Neural Dynamics of Interoceptive Attention and Awareness: A Within-Participant fMRI Study

Interoception, the representation of the bodys internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoception are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions (N = 44) as part of a randomized control trial of Mindful Awareness in Body-oriented Therapy (MABT). Compared to Exteroception, Interoception deactivated somatomotor and prefrontal regions. Greater interoceptive sensibility (MAIA scale) predicted sparing from deactivation along the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula--typically described as a primary interoceptive cortex--was only implicated by its further deactivation during an exogenously paced respiration condition (Active Matching). Psychophysiological interaction analysis characterized Active Interoception as promoting greater ACC connectivity with lateral frontal and parietal regions commonly referred to as the Dorsal Attention Network. Interoception of the breath may therefore involve reduced cortical activity but greater connectivity, with greater sensibility sparing cortical inhibition within well-characterized attentional networks. In contrast to a literature that relates detection of liminal signals such as the heartbeat to anterior insula activity, attention towards accessible body sensations such as the breath may lead to a low activity, high connectivity state in which sensory signals from the body may be better discerned. Significance StatementInteroception, the representation of the bodys internal state, is poorly understood compared to the external senses, with existing neuroimaging studies failing to match task difficulty between interoceptive and exteroceptive tasks. The present study used a novel fMRI task to compare interoceptive and exteroceptive attention, and how this distinction was moderated by self-reported interoceptive awareness. The results implicate three novel interoceptive mechanisms: interoception reduces cortical activity while increasing connectivity, wherein awareness is linked to preserved activation of the brains salience network and left-lateralized language regions. These findings characterize interoception as a lower activity state in which awareness depends upon the ability to notice and report on body signals typically obscured by the processing of exteroceptive information and other forms of cognition.

neuroscience↗

bioRxiv2022

Degeneracy in the neurological model of auditory speech repetition

In the neurological model of language, repeating heard speech involves four left hemisphere regions: primary auditory cortex for processing sounds; Wernickes area for processing auditory images of speech; Brocas area for processing motor images of speech; and primary motor cortex for overt speech articulation. Previous functional-MRI (fMRI) studies confirm that auditory repetition activates these regions. Here, we used dynamic causal modelling (DCM) to test how the four regions interact with each other during single word and pseudoword auditory repetition. Contrary to expectation, we found that, for both word and pseudoword repetition, the effective connectivity between Wernickes and Brocas areas was predominantly bidirectional and inhibitory; activity in the motor cortex could be driven by either Wernickes area or Brocas area; and the latter effect varied both within and between individuals. Such variability speaks to degenerate functional architectures that support auditory repetition and may explain resilience to functional loss after brain damage.

neuroscience↗

bioRxiv2021

Lesion site and therapy time predict responses to a therapy for anomia after stroke: a prognostic model development study

BACKGROUNDStroke is a leading cause of disability, and language impairments (aphasia) after stroke are both common and particularly feared. Most stroke survivors with aphasia exhibit anomia (difficulties with naming common objects), but while many therapeutic interventions for anomia have been proposed, treatment effects are typically much larger in some patients than others. Here, we asked whether that variation might be more systematic, and even predictable, than previously thought. METHODS18 patients, each at least 6 months after left hemisphere stroke, engaged in a computerised treatment for their anomia over a 6 week period. Using only: (a) the patients initial accuracy when naming (to-be) trained items; (b) the hours of therapy that they devoted to the therapy; and (c) whole-brain lesion location data, derived from structural MRI; we developed Partial Least Squares regression models to predict the patients improvements on treated items, and tested them in cross-validation. RESULTSSomewhat surprisingly, the best model included only lesion location data and the hours of therapy undertaken. In cross-validation, this model significantly out-performed the null model, in which the prediction for each patient was simply the mean treatment effect of the group. This model also made promisingly accurate predictions in absolute terms: the correlation between empirical and predicted treatment response was 0.62 (95%CI: 0.27, 0.95). DISCUSSIONOur results indicate that individuals variation in response to anomia treatment are, at least somewhat, systematic and predictable, from the interaction between where and how much lesion damage they have suffered, and the time they devoted to the therapy.

neuroscience↗

bioRxiv2020

Active Listening

This paper introduces active listening, as a unified framework for synthesising and recognising speech. The notion of active listening inherits from active inference, which considers perception and action under one universal imperative: to maximise the evidence for our (generative) models of the world. First, we describe a generative model of spoken words that simulates (i) how discrete lexical, prosodic, and speaker attributes give rise to continuous acoustic signals; and conversely (ii) how continuous acoustic signals are recognised as words. The active aspect involves (covertly) segmenting spoken sentences and borrows ideas from active vision. It casts speech segmentation as the selection of internal actions, corresponding to the placement of word boundaries. Practically, word boundaries are selected that maximise the evidence for an internal model of how individual words are generated. We establish face validity by simulating speech recognition and showing how the inferred content of a sentence depends on prior beliefs and background noise. Finally, we consider predictive validity by associating neuronal or physiological responses, such as the mismatch negativity and P300, with belief updating under active listening, which is greatest in the absence of accurate prior beliefs about what will be heard next.

neuroscience↗

bioRxiv2019

Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs harbouring recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms yielding a drift from predominantly wild-type to variant cell populations remain poorly understood. Here we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions resulting in elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster growing variants, causing a redistribution of F-actin and sequestration of YAP in the cytoplasm that induces apoptosis in wild-type cells. Importantly, YAP overexpression in wild-type cells is sufficient to alleviate their loser phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighbouring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.

cell biology↗

bioRxiv2019

Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells

Human pluripotent stem cells (PSC) often acquire genetic changes on prolonged culture, which pose concerns for their use in research and regenerative medicine (Amps et al., 2011, Seth et al., 2011). The acquisition of these changes during culture necessarily first requires mutation and then selection of those mutations that provide a growth advantage. Whilst selection accounts for the recurrent nature of the variants commonly reported (Draper et al., 2004, Olariu et al., 2010), the mechanisms of mutation in PSC remain largely elusive. Here we show that, in contrast to somatic cells, human PSC have an increased susceptibility to DNA damage and mitotic errors, both of which are caused by heightened replication stress in PSC and this can be alleviated by culture with exogenous nucleosides. These results reflect the requirement for rapid replication of human PSC enabled by a truncated G1 (Becker et al., 2006, Becker et al., 2010) that impairs the preparation of these cells for the ensuing DNA replication. A similar relationship has been shown in relation to chromosomal instability in cancer cells (Burrell et al., 2013, Wilhelm et al., 2019) but PSC differ by replication stress triggering apoptosis (Desmarais et al., 2012, Desmarais et al., 2016). Nevertheless, evasion of this response still leads to the appearance of genetic variants that are of concern for regenerative medicine. The inclusion of nucleosides into culture media greatly improves the efficiency of human PSC culture and minimises the acquisition of genomic damage.

cell biology↗

bioRxiv2019

Evidence for shared conceptual representations for sign and speech

Do different languages evoke different conceptual representations? If so, greatest divergence might be expected between languages that differ most in structure, such as sign and speech. Unlike speech bilinguals, hearing sign-speech bilinguals use languages conveyed in different modalities. We used functional magnetic resonance imaging and representational similarity analysis (RSA) to quantify the similarity of semantic representations elicited by the same concepts presented in spoken British English and British Sign Language in hearing, early sign-speech bilinguals. We found shared representations for semantic categories in left posterior middle and inferior temporal cortex. Despite shared category representations, the same spoken words and signs did not elicit similar neural patterns. Thus, contrary to previous univariate activation-based analyses of speech and sign perception, we show that semantic representations evoked by speech and sign are only partially shared. This demonstrates the unique perspective that sign languages and RSA provide in understanding how language influences conceptual representation.

neuroscience↗

bioRxiv2018

Not so proportional after all?

BackgroundThe proportional recovery rule asserts that most stroke survivors recover a fixed proportion of lost function. Reports that the rule can be used to predict recovery, extraordinarily accurately, are rapidly accumulating. Here, we show that the rule may not be as powerful as it seems.\n\nMethodsWe provide a formal analysis of the relationship between baseline scores (X), outcomes (Y) and recovery (Y-X), to highlight the shortcomings of the proportional recovery rule, and illustrate those problems with simulations in which synthetic recovery data are derived from different types of recovery processes.\n\nFindingsWhen the correlation between baseline scores and recovery is stronger than that between baselines scores and outcomes, the former can create an inflated impression of how predictable outcomes really are given baseline scores. This often happens when outcomes are less variable than baseline scores, as is common in empirical studies of recovery after stroke. Moreover, we cannot use the results of these correlations to distinguish proportional recovery from recovery which is either not consistently proportional, or not proportional at all.\n\nInterpretationAnalyses relating baseline scores to subsequent change are a minefield: our formal analysis applies as consistently outside the area of stroke as it does within it. One implication of our analysis is that the proportional recovery rule is not as predictive of real recovery after stroke as recent empirical studies suggest. Another is that different analytical methods will be required to ascertain whether recovery is even proportional at all.

neuroscience↗