Biology subjects

Lambon Ralph, M.

Publications and source records attributed to Lambon Ralph, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Neurotransmitter receptor architecture links local neurochemistry to semantic memory

A fundamental challenge in neuroscience is understanding how the molecular and neurochemical architecture of the human cortex gives rise to sophisticated higher cognitive functions. The anterior temporal lobe (ATL) is a key hub for semantic memory, and its underlying GABAergic and glutamatergic neurochemistry supports semantic memory performance. However, the molecular receptor architecture underlying these neurochemical-cognitive relationships remains unknown. Here, we combined imaging transcriptomics and in vivo magnetic resonance spectroscopy (MRS) to investigate how neurotransmitter receptor organisation relates to local neurochemistry and semantic memory in the human ATL. We found that the ATL exhibited a distinct transcriptomically inferred receptor-subunit profile relative to control cortical regions (occipital cortex and vertex). Individual-specific spatial estimates of receptor-subunit gene expression were systematically associated with local GABA+ and Glx concentrations, revealing preferential coupling between GABAergic receptor genes and GABA+ and between glutamatergic receptor genes and Glx, alongside widespread cross-system associations between GABAergic receptor architecture and Glx. ATL GABA+ and Glx concentrations were positively associated with semantic memory performance, and GABAergic and glutamatergic receptor-subunit expression showed selective relationships with semantic memory accuracy. Crucially, mediation analyses revealed that GABA+ mediated associations between GABAergic receptor architecture and semantic performance, whereas Glx mediated both glutamatergic and widespread GABAergic receptor associations. Together, these findings reveal a coupled molecular-neurochemical architecture of the human ATL, linking neurotransmitter receptor organisation to regional neurochemical state and individual differences in semantic memory. Our findings provide a multiscale account of how cortical molecular organisation is associated with human higher cognitive function.

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bioRxiv2026

Anterior temporal lobes show route-dependent sensitivity to conceptual specificity: Evidence from MEG and EEG

Understanding how the brain represents meaning at different levels of specificity, from general categories (bird) through combined phrases (nocturnal bird) to specific exemplars (owl), is a central question in semantic cognition and its disorders. The anterior temporal lobes (ATL) have been implicated in both activating stored conceptual representations and combining them, yet whether these two routes to conceptual content engage the ATL in the same way remains an open question. We recorded concurrent MEG-EEG from 36 participants reading 100 conceptual triads varying parametrically in specificity: general words (bird), adjective-noun phrases (nocturnal bird), and specific words (owl). Source analyses revealed a non-linear pattern in bilateral ATL (400-520ms): high-specificity concepts elicited greater activity than both low-specificity words and mid-specificity phrases. Bilateral inferior frontal cortex showed this effect with similar timing (430-630ms). N400 amplitude and ATL source activity showed a functional dissociation in their sensitivity to word frequency, ruling out a purely frequency account of the ATL and IFC effects. Results imply that accessing high-specificity concepts requires individuating stored representations among competitors, whereas phrases construct meaning through a different route. These findings extend the unified semantic hub account by revealing that computational operations within the ATL vary depending on task and stimulus demands.

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bioRxiv2026

Establishing parallel and scalar measures of executive and semantic demand: an online norming study of matched, cross-domain judgement tasks

Task demand has a long-standing history in experimental psychology, with numerous investigations of the capacity of different systems and processes under varying cognitive load. Whilst demand is a broadly used term in the literature, it is limited by a lack of cross-domain operationalisation, and thus can be a confound in many inter-domain investigations. To address this, we generated and validated two large-scale, open-source, widely applicable stimuli sets that: (i) can probe a wide, continuous range of objective behaviourally-measured processing demand, and (ii) can be directly matched across two highly contrastive cognitive domains (semantic and visuospatial processing). We normed these tasks in a large, online cohort of healthy adults, enabling future studies to utilise and benefit from reliable baseline measures of demand. Using a matching algorithm that takes into account both speed and accuracy, we then closely paired each semantic judgement trial with a trial of comparable difficulty from the corresponding visuospatial task to produce a cross domain matched set of over 400 items. Finally, we analysed the psycholinguistic and perceptual properties of these stimuli to explore some of the underlying factors driving demand.

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bioRxiv2025

A common framework for semantic memory and semantic composition

How the brain constructs meaning from individual words and phrases is a fundamental question for research in semantic cognition, language and their disorders. These two aspects of meaning are traditionally studied separately, resulting in two large, multi-method literatures, which we sought to bring together in this study. Not only would this address basic cognitive questions of how semantic cognition operates but also because, despite their distinct focuses, both literatures ascribe a critical role to the anterior temporal lobe (ATL) in each aspect of semantics. Given these considerations, we explored the notion that these systems rely on common underlying computational principles when activating conceptual semantic representations via single words, vs. building a coherent semantic representation across sequences of words. The present pre-registered study used magnetoencephalography and electroencephalography to track brain activity in participants reading nouns and adjective-noun phrases, whilst integrating conceptual variables from both literatures: the concreteness of nouns (e.g., "lettuce" vs. "fiction") and the denotational semantics of adjectives (subsective vs. privative, e.g., "bad" vs. "fake"). Region-of-interest analyses show that bilateral ATLs responded more strongly to phrases at different timepoints, irrespective of concreteness. Decoding analyses on ATL signals further revealed a time-varying representational format for adjective semantics, whereas representations of noun concreteness were more stable and maintained for around 300 ms. Further, the neural representation of noun concreteness was modulated by the preceding adjectives: decoders learning concreteness signals in single words generalised better to subsective relative to privative phrases. These findings point to a unified ATL function for semantic memory and composition.

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bioRxiv2025

The cognitive and neural bases of creative thought: a cross-domain meta-analysis of transcranial direct current stimulation studies

Creative thought enables humans to flexibly generate, evaluate and select novel and adaptive ideas according to different contexts. Decades of creativity research indicates that it involves at least two aspects: retrieval of previously acquired knowledge and manipulation of that knowledge. However, the cognitive processes underpinning these two aspects of creative thought remain underspecified. The broader clinical-cognitive neuroscience literature suggests that retrieval and manipulation of knowledge is underpinned by general purpose cognitive mechanisms supporting semantic cognition, controlled episodic memory retrieval, and executive mechanisms. To identify commonalities from converging evidence that points towards a unifying theory for the neurocognitive bases of creative thought, we reviewed and meta-analysed 152 studies from creativity and the relevant parallel cognitive neuroscience literature using transcranial direct current stimulation (tDCS). The results revealed three things: 1) current tDCS studies are heavily biased towards the frontal cortex (459/591 effect sizes; 77.7%); 2) only anodal tDCS over the left lateral frontal cortex promotes creativity (p <.01); and 3) anodal tDCS stimulation over the same region also promotes improvement in many other cognitive processes. The latter includes more efficient processing of semantic knowledge (p <.05), more accurate episodic memory retrieval (p <.05), better and more efficient manipulation of buffered knowledge (all p <.001), and more efficient response selection amongst competing options (i.e., task-setting; p <.01). By merging these previously separate literatures, tDCS studies support the notion that creative thought arises from general purpose cognitive mechanisms including controlled retrieval and temporary storage of semantic and episodic information, as well as executive mechanisms.

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bioRxiv2025

The neural basis of creative thought: An activation likelihood estimation meta-analysis involving over 17,000 participants

Humans can create impressive art, make major scientific breakthroughs, and generate creative solutions that solve everyday life problems. But how are these creative activities supported by the brain? This question is of great scientific interest but remains unanswered. New hypotheses, grounded in converging evidence from cognitive neuroscience, are needed to guide breakthroughs in understanding the neural basis of creative thought. It has long been suggested that creativity is a distinct mental function. However, converging clinical-cognitive neuroscience evidence is starting to suggest that creative thought is not functionally distinct but, instead, might arise from general purpose cognitive mechanisms supporting semantic cognition, controlled episodic memory retrieval, and executive mechanisms (i.e., Cognitive Cornerstones Hypothesis; Chan et al., 2023). Results from this large-scale activation likelihood estimation (ALE) meta-analysis, based on 787 experiments with 10,357 foci from 17,228 healthy adult participants, showed that the brain regions implicated in creativity tasks heavily overlap with the brain regions implicated in the cognitive cornerstones of creative thought (i.e., pre-existing knowledge and executive mechanisms). These striking results suggest that innovative insights will arise from considering the roles of these fundamental cognitive functions and their interactions in supporting creative thought.

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bioRxiv2024

Ventricle stimulation as a potential gold-standard control stimulation site for transcranial focused ultrasound stimulation

This research investigates whether ventricular-focused ultrasound stimulation (ventricle-FUS) can serve as an effective control in studies using transcranial FUS, a non-invasive technology for brain modulation. FUS has notable potential for therapeutic applications but requires a robust control to accurately assess its effects. We evaluated the effectiveness of ventricle-FUS, as an active, non-cerebrum control for FUS research, comparing it to sham stimulation. We conducted a comprehensive assessment of ventricle-FUS, employing both questionnaires and multiple neuroimaging metrics such as grey matter and white matter volumes, and functional connectivity. Ventricle-FUS did not alter any of these metrics, thereby successfully retaining the auditory, somatosensory, and experiential elements of FUS without affecting brain structure or function. Importantly, participants were unable to distinguish whether they received ventricle-FUS or sham FUS. Our findings confirm that ventricle-FUS establishes it as a reliable control approach in FUS research, crucial for advancing its therapeutic applications.

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bioRxiv2023

Mapping the task-general and task-specific neural correlates of speech production: meta-analysis and fMRI direct comparisons of category fluency and picture naming

Improving our understanding of the neural network engaged by different forms of speech production is a crucial step for both cognitive and clinical neuroscience. We achieved this aim by exploring two of the most commonly utilised speech production paradigms in research and the clinic, which have been rarely, if ever, compared directly: picture naming and category fluency. This goal was achieved in this two study investigation through a full ALE meta-analysis as well as a targeted fMRI study. Harnessing the similarities and differences between the two tasks offers a powerful methodology to delineate the core systems recruited for speech production, as well as revealing task-specific processes. The results showed that both tasks engaged a bilateral fronto-temporal speech production network, including executive and motor frontal areas, as well as semantic representational regions in the ATL, bilaterally. In addition, it was found that the extent of relative frontal lateralisation was task-dependent with the more executively-demanding category fluency task showing augmented left hemisphere activation. The results have implications for neurocomputational speech production models and the clinical assessment of speech production impairments. Open access: For the purpose of open access, the UKRI-funded authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.

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bioRxiv2023

Linguistic and attentional factors -not statistical regularities- contribute to word-selective neural responses with FPVS-oddball paradigms

In recent years, a fast periodic oddball-like paradigm has proved to be highly sensitive to measure category-selective visual word representation and characterize its development and neural basis. In this approach, deviant words are inserted in rapid streams of base stimuli every nth occurrence (e.g., Lochy et al., 2015). To understand the nature of word-selective representation and improve its measurement, we tested 22 adults with EEG, assessing the impact of discrimination coarseness (deviant words among nonwords or pseudowords), the relative frequency of item repetition (set size or item repetition controlled for deviant vs. base stimuli), and the nature of the orthogonal attentional task (focused or deployed spatial attention). In all stimulation sequences, base stimuli were presented at 10 Hz, with words inserted every 5 stimuli generating word-selective responses in the EEG spectra at 2 Hz and harmonics. Word-selective occipito-temporal responses were robust at the individual level, left-lateralized and sensitive to wordlikeness of base stimuli, being stronger in the coarser categorical contrast (among nonwords). Amplitudes were not affected by item repetition, showing that implicit statistical learning about a relative token frequency difference for deviant stimuli does not contribute to the word-selective neural activity, at least with relatively large stimulus set sizes (n=30). Finally, the broad attentional deployment task produced stronger responses than a focused task, an important finding for future studies in the field. Taken together, these results confirm the linguistic nature of word-selective responses, strengthen the validity and increase the sensitivity of the FPVS-EEG oddball paradigm to measure visual word recognition. HighlightsO_LIWord-selective responses measured in fast periodic visual stimulation with EEG are linguistic in nature C_LIO_LIWord-selective responses reflect prelexical or lexical processes depending on the contrast (words in nonwords or pseudowords respectively) C_LIO_LIUsing sufficiently large sets (30 items) prevents the extraction of statistical regularities and hence, statistical learning C_LIO_LIUsing an orthogonal task involving broad, rather than focused, spatial attention increases amplitude of the neural responses C_LIO_LISensitivity of the paradigm to detect significant responses at the individual level is very good (95% for prelexical and about 80% for lexical word responses) C_LI

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bioRxiv2022

The Role of the Posterior Medial Network in Language Comprehension: Dissociating Construction of Episodic versus Semantic Representations

Language comprehension involves the construction of complex mental representations, i.e., "event representations", reflecting current events or situation models. The construction of these representations requires manipulation of both semantic and episodic content and has been widely associated with the functioning of the posterior medial network, a subsystem of the default network. However, it is still unknown the extent to which activity in posterior medial network reflects construction of the variable episodic versus semantic content of event representations. In this fMRI study, we establish the unique neural correlates of (1) episodic richness and (2) semantic coherence measured during a narrative reading task. Interestingly, we observed a functional fractionation within the posterior medial network in terms of brain regions whose activity was modulated by semantic or episodic content. Specifically, the number of episodic details in the narratives modulated the activity in the left angular gyrus and the retrosplenial cortex/ventral posterior cingulate cortex. Semantic coherence, in contrast, modulated neural responses in the right anterior temporal lobe/middle temporal gyrus, but also in brain regions within the posterior medial network, such as the dorsal posterior cingulate cortex. These results provide the first demonstration of functional dissociations within the posterior medial network in terms of brain regions involved in the construction of semantic versus episodic representational content during a language comprehension task. Significance StatementThe construction of "event representations", which is crucial to understand the world around us, predict the future and make plans, requires manipulation of both semantic and episodic information. The functioning of the posterior medial network has been tightly linked to formation of event representations. However, it is unclear the extent to which activity in this network reflects construction of the variable episodic versus semantic content of event representations. The present study provides the first demonstration of functional dissociations within posterior medial network in terms of brain regions involved in construction of semantic versus episodic representational content during language comprehension. These findings represent a first step towards understanding how episodic and semantic memory systems operate during the construction of event representations.

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bioRxiv2022

Distance-dependent distribution thresholding in probabilistic tractography

Tractography is widely used in human studies of connectivity with respect to every brain region, function, and is explored developmentally, in adulthood, aging, and in disease. However, the core issue of how to systematically threshold, taking into account the inherent differences in connectivity values for different track lengths, and to do this in a comparable way across studies has not been solved. The study adopted Monte Carlo derived distance-dependent distributions (DDDs) to generate distance-dependent thresholds with various levels of alpha for connections of varying lengths. As a test case, we applied the DDD approach to generate a language connectome. The resulting connectome showed expected short- and long-distance structural connectivity in the close and distant regions within the language network. The finding demonstrates that the DDD approach can be used for both individual and group thresholding. Critically, it offers a standard method that can be applied to various probabilistic tracking datasets.

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bioRxiv2022

The angular gyrus is engaged by autobiographical recall not object-semantics, or event-semantics: Evidence from contrastive propositional speech production

The angular gyrus (AG) has been implicated in a myriad of cognitive functions. Using the previously under-studied naturalistic task of propositional speech production, we investigated the engagement of the left posterior AG (pAG) by three forms of memory: 1) episodic/autobiographical memory, 2) object semantic-memory, and 3) event-semantic knowledge. We conducted an ALE meta-analysis, followed by an fMRI study. The meta-analysis showed that pAG is only engaged as part of the propositional speech network when the task carries an autobiographical component. This finding was supported by the fMRI results, which also showed that: 1) pAG was positively engaged during autobiographical memory retrieval; 2) pAG was strongly deactivated for definitions of object semantics and non-propositional speech; 3) pAG activation increased with the degree to which the event descriptions relied on autobiographical information; 4) critically, the pAG showed a different pattern to known semantic representation regions (e.g., ventral anterior temporal lobe (vATL)) thereby providing clear evidence that the pAG is not acting as a semantic hub. Instead, the pAG activation profile directly mirrored that found in the wider autobiographical retrieval network. We propose that information stored elsewhere in the episodic system is temporally buffered online in the pAG during autobiographical retrieval/memory construction.

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bioRxiv2022

The cross-domain functional organisation of posterior lateral temporal cortex: Insights from ALE meta-analyses of seven cognitive domains spanning 9515 participants

The posterior lateral temporal cortex is implicated in many verbal, nonverbal and social cognitive domains and processes. Yet without directly comparing these disparate domains, the regions organisation remains unclear; do distinct processes engage discrete subregions, or could different domains engage shared neural correlates and processes? Here, using activation likelihood estimation meta-analyses, the bilateral posterior lateral temporal cortex subregions engaged in seven domains were directly compared. These domains comprised semantics, semantic control, phonology, biological motion, face processing, theory of mind, and representation of tools. Whilst phonology and biological motion were predominantly associated with distinct regions, other domains implicated overlapping areas, perhaps due to shared underlying processes. Theory of mind recruited regions implicated in semantic representation in the left hemisphere, tools engaged semantic control areas, and faces engaged subregions for biological motion and theory of mind. This cross-domain approach provides insight into how posterior lateral temporal cortex is organised and why.

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bioRxiv2021

Mapping lesion, structural disconnection, and functional disconnection to symptoms in semantic aphasia

Patients with semantic aphasia have impaired control of semantic retrieval, often accompanied by executive dysfunction following left hemisphere stroke. Many but not all of these patients have damage to the left inferior frontal gyrus, important for semantic and cognitive control. Yet semantic and cognitive control networks are highly distributed, including posterior as well as anterior components. Accordingly, semantic aphasia might not only reflect local damage but also white matter structural and functional disconnection. Here we characterise the lesions and predicted patterns of structural and functional disconnection in individuals with semantic aphasia and relate these effects to semantic and executive impairment. Impaired semantic cognition was associated with infarction in distributed left- hemisphere regions, including in the left anterior inferior frontal and posterior temporal cortex. Lesions were associated with executive dysfunction within a set of adjacent but distinct left frontoparietal clusters. Performance on executive tasks was also associated with interhemispheric structural disconnection across the corpus callosum. In contrast, poor semantic cognition was associated with small left-lateralized structurally disconnected clusters, including in the left posterior temporal cortex. Little insight was gained from functional disconnection symptom mapping. These results demonstrate that while left- lateralized semantic and executive control regions are often damaged together in stroke aphasia, these deficits are associated with distinct patterns of structural disconnection, consistent with the bilateral nature of executive control and the left-lateralized yet distributed semantic control network.

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bioRxiv2021

Couching the brain's multiple-demand and language-specific systems within a macroscale gradient of cortical connectivity

Semantic control is the capability to operate on meaningful representations, selectively focusing on certain aspects of meaning while purposefully ignoring other aspects based on ones behavioural aim. This ability is especially vital for comprehending figurative/ambiguous language. It remains unclear, at the topographical level, why/how regions involved in semantic control seem reliably juxtaposed alongside other functionally specialised regions in the association cortex. We investigated this issue by characterising how semantic control regions topographically relate to the default-mode network (associated with memory and abstract cognition) and multiple-demand network (associated with executive control). Topographically, we confirmed that semantic control areas were sandwiched by the default-mode and multi-demand networks, forming an orderly arrangement observed both at the individual- and group-level. Functionally, semantic control regions exhibited hybrid responses, fusing a preference for cognitively demanding processing (multiple-demand) and a preference for meaningful representations (default-mode) into a domain-specific preference for difficult operations on meaningful representations. When projected onto the principal gradient of human connectome, the neural activity of semantic control showed a robustly dissociable trajectory from visuospatial control, implying different roles in the functional transition from sensation to cognition. We discuss why the hybrid functional profile of semantic control regions might result from their intermediate topographical positions.

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bioRxiv2021

Subregions of DLPFC display graded yet distinct structural and functional connectivity

The human dorsolateral prefrontal cortex (DLPFC, approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along with rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography and resting-state functional magnetic resonance imaging were employed to map out the patterns of connectivity from each DLPFC subregions. Structural connectivity demonstrated graded intra-regional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that he dorsal-rostral subregions was restricted to connect to other frontal and limbic areas, whereas the ventral-caudal region was widely connected to frontal, temporal, parietal, and limbic cortex. Functional connectivity analysis demonstrated that subregions of DLPFC were strongly interconnected to each other. The dorsal subregions were associated with the default mode network (DMN), while middle dorsal-rostral subregions were linked with the multiple demand network (MDN), respectively. Similar to the results of structural connectivity, the ventral-caudal subregion showed increased functional coupling with both DMN and MDN. Our results suggest that DLPFC may be subdivided by the diagonal axis of the dorsal-ventral axis and rostral-caudal axis, which support the patterns of connectivity the parts of the DLPFC reflects its integrative executive function.

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bioRxiv2021

Bipartite functional fractionation within the neural system for social cognition supports the psychological continuity of self vs. other

Research of social neuroscience establishes that regions in the brains default network (DN) and semantic network (SN) are engaged by socio-cognitive tasks. Research of the human connectome shows that DN and SN regions are both situated at the high-order end of cortical gradient but differ in their positions on this gradient. In the present study, we integrated these two bodies of research, used the psychological continuity of self vs. other as a test-case, and used fMRI to investigate whether these networks would encode social concepts differently. We found a robust dissociation between the DN and SN - while both networks contained sufficient information for decoding broad-stroke distinction of social categories, the DN carried more generalisable information for cross-classifying across social distance and emotive valence than did the SN. We also found that the overarching distinction of self vs. other was a principal divider of the representational space while social distance was an auxiliary factor (subdivision, nested within the principal dimension), and this representational landscape was more manifest in the DN than in the SN. Taken together, our findings demonstrate how insights from connectome research can benefit social neuroscience, and have implications for clarifying the two networks differential contributions to social cognition.

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bioRxiv2021

Multiple dimensions underlying the functional organisation of the language network

Understanding the different neural networks that support human language is an ongoing challenge for cognitive neuroscience. Which divisions are capable of distinguishing the functional significance of regions across the language network? A key separation between semantic cognition and phonological processing was highlighted in early meta-analyses, yet these seminal works did not formally test this proposition. Moreover, organisation by domain is not the only possibility. Regions may be organised by the type of process performed, as in the separation between representation and control processes proposed within the Controlled Semantic Cognition framework. The importance of these factors was assessed in a series of activation likelihood estimation meta-analyses that investigated which regions of the language network are consistently recruited for semantic and phonological domains, and for representation and control processes. Whilst semantic and phonological processing consistently recruit many overlapping regions, they can be dissociated (by differential involvement of bilateral anterior temporal lobes and superior temporal gyri) only when using both formal analysis methods and sufficient data. Both semantic and phonological regions are further dissociable into control and representation regions, highlighting this as an additional, distinct dimension on which the language network is functionally organised. Furthermore, some of these control regions overlap with multiple-demand network regions critical for control beyond the language domain, suggesting the relative level of domain-specificity is also informative. Multiple, distinct dimensions are critical to understand the role of language regions. Here we present a proposal as to the core principles underpinning the functional organisation of the language network. SIGNIFICANCE STATEMENTTraditional theories of the organisation of the cortical language network separate areas based on the type of information processed, such as distinct regions representing the meaning of words or their sounds. Here, we re-analyse and update a seminal study, to directly compare these networks. This differentiates some language regions, yet a high degree of overlap is found, suggesting this division alone, does not provide a full mapping of the language network. Additional dimensions, reflecting different kinds of information, are demonstrated to underlie the functional organisation of the language network. First, representation and control processes engage distinct regions in each subdomain. Secondly, comparison outside of language highlights the importance of a domain-specificity dimension, distinguishing subdomain-specific semantic control and domain-general control regions.

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