Biology subjects

Robinson, G. A.

Publications and source records attributed to Robinson, G. A..

9 recordsLinked to original sources

bioRxiv2025

Methodological choices strongly modulate the sensitivity and specificity of lesion-symptom mapping analyses

Lesion mapping results can vary substantially as a function of specific analysis parameters, but the extent to which individual methodological choices interact to modulate the sensitivity and specificity of results is not clear. Here, we employed a large-scale simulation approach to inform practical recommendations for lesion symptom mapping studies. Routine clinical imaging from 959 stroke survivors (mean age = 72.5, 49.3% female) was used to conduct 384,780 lesion mapping analyses based on simulated behavioural data. Each simulated analysis used different combinations of plausible sample inclusion criteria, analysis parameters (e.g., correction factors), analysis types (e.g., univariate vs. multivariate), and underlying target correlates. Simulated analysis accuracy (Dice similarity coefficient and percent coverage of target correlates) was compared across designs. Overall, analysis accuracy varied widely and was substantially modulated by the specific design used. Analyses that maximised lesion coverage by including large and diverse samples reliably outperformed analyses using more restricted samples. Analyses using direct total lesion volume controls outperformed analyses using other (or no) volume corrections across all accuracy measures. False discovery rate corrections yielded the best performance in terms of target coverage, while permutation corrections yielded the best Dice coefficients. While multivariate approaches were more accurate than univariate analyses in terms of Dice coefficient, univariate analyses generated higher target hit rates and percent target coverage. These results identify specific analysis designs suitable for studies aiming to maximise their sensitivity and/or specificity to underlying critical correlates, while highlighting the inferential strengths and weaknesses of these complementary approaches.

neuroscience↗

bioRxiv2025

Differential effects of neurodegenerative disorders on verbal creative idea generation and its cognitive cornerstones

Clinical research has documented a heterogeneous effect of neurodegenerative disorders on creativity. Some disorders are associated with impaired creative performance, while others may preserve, or even enhance, it. However, the underlying cognitive mechanisms that give rise to the heterogeneous behavioural manifestations remain poorly understood. From a theory-driven approach, we conducted a neuropsychological investigation to examine how frontotemporal lobar degeneration (FTLD), and Alzheimer's Disease (AD) differentially affected the cognitive mechanisms underlying creative thought (semantic cognition, episodic memory, executive control functions). In parallel, we assessed participants' verbal creative idea generation performance using the ideational fluency task (also known as the Alternate Uses Task). We analysed data from 24 individuals with FTLD [clinical consensus diagnosis corticobasal syndrome (CBS: n=20) or progressive supranuclear palsy (PSP: n=4)], 24 individuals with clinical consensus diagnosis AD, and 24 healthy individuals. We reached four major conclusions. First, while both disease groups exhibited deficits in controlled semantic retrieval and executive control functions, only participants with AD exhibited degradation in semantic representations and episodic memory. Second, both disease groups generated fewer responses in both typical and creative conditions across objects that were context-free - i.e., associated with multiple contexts (e.g., brick) and context-bound -i.e., associated with a dominant context (e.g., table knife). Third, when given a context-free object prompt, the ability to generate novel responses appeared to be preserved in participants with FTLD, which contrasted with an impaired ability when prompted to give creative uses for the context-bound object. Fourth, participants with AD produced similar levels of response novelty for both context-free and context-bound objects. From a clinical-cognitive neuroscience perspective, this study demonstrates that distinct cognitive profiles resulting from different neurodegenerative conditions yield differential effects on creative thought. As the first study to show that the contextual information of semantic stimuli can mediate the novelty of verbal responses, we suggest that future research should carefully examine how this factor influences creative task performance.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2024

Oestrogen influences B cell class-switching in individuals with an XX sex chromosome complement

Sex differences in humoral immunity are well-documented, though the mechanisms underpinning these differences remain ill-defined. Here, we demonstrate that post-pubertal cisgender females have higher levels of class-switched B cells compared to age-matched cisgender males. However, whilst sex chromosome-encoded genes characterise most of the differences in total B cell transcriptomes between cisgender-females and -males, sex differences in class-switched B cells are only observed post-pubertally. Accordingly, B cells express high levels of oestrogen receptor 2 (ESR2) and genes known to regulate B cell class-switching are enriched for ESR2-binding sites. Using a gender-diverse cohort of young people, we show that in transgender males (XX chromosomal background), blockade of natal oestrogen reduced the frequency of class-switched B cells, whilst gender-affirming oestradiol treatment in transgender females (XY chromosomal background), did not increase the frequency of class-switched B cells. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen only supporting B cell class-switching on an XX chromosomal background. eTOC summarySex hormones and chromosomes work in tandem to impact immune responses, with oestrogen influencing B cell class-switching exclusively on an XX chromosomal background.

immunology↗

bioRxiv2022

A snapshot of brain and cognition in healthy mid-life and older adults

Deficits in memory are seen as a canonical sign of ageing and a prodrome to dementia in older adults. However, the nature of cognitive and brain changes across a wider aperture of adulthood is not well known. We quantify the relationship between cognitive function and brain morphology from mid-life to older adulthood, and the influence of age, sex, amyloid and genetic risk for dementia. We analyzed three observational cohorts (PISA, AIBL, ADNI) with cognitive, genetic and neuroimaging measures comprising a total of 1570 healthy mid-life and older adults (mean age 72, range 49-90 years, 1330 males) and 1365 age- and sex-matched adults with mild cognitive impairment or Alzheimers disease. Among healthy adults, we find robust modes of co-variation between regional sulcal width and multidomain cognitive function that change from mid-life to the older age range. The most prominent cortical changes in mid-life are predominantly associated with changes in executive functions, whereas they are most strongly associated with poorer memory function in older age. These cognitive changes are accompanied by an age-dependent pattern of sulcal widening. Amyloid exerts a weak, but significant, influence on cognition, but not on sulcal width. The APOE {varepsilon}4 allele also exerts a weak influence on cognition, but only significantly in the (larger and older) AIBL cohort. These findings provide new insights into brain and cognition in mid-life and older adults, suggesting that cognitive screening in mid-life cohorts should encompass executive functions as well as memory.

neuroscience↗

bioRxiv2019

Sex differences in autoimmunity could be associated with altered regulatory T cell phenotype and lipoprotein metabolism

Male and female immune responses are known to differ resulting in an increased prevalence of autoimmunity in women. Here sex differences in T-cell subset frequency and function during adolescence were examined in healthy donors and patients with the autoimmune disease juvenile (J)SLE; onset of JSLE commonly occurs during puberty suggesting a strong hormonal influence. Healthy adolescent males had increased regulatory T-cell (Treg) frequency, and increased Treg suppressive capacity and IL-4 production compared to healthy adolescent females. The T-helper 2-like profile in male Tregs was associated with increased expression of GATA3 which correlated significantly with elevated Treg plasma membrane glycosphingolipid expression. Differential Treg phenotype was associated with unique serum metabolomic profiles in males compared to female adolescents. Notably, very low density lipoprotein (VLDL) metabolomic signatures correlated positively with activated Tregs in males but with resting Tregs in females. Consistently, only VLDL isolated from male serum was able to induce increased Treg IL-4 production and glycosphingolipid expression following in cultured cells. Remarkably, gender differences in Treg frequency, phenotype and function and serum metabolomic profiles were lost in adolescents with JSLE. This work provides evidence that a combination of pubertal development, immune cell defects and dyslipidemia may contribute to JSLE pathogenesis.

immunology↗

bioRxiv2019

Activation of the liver X receptors alters CD4+ T cell membrane lipids and signalling through direct regulation of glycosphingolipid synthesis

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells, and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol) which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase (UGCG) as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened pro-inflammatory T cell function. Finally, compared to responder T cells, regulatory T cells had a distinct pattern of LXR-target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a novel mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism, and demonstrate its relevance in modulating T cell function.

immunology↗

bioRxiv2018

Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis

Cognitive reasoning is thought to require functional interactions between whole-brain networks. Such networks rely on both cerebral hemispheres, with the corpus callosum providing cross-hemispheric communication. Here we used high-field functional magnetic resonance imaging (7T fMRI), a well validated cognitive task, and brain network analyses to investigate the functional networks underlying cognitive reasoning in individuals with corpus callosum dysgenesis (CCD), an anatomical abnormality that affects the corpus callosum. Participants with CCD were asked to solve cognitive reasoning problems while their brain activity was measured using fMRI. The complexity of these problems was parametrically varied by changing the complexity of relations that needed to be established between shapes within each problem matrix. Behaviorally, participants showed a typical reduction in task performance as problem complexity increased. Task-evoked neural activity was observed in brain regions known to constitute two key cognitive control systems: the fronto-parietal and cingulo-opercular networks. Under low complexity demands, network topology and the patterns of local neural activity in the CCD group closely resembled those observed in neurotypical controls. By contrast, when asked to solve more complex problems, participants with CCD showed a reduction in neural activity and connectivity within the fronto-parietal network. These complexity-induced, as opposed to resting-state, differences in functional network activity help resolve the apparent paradox between preserved network architecture found at rest in CCD individuals, and the heterogeneous deficits they display in response to cognitive task demands [preprint: https://doi.org/10.1101/312629].

neuroscience↗