Biology subjects

Steele, D.

Publications and source records attributed to Steele, D..

11 recordsLinked to original sources

bioRxiv2026

General cognitive function and the brain's structural connectome

General cognitive function ( g) reflects a broad capacity for flexible information processing, yet how brain-wide structural connectivity supports it remains unclear. In 38,824 individuals (26-84 years) across three cohorts, we show that g is supported by a widely distributed white matter network. Across streamline count, fractional anisotropy (FA), and mean diffusivity (MD), meta-analytic associations with g were widespread at global, nodal and edge levels, spanning all cerebral lobes and key subcortical structures and dependent on both inter- and intra-hemispheric connectivity, particularly ipsilateral long-range inter-lobar connections. White matter node-g associations spatially mirrored independent cortical morphometry-g associations, indicating convergence of grey and white matter contributions. Effect sizes increased with age: MD associations became more negative and FA more positive, especially in frontal regions. Edge-level findings replicated across cohorts and predicted g in a hold-out sample. These findings suggest g reflects a distributed structural communication backbone which becomes increasingly important with age.

neuroscience↗

bioRxiv2026

Electrophysiological Correlates of Reinforcement Learning in the Human Ventral Tegmental Area

The ventral tegmental area (VTA) is the principal source of dopaminergic input to the human prefrontal cortex and is hypothesised to play a central role in reward-based learning. However, direct electrophysiological evidence in humans has been lacking. Here, using intracranial recordings obtained during an instrumental learning task in patients undergoing deep brain stimulation surgery for chronic cluster headache (n=13), we show that VTA local field potentials selectively encode rewarding outcomes compared with losses or neutral outcomes independently of whether behavioural learning occurred. In a subset of participants (n= 8) who learned to prefer a high-reward option, VTA responses to unexpected rewards were larger than to expected rewards. In two participants who sufficiently explored both options, VTA activity reflected the expected value of the chosen option during decision-making. These findings provide direct electrophysiological evidence that the human VTA encodes reward-related signals consistent with reinforcement learning mechanisms described in animal models.

neuroscience↗

bioRxiv2025

Focused ultrasound neuromodulation of mediodorsal thalamus disrupts decision flexibility during reward learning

When learning to find the most beneficial course of action, the prefrontal cortex guides decisions by comparing estimates of the relative value of the options available. Basic neuroscience studies in animals support the view that the thalamus can regulate this activity within and across the prefrontal cortex. We studied a group of patients (n=37) undergoing unilateral MR guided focused ultrasound for essential tremor, performing the restless bandit, a reward reinforcement learning task, immediately before and after thalamotomy. Thalamotomy significantly impaired the proportion of switch choices during the task without affecting overall performance. This effect was observed when the task was delivered to co-incide with maximal vasogenic thalamic oedema but not in a control group tested on the same day of their treatment. A reinforcement learning model fitted to the patients choices replicated the effect of thalamotomy when the model increased exploitation of the bandits learnt value estimate. This shift in the explore-exploit trade-off, manifesting as reduced choice flexibility, co-varied with the pattern of post-operative oedema extension into mediodorsal nucleus. These findings confirm a causal role of the thalamus and specifically the mediodorsal nucleus, in regulating the extent to which value estimates are used to guide decisions and learning from reward.

neuroscience↗

bioRxiv2023

Impaired value-based decision-making in Parkinson's Disease Apathy

Apathy is a common and disabling complication of Parkinsons disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within pre-frontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, non-dopaminergic neuromodulators, influence decisions to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesised that Apathy in Parkinsons disease should be associated with a failure to adequately monitor and make adaptive choices when the rewarding outcome of decisions are uncertain. Using a 4-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinsons disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with Apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patients apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patients choices confirmed the apathy group made decisions that that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001). We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinsons disease, which was more marked in Apathy, but not predictive of their individual Apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated pre-frontal cortex to a similar degree to the age-matched controls. In contrast, Parkinsons patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinsons disease.

neuroscience↗

bioRxiv2023

General and specific patterns of cortical gene expression as substrates of complex cognitive functioning

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given genes expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components : gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 41 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|{beta}| range = 0.15 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

neuroscience↗

bioRxiv2023

Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease

Rapid release of calcium from internal stores via ryanodine receptors (RyRs) is one of the fastest types of cytoplasmic second messenger signalling in excitable cells. In the heart, rapid summation of the elementary events of calcium release, calcium sparks, determine the contraction of the myocardium. Recent advances in super-resolution microscopy methods have revealed complex clustering patterns of RyRs at single-channel resolution. Here, we have experimentally correlated sub-sarcolemmal spontaneous calcium sparks in rat right ventricular myocytes with the underlying nanoscale sub-sarcolemmal RyR patterns resolved with super-resolution DNA-PAINT microscopy. Local functional groupings and clustering patterns of RyR were sampled by the location and the two-dimensional area of each calcium spark to reveal a steep dependence of the integral of a calcium spark on the sum of the local RyRs. Visualisation of recurring spark sites showed evidence of repeated and triggered saltatory activation of multiple local RyR clusters. In similar myocytes taken from rats with induced right ventricular failure, RyR clusters themselves showed a dissipated morphology and fragmented (smaller) clusters. The failing myocytes featured greater heterogeneity in both the spark properties and the relationship between the integral of the calcium spark and the local ensemble of RyRs. Whilst fragmented (smaller) RyR clusters were rarely observed to directly underlying the larger sparks or the recurring spark sites, local interrogation of the channel-to-channel distances confirmed a clear link between the positions of each calcium spark and the tight non-random clustering of the local RyRs in both healthy and failing ventricles.

biophysics↗

bioRxiv2022

Pallidal neuromodulation of the explore/exploit trade-off in decision-making

Every decision that we make involves a conflict between exploiting our current knowledge of an actions value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit dilemma. To test this hypothesis, we examined the effects of neuromodulating the basal ganglias output nucleus, the globus pallidus interna, in patients who had undergone deep brain stimulation (DBS) for isolated dystonia. Neuromodulation enhanced the number of exploratory choices to the lower value option in a 2-armed bandit probabilistic reversal-learning task. Enhanced exploration was explained by a reduction in the rate of evidence accumulation (drift rate) in a reinforcement learning drift diffusion model. We estimated the functional connectivity profile between the stimulating DBS electrode and the rest of the brain using a normative functional connectome derived from heathy controls. Variation in the extent of neuromodulation induced exploration between patients was associated with functional connectivity from the stimulation electrode site to a distributed brain functional network. We conclude that the basal ganglias output nucleus, the globus pallidus interna, can adaptively modify decision choice when faced with the dilemma to explore or exploit.

neuroscience↗

bioRxiv2020

Tonic dopamine, uncertainty and basal ganglia action selection.

To make optimal decisions in uncertain circumstances flexible adaption of behaviour is required; exploring alternatives when the best choice is unknown, exploiting what is known when that is best. Using a detailed computational model of the basal ganglia, we propose that switches between exploratory and exploitative decisions can be mediated by the interaction between tonic dopamine and cortical input to the basal ganglia. We show that a biologically detailed action selection circuit model of the basal ganglia, endowed with dopamine dependant striatal plasticity, can optimally solve the explore-exploit problem, estimating the true underlying state of a noisy Gaussian diffusion process. Critical to the models performance was a fluctuating level of tonic dopamine which increased under conditions of uncertainty. With an optimal range of tonic dopamine, explore-exploit decision making was mediated by the effects of tonic dopamine on the precision of the model action selection mechanism. Under conditions of uncertain reward pay-out, the models reduced selectivity allowed disinhibition of multiple alternative actions to be explored at random. Conversely, when uncertainly about reward pay-out was low, enhanced selectivity of the action selection circuit was enhanced, facilitating exploitation of the high value choice. When integrated with phasic dopamine dependant influences on cortico-striatal plasticity, the models performance was at the level of the Kalman filter which provides an optimal solution for the task. Our model provides an integrative account of the relationship between phasic and tonic dopamine and the action selection function of the basal ganglia and supports the idea that this subcortical neural circuit may have evolved to facilitate decision making in non-stationary reward environments, allowing a number of experimental predictions with relevance to abnormal decision making in neuropsychiatric and neurological disease.

neuroscience↗

bioRxiv2020

A super-resolution protocol to correlate structural underpinnings of fast second-messenger signalling in primary cell types

Nanometre-scale cellular information obtained through super-resolution microscopies are often unaccompanied by functional information, particularly transient and diffusible signals through which life is orchestrated in the nano-micrometre spatial scale. We describe a correlative imaging protocol which allows the ubiquitous intracellular second messenger, calcium (Ca2+), to be directly visualised against nanoscale patterns of the ryanodine receptor (RyR) Ca2+ channels which give rise to these Ca2+ signals in wildtype primary cells. This was achieved by combining total internal reflection fluorescence (TIRF) imaging of the elementary Ca2+ signals, with the subsequent DNA-PAINT imaging of the RyRs. We report a straightforward image analysis protocol of feature extraction and image alignment between correlative datasets and demonstrate how such data can be used to visually identify the ensembles of Ca2+ channels that are locally activated during the genesis of cytoplasmic Ca2+ signals.

biophysics↗

bioRxiv2020

Peptide ligands of the cardiac ryanodine receptor as super-resolution imaging probes

To study the structural basis of pathological remodelling and altered calcium channel functional states in the heart, we sought to re-purpose high-affinity ligands of the cardiac calcium channel, the ryanodine receptor (RyR2), into super-resolution imaging probes. Imperacalcin (IpCa), a scorpion toxin peptide which induces channel sub-conduction states, and DPc10, a synthetic peptide corresponding to a sequence of the RyR2, which replicates arrhythmogenic CPVT functional changes, were used in fluorescent imaging experiments. Isolated adult rat ventricular cardiomyocytes were saponin-permeabilised and incubated with each peptide. IpCa-A546 became sequestered into the mitochondria. This was prevented by treatment of the permeabilised cells with the ionophore FCCP, revealing a striated staining pattern in confocal imaging which had weak colocalisation with RyR2 clusters. Poor specificity (as an RyR2 imaging probe) was confirmed at higher resolution with expansion microscopy (proExM) (~70 nm). DPc10-FITC labelled a striated pattern, which had moderate colocalisation with RyR2 cluster labelling in confocal and proExM. There was also widespread non-target labelling of the Z-discs, intercalated discs, and nuclei, which was unaffected by incubation times or 10 mM caffeine. The inactive peptide mut-DPc10-FITC (which causes no functional effects) displayed a similar labelling pattern. Significant labelling of structures unrelated to RyR2 by both peptide conjugates makes their use as highly specific imaging probes of RyR2 in living isolated cardiomyocytes highly challenging. We investigated the native DPc10 sequence within the RyR2 structure to understand the domain interactions and proposed mechanism of peptide binding. The native DPc10 sequence does not directly interact with another domain, and but is downstream of one such domain interface. The rabbit Arg2475 (equivalent to human Arg2474, mutated in CPVT) in the native sequence is the most accessible portion and most likely location for peptide disturbance, suggesting FITC placement does not impact peptide binding.

cell biology↗

bioRxiv2019

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

Patients with dystonia caused by the mutated TOR1A gene exhibit a risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. We hypothesised this increased risk taking could be reproduced by a reinforcement learning model which included biologically realistic striatal plasticity learning rules. We aimed to test whether a specific combination of cortico-striatal plasticity abnormalities at D1 and D2 receptors could explain the abnormal behaviour. We found a model of cortico-striatal plasticity could generate simulated behaviour indistinguishable from patients only when both D1 and D2 plasticity was abnormally increased in opposite directions: specifically when D1 synaptic potentiation and D2 depotentiation were both increased. This result is consistent with previous observations in rodent models of cortico-striatal plasticity at D1 receptors, but contrasts with the pattern reported in vitro for D2 synapses. This suggests that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 synaptic plasticity that are not apparent in rodent models of this disease.

neuroscience↗