Biology subjects

Christakou, A.

Publications and source records attributed to Christakou, A..

7 recordsLinked to original sources

bioRxiv2024

The influence of trait intolerance of uncertainty on behavioural flexibility

Identifying and responding adaptively to a change in our environment is an essential skill. However, differences in our ability to detect and our disposition to react to these changes mean that some individuals are better equipped to deal with change than others. Here, we investigate whether intolerance of uncertainty, a transdiagnostic dimension of psychopathology, is associated with performance during a reversal learning task. We assessed task performance of 145 subjects using behavioural measures and computational modelling across two time points (approximately 12 days apart). Intolerance of uncertainty and its prospective and inhibitory subscales were associated with task performance, irrespective of self-reported levels of trait anxiety. Intolerance of uncertainty and its inhibitory subscale were positively associated with increased sensitivity to reinforcement from positive, but not negative, feedback. Furthermore, the inhibitory subscale was positively associated with better performance, both overall (as indexed by accuracy) and immediately following a change in reward contingencies (as indexed by perseveration). Lastly, the prospective subscale interacted with the extent to which choice was driven by expected value across time points. These findings provide novel evidence for how trait intolerance of uncertainty may modulate behavioural flexibility in changeable environments. The study points towards exciting avenues for further research into the development of IU-related behaviours across the lifespan and their implications for mental health.

animal behavior and cognition↗

bioRxiv2024

Evidence for direct control of neurovascular function by circulating platelets in healthy older adults

Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as athero-thrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and neurovascular function in 52 healthy mid- to older-age adults. To do this we combined, for the first time, magnetic resonance imaging (MRI) of neurovascular function, peripheral vascular physiology, and in vitro platelet assaying. We show a direct association between platelet reactivity and neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (Adenosine 5-diphosphate, Collagen-Related Peptide, Thrombin Receptor Activator Peptide 6) were directly associated with different physiological components of the haemodynamic response to neural (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Since altered neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association becomes now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology. Key points summaryO_LIHaemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood. C_LIO_LIThis study asks whether a causal mechanism exists through athero-thrombotic effects on the vasculature which can in turn affect brain health, or through direct platelet effects on brain physiology. C_LIO_LIHere we show that elevated platelet reactivity is associated with blunted (delayed, shorter, and smaller) blood flow responses to neural activation in healthy middle-aged and older adults. C_LIO_LIHowever, the association between platelet reactivity and neurovascular function was not mediated by systemic vascular reactivity. C_LIO_LIThis finding challenges the previous belief that systemic vascular health determines the vascular component of neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit in early dementia pathophysiology. C_LI

neuroscience↗

bioRxiv2021

Dissociable roles for the striatal cholinergic system in different flexibility contexts.

The production of behavioural flexibility requires the coordination and integration of information from across the brain, by the dorsal striatum. In particular, the striatal cholinergic system is thought to be important for the modulation of striatal activity. Research from animal literature has shown that chemical inactivation of the dorsal striatum leads to impairments in reversal learning. Furthermore, proton magnetic resonance spectroscopy work has shown that the striatal cholinergic system is also important for reversal learning in humans. Here, we aim to assess whether the state of the dorsal striatal cholinergic system at rest is related to flexible behaviour in reversal learning. We provide preliminary results showing that variability in choline in the dorsal striatum is significantly related to both the number perseverative and regressive errors that participants make, and their rate of learning from positive and negative prediction errors. These findings, in line with previous work, suggest the resting state of dorsal striatal cholinergic system has important implications for producing flexible behaviour. However, these results also suggest the system may have heterogeneous functionality across different types of tasks measuring behavioural flexibility. These findings provide a starting point for further interrogation into understanding the functional role of the striatal cholinergic system in flexibility.

neuroscience↗

bioRxiv2021

Cortical and thalamic influences on striatal involvement in instructed, serial reversal learning; implications for the organisation of flexible behaviour.

Cognitive flexibility is essential for enabling an individual to respond adaptively to changes in their environment. Evidence from human and animal research suggests that the control of cognitive flexibility is dependent on an array of neural architecture. Cortico-basal ganglia circuits have long been implicated in cognitive flexibility. In particular, the role of the striatum is pivotal, acting as an integrative hub for inputs from the prefrontal cortex and thalamus, and modulation by dopamine and acetylcholine. Striatal cholinergic modulation has been implicated in the flexible control of behaviour, driven by input from the centromedian-parafascicular nuclei of the thalamus. However, the role of this system in humans is not clearly defined as much of the current literature is based on animal work. Here, we aim to investigate the roles corticostriatal and thalamostriatal connectivity in serial reversal learning. Functional connectivity between the left centromedian-parafascicular nuclei and the associative dorsal striatum was significantly increased for negative feedback compared to positive feedback. Similar differences in functional connectivity were observed for the right lateral orbitofrontal cortex, but these were localised to when participants switched to using an alternate response strategy following reversal. These findings suggest that connectivity between the centromedian-parafascicular nuclei and the striatum may be used to generally identify potential changes in context based on negative outcomes, and the effect of this signal on striatal output may be influenced by connectivity between the lateral orbitofrontal cortex and the striatum.

neuroscience↗

bioRxiv2018

Regional Striatal Cholinergic Involvement in Human Behavioural Flexibility

Animal studies have shown that the striatal cholinergic system plays a role in behavioural flexibility but, until recently, this system could not be studied in humans due to a lack of appropriate non-invasive techniques. Using proton magnetic resonance spectroscopy (1H-MRS) we recently showed that the concentration of dorsal striatal choline (an acetylcholine precursor) changes during reversal learning (a measure of behavioural flexibility) in humans. The aim of the present study was to examine whether regional average striatal choline was associated with reversal learning. We measured choline at rest in both the dorsal and ventral striatum using 1H-MRS and examined its relationship with performance on a probabilistic learning task with a reversal component. Task performance was described using a simple reinforcement learning model that dissociates the contributions of positive and negative prediction errors to learning. Average levels of choline in the dorsal striatum were associated with performance during reversal, but not during initial learning. Specifically, lower levels of choline in the dorsal striatum were associated with a lower number of perseverative trials. Moreover, choline levels explained inter-individual variance in perseveration over and above that explained by learning from negative prediction errors. These findings suggest that the dorsal striatal cholinergic system plays an important role in behavioural flexibility, in line with evidence from the animal literature and our previous work in humans. Additionally, this work provides further support for the idea of measuring choline with 1H-MRS as a non-invasive way of studying human cholinergic neurochemistry.\n\nSIGNIFICANCE STATEMENTBehavioural flexibility is a crucial component of adaptation and survival, as well as everyday living. Evidence from the animal literature shows the striatal cholinergic system is fundamental to reversal learning, a key paradigm for studying behavioural flexibility. However, this system remains understudied in humans, largely due to a lack of non-invasive techniques. Using proton magnetic resonance spectroscopy (1H-MRS), we showed that choline levels at rest in the dorsal striatum are associated with individual differences in performance specifically during reversal learning. These novel findings help to bridge the gap between animal studies of the striatal cholinergic system and human studies of basal ganglia function, by demonstrating the importance of cholinergic function in the dorsal striatum in human behavioural flexibility. Importantly, the methods described here can not only be applied to furthering our understanding of healthy human neurochemistry, but can also be applied to extending our understanding of cholinergic disorders.

neuroscience↗

bioRxiv2018

Multimodal evidence for delayed fear extinction in adolescence and young adulthood.

Previous research in rodents and humans points to an evolutionarily conserved profile of blunted fear extinction during adolescence, underpinned by brain structures such as the amygdala and medial prefrontal cortex (mPFC). In this study, we examine age-related effects on the function and structural connectivity of this system in fear extinction in adolescence and young adulthood. Younger age was associated with greater amygdala activity and delayed mPFC engagement to learned threat cues as compared to safety cues. Furthermore, greater structural integrity of the uncinate fasciculus, a white matter tract that connects the amygdala and mPFC, mediated the relationship between age and acceleration of mPFC engagement during extinction. These findings suggest that age-related changes in the structure and function of amygdala-mPFC circuitry may underlie the protracted maturation of fear regulatory processes, rendering younger individuals more vulnerable to anxiety disorders, which emerge during development.

neuroscience↗

bioRxiv2018

Thalamostriatal Interactions in Human Reversal Learning

Cognitive flexibility is crucial for adaptation and is disrupted in neuropsychiatric disorders and psychopathology. Human studies of flexibility using reversal learning tasks typically contrast error trials before and after reversal, which provides little information about the mechanisms that support learning and expressing a new response. However, animal studies suggest a specific role in this latter process for the connections between the dorsal striatum and the centromedian parafascicular (CM-Pf) thalamus, a system which may recruit the striatal cholinergic interneurons, but which is not well understood in humans. This study investigated the role of this system in human probabilistic reversal learning, specifically with respect to learning a new response strategy, contrasting its function to that of the better understood orbitoftontal-striatal systems. Using psychophysiological interaction (PPI) analysis of functional magnetic resonance imaging (fMRI) data we show that connectivity between the striatum and both the lateral orbitofrontal cortex (lOFC) and CM-Pf pathways increased during reversal, but not initial learning. However, while the strength of lOFC-striatal connectivity was associated with the speed of the reversal, the strength of CM-Pf-striatal connectivity was associated specifically with the quality of the reversal (reduced regressive errors). These findings expand our understanding of flexibility mechanisms in the human brain, bridging the gap with animal studies of this system.

neuroscience↗