Biology subjects

Scholz, V.

Publications and source records attributed to Scholz, V..

5 recordsLinked to original sources

bioRxiv2025

Continuous theta-burst stimulation of the ventromedial prefrontal cortex reduces Pavlovian go-invigoration and enhances thalamo-striatal reward prediction error signals

The ventromedial prefrontal cortex (vmPFC) represents value, i.e. whether environmental cues are good or bad. Rewarding cue value is aligned with a tendency to act or to inhibit in case of potential punishment, a so-called Pavlovian Bias. Value-related vmPFC activation may therefore impact Pavlovian bias. However, it remains unknown how the activity in the vmPFC modulates the Pavlovian bias. Thus, we applied continuous theta-burst stimulation (cTBS), a non-invasive protocol that transiently reduces cortical excitability, over the vmPFC in a single-blinded, between-subject study. 90 healthy adults performed a motivational Go/NoGo learning task during fMRI after receiving cTBS (n=45) or sham (n=45) stimulation. Behaviourally, cTBS reduced overall Go response rates and slowed reaction times. Computational modelling showed a decrease in the learning rate, selectively for rewarding outcomes. Computational fMRI analysis showed stronger reward prediction error (RPE) signals in the vmPFC, mediodorsal thalamus, and left dorsal striatum after cTBS, without changes in neural signals at cue onset. These findings provide causal evidence that the vmPFC drives the action-invigoration component of the Pavlovian bias. Significance statementWe causally link ventromedial prefrontal cortex (vmPFC) function to motivated action in humans. In a single-blind cTBS-fMRI study (n=90), transient vmPFC inhibition reduced Go responding, slowed reaction times, and selectively lowered the positive learning rate early in learning. At the same time, reward-prediction-error signals increased in mediodorsal thalamus, dorsal striatum, and vmPFC, while cue-onset value/choice signals were unchanged. Together, the results indicate that vmPFC normally speeds value updating and invigorates actions; when inhibited, control shifts toward slower, subcortically supported learning under higher uncertainty.

neuroscience↗

bioRxiv2024

Parallel in-depth analysis of repeat expansions: an updated Clin-CATS workflow for nanopore R10 flow cells

Hereditary ataxias, caused by expansions of short tandem repeats, are difficult to diagnose using traditional PCR and Southern blot methods, which struggle to detect complex repeat expansions and cannot assess repeat interruptions or methylation. We present an updated Clinical Nanopore Cas9-Targeted Sequencing (Clin-CATS) workflow for analyzing repeat expansions, now compatible with the Oxford Nanopore Technologies R10 flow cell. The workflow incorporates the ONT wf-human-variation Epi2Me workflow, including the Straglr tool to analyze basecalled reads, ensuring compatibility with past, current, and future sequencing chemistries. It expands the number of genes analyzed from 10 to 27 within the ataxia panel and introduces new gene panels for myopathy, neurodegeneration, and ALS/motor neuron disease. Validated with Coriell reference and clinical samples, this method improves the analysis of pathogenic repeat expansions, providing deeper insights into repeat structures while addressing the limitations of traditional approaches.

genetics↗

bioRxiv2022

Cortical grey matter mediates increases in model-based control and learning from positive feedback from adolescence to adulthood

Adolescents undergo maturation in cognition and brain structure. Model-based (MB) control is known to increase from childhood to young adulthood, which is mediated by cognitive abilities. Here, we asked two questions unaddressed in previous developmental studies: Firstly, what are the brain structural correlates of age-related increases in MB control? Secondly, how are age-related increases in MB control from adolescence to adulthood influenced by motivational context? A developmental sample (n=103, age: 12-42) completed structural MRI and an established task to capture MB control. The task was modified with respect to outcome valence by including (1) reward and punishment blocks to manipulate the motivational context and (2) an additional choice test to assess learning from positive vs. negative feedback. After replicating that an age-dependent increase in MB control is mediated by cognitive abilities, we demonstrate first-time evidence that grey matter density (GMD) in the parietal cortex mediates the increase of MB control with age. While motivational context did not relate to age-related changes in MB control, learning from positive feedback improved with age. Meanwhile, negative feedback learning showed no age effects. We present a first report that an age-related increase in learning from positive feedback was mediated by reduced GMD in the parietal, medial and dorsolateral prefrontal cortex. Our findings indicate that efficient brain maturation, as putatively reflected in lower GMD, in distinct and partially overlapping brain regions is a key developmental step towards age-related increases in planning and value-based choice. Significance StatementAdolescents undergo extensive maturation in cognition and brain structure. Interestingly, model-based decision-making is also known to increase from childhood to adulthood. Here, we demonstrate for the first time that grey matter density in the parietal cortex mediates an age-dependent increase in model-based control. An age-related increase in positive feedback learning was mediated by reduced grey matter density in the parietal, medial and dorsolateral prefrontal cortex. Interestingly, a manipulation of motivational context (gain reward vs. avoid punishment) did not impact age-related changes in model-based control. These findings highlight that efficient brain maturation in distinct and overlapping cortical brain regions constitutes a key developmental step towards increases in model-based planning and value-based choice.

neuroscience↗

bioRxiv2021

Cortical dopamine reduces the impact of motivational biases governing automated behaviour

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n=35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomized, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

neuroscience↗

bioRxiv2021

Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determine Mycobacterium tuberculosis bacterial burden

It is estimated that approximately one-fourth of the world's population is infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agents of tuberculosis (TB). In this study, we present rationally developed molecular markers for bacterial burden, which are derived from mycobacterial phospholipids. Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PI) are present in all clinically relevant MTBC lineages investigated. For the major abundant lipid PI 16:0_19:0 (TSA), a detection limit equivalent to 102 colony forming units (CFU) was determined for bacterial cultures and approximately 103 for cell culture systems. We further developed a mass spectrometry based targeted lipid assay, which - in contrast to bacterial quantification on solid medium - can be performed within several hours including sample preparation. Translation of this indirect and culture-free detection approach allowed the determination of pathogen loads in infected murine macrophages, human neutrophils and murine lung tissue. We show that marker lipids inferred from the mycobacterial PIs are increased in peripheral blood mononuclear cells (PBMCs) of TB patients beyond the lipid metabolic background in comparison to healthy controls. In a small cohort of drug-susceptible TB patients elevated levels of these marker molecules were detected at therapy start and declined following successful anti-tuberculosis treatment. The concentration of TSA-containing PIs can be used as correlate for reliable and rapid quantification of Mycobacterium tuberculosis (Mtb) burden in experimental in vitro model systems and may also provide a clinically relevant tool for monitoring TB therapy. One Sentence SummaryTuberculostearic acid containing phosphatidylinositols represent a novel, fast to measure, reliable correlate of Mycobacterium tuberculosis bacterial burden in experimental model systems, which makes a future clinical application conceivable.

biochemistry↗