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Böken, D.

Publications and source records attributed to Böken, D..

5 recordsLinked to original sources

Toward navigating emotional states using real-time representational similarity analysis fMRI neurofeedback - a feasibility study

Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a promising non-invasive brain-computer-interface (BCI) technique for enhancing self-regulation of affective states in the brain. However, conventional univariate rt-fMRI-NF approaches are limited in their ability to distinguish neural patterns of distinct emotions that involve overlapping brain regions. In this study, we applied an rt-fMRI semantic neurofeedback (rt-fMRI-sNF) paradigm, incorporating real-time representational similarity analysis (rt-RSA) to enable navigation between emotional states. Four emotional patterns were first derived from functional localizer runs, each designed to evoke a specific emotion, and then applied as target patterns during neurofeedback. Using an RSA-informed circular semantic map (CSM), participants received real-time visual feedback indicating both the similarity and intensity of their current brain activity relative to target emotional patterns. Participants were instructed to use mental imagery to shift their brain activity toward the specific target pattern and increase its intensity. Twenty-four healthy participants completed the localizer runs, and two consecutive neurofeedback runs in the same session. Ten participants successfully engaged with both the similarity and intensity components of the CSM, showing effective modulations of their mental states. Analyses of the localizer runs revealed overlapping regional activations across emotions and demonstrated that RSA outperformed univariate analysis in distinguishing between them. For the neurofeedback runs, linear mixed-effects model (LMM) analyses across multiple performance metrics indicated consistent within-run improvements and higher initial performance in the second run, while significant between-run learning effects emerged only in exploratory models with quadratic time terms. A block-wise comparison also showed significantly higher performance at the end of each run compared to the beginning based on the intensity metric. These findings support the usability of RSA in differentiating multiple emotional states and demonstrate the feasibility of the rt-fMRI-sNF paradigm for emotion regulation.

neuroscience↗

Neurodegeneration emerges at a cellular tipping point between protein accumulation and removal.

Protein aggregates are a pathological hallmark across neurodegenerative diseases. Yet, the disconnect between molecular-level aggregation and the emergence of disease severely limits mechanistic understanding of neurodegeneration. Here, we bridge this disconnect by showing that a cellular tipping point emerges as a universal feature across diseases from the competition between aggregate accumulation and removal. We map the resulting cellular phase transition with our high-throughput live-cell assay, measuring the tipping point that separates healthy cells from those with large aggregate loads. Using super-resolution imaging of brain tissue from Alzheimers and Parkinsons disease, we quantify how the balance of accumulation and removal is shifted in disease. We validate our framework by predicting how designed aggregation inhibitors shift the tipping point to restore cellular homeostasis. Our results provide a mechanistic framework connecting molecular-level aggregation to disease, paving the way for a quantitative, unified understanding of neurodegeneration and enabling predictions of therapeutic efficacy.

neuroscience↗

Small tau aggregates exhibit disease-specific molecular profiles across tauopathies

Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterise these small tau aggregates from post-mortem brain of individuals with Alzheimers disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Picks disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine-356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate, but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets. Key pointsSmall tau aggregates show disease-specific signatures across tauopathies, differing in abundance, morphology, and post-translational modifications. Tau aggregates in AD show enhanced phosphorylation density and structural heterogeneity, including a distinct population of long fibrillar species detectable in the soluble fraction. Alzheimers disease is characterised by specific long, fibrillar-shaped tau aggregates enriched in disease-relevant phospho-epitopes. PSP features round pSer356-positive aggregates that correlate with apoptotic and inflammatory markers, suggesting a distinct mechanism of toxicity. Isoform-specific biosensor assays reveal divergent seeding behaviour: CBD shows strong 4R seeding, while PSP lacks seeding activity. Features of small aggregates co-vary with distinct patterns of gliosis and cell stress, suggesting disease-specific mechanisms of tau-mediated toxicity.

neuroscience↗

Fingerprinting disease-derived protein aggregates reveals unique signature of Motor Neuron Disease

Inappropriate aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of motor neuron disease (MND). Current methods for quantifying heterogeneous aggregate populations in biofluids are limited, precluding their routine use in diagnosis and disease monitoring. Single molecule microscopy methods overcome these limitations to deliver quantitative morphological and compositional fingerprinting of molecular assemblies containing TDP-43. Here, we demonstrate the application of such methods to extracts from donor brain tissues. We show the number and morphology of aggregates derived from frontal cortex and cerebellar samples is sufficient to distinguish MND donors from neurologically normal controls, as well as between different MND cohorts. In addition, we compare proteomic and microscopic compositional profiles, demonstrating how complementary insights delivered by each technique can enhance our understanding of disease mechanisms. These single molecule assays will inform future diagnostic and stratification technologies, improving our ability to deliver patient care in a timely and targeted manner.

molecular biology↗

Improving split reporters of protein-protein interactions through orthology-based protein engineering

Protein-protein interactions (PPI) can be detected through selective complementation of split fluorescent reporters made of two complementary fragments that reassemble into a functional fluorescent reporter when in close proximity. We previously introduced splitFAST, a chemogenetic PPI reporter with rapid and reversible complementation. Here, we present the engineering of RspA-splitFAST, an improved reporter displaying higher brightness, lower self-complementation and higher dynamic range for optimal monitoring of PPI using an original protein engineering strategy that exploits proteins with orthology relationships. Our study allowed the identification of a system with improved properties and enabled a better understanding of the molecular features controlling the complementation properties. Because of the rapidity and reversibility of its complementation, its low self-complementation, high dynamic range, and improved brightness, RspA-splitFAST is well suited to study PPI with high spatial and temporal resolution, opening great prospects to decipher the role of PPI in various biological contexts.

cell biology↗