Biology subjects

Kobbersmed, J. R. L.

Publications and source records attributed to Kobbersmed, J. R. L..

3 recordsLinked to original sources

bioRxiv2026

Whole-brain normative modeling across multiple functional connectivity metrics in MEG

Normative modeling has recently emerged in structural and functional neuroimaging as a promising approach to characterize neuropathology at the individual level. Trained on large healthy cohorts, these models predict expected measurements from covariates such as age and sex while quantifying normal population variability. Individual measurements can then be compared against the model to identify deviations associated with pathology. While most normative models of brain function have been based on functional MRI, EEG and MEG offer more direct measurements of brain activity at higher temporal resolution. Despite the promise, how to adequately perform normative modelling at the whole-brain level on these modalities remains challenging. We here propose M/EEG-FUNCOIN to identify age- and sex-related dimensions of change in functional connectivity from a plethora of FC measures from electrophysiology: amplitude envelope correlation, phase-locking value, and time-delay embedding covariance. Using resting-state MEG data from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) dataset, we show that M/EEG-FUNCOIN can: (i) characterize age- and sex-related whole-brain functional connectivity patterns in greater detail than existing methods; and (ii) effectively capture meaningful deviations in connectivity in individuals that rank high and low in cognitive ability. Altogether, these results show great potential for applications in complex, network-level brain pathology.

neuroscience↗

bioRxiv2025

One-shot normative modelling of whole-brain functional connectivity

Many brain diseases and disorders lack objective measures of brain function as indicators of pathology. The search for brain function biomarkers is complicated by the fact that these conditions are often heterogenous and described as a spectrum from normal to abnormal rather than a sick-healthy dichotomy. Normative modelling addresses these challenges by characterizing the normal variation of brain function given sex and age and identifying abnormalities as deviations from this norm. Focusing on functional connectivity (FC) as a way to capture the network properties of the brains activity, we here argue that the pathological effects of neurological or psychiatric disease lie at the systemic level, and that whole-brain normative models are more suitable to capture individual variations associated to these complex conditions than existing localized approaches that analyze one connection at a time. To be able to capture the whole-brain effects of disease, we thus propose Functional Connectivity Integrative Normative Modelling (FUNCOIN) as a novel whole-brain approach to normative modelling of FC. Using FUNCOIN and UK Biobank resting-state fMRI data from 46,000 healthy subjects across training and testing sets, we found that subjects with bipolar disorder and Parkinsons disease were significantly, and substantially, more likely than healthy subjects to exhibit abnormal FC patterns, which was not seen in localized models. Subjects with bipolar disorder divided into two distinct subgroups characterized by different brain function deviations. In Parkinsons disease subjects, abnormal FC patterns were significant even on scans up to 8 years before diagnosis.

neuroscience↗

bioRxiv2021

Allosteric stabilization of calcium and lipid binding engages three synaptotagmins in fast exocytosis

Synaptic communication relies on the fusion of synaptic vesicles with the plasma membrane, which leads to neurotransmitter release. This exocytosis is triggered by brief and local elevations of intracellular Ca2+ with remarkably high sensitivity. How this is molecularly achieved is unknown. While synaptotagmins confer the Ca2+ sensitivity of neurotransmitter exocytosis, biochemical measurements reported Ca2+ affinities too low to account for synaptic function. However, synaptotagmins Ca2+ affinity increases upon binding the plasma membrane phospholipid PI(4,5)P2 and, vice versa, Ca2+-binding increases synaptotagmins PI(4,5)P2 affinity, indicating a stabilization of the Ca2+/PI(4,5)P2 dual-bound syt. We here devise a molecular exocytosis model based on this positive allosteric stabilization and the assumptions that (1.) synaptotagmin Ca2+/PI(4,5)P2 dual binding lowers the energy barrier for vesicle fusion and that (2.) the effect of multiple synaptotagmins on the energy barrier is additive. The model, which relies on biochemically measured Ca2+/PI(4,5)P2 affinities and protein copy numbers, reproduced the steep Ca2+ dependency of neurotransmitter release. Our results indicate that each synaptotagmin dual binding Ca2+/PI(4,5)P2 lowers the energy barrier for vesicle fusion by 4.85 kBT and that allosteric stabilization of this state enables the synchronized engagement of three synaptotagmins for fast exocytosis. Furthermore, we show that mutations altering synaptotagmins allosteric properties may show dominant-negative effects, even though synaptotagmins act independently on the energy barrier, and that dynamic changes of local PI(4,5)P2 (e.g. upon vesicle movement) dramatically impact synaptic responses. We conclude that allosterically stabilized Ca2+/PI(4,5)P2 dual binding enables synaptotagmins to exert their coordinated function in neurotransmission.

neuroscience↗