Biology subjects

Lund, T. E.

Publications and source records attributed to Lund, T. E..

6 recordsLinked to original sources

bioRxiv2025

Porcine model of BRD1 haploinsufficiency reveals neurodevelopmental, behavioral, and molecular altera-tions relevant to psychiatric disorders

Psychiatric disorders are complex conditions characterized by substantial overlap in genetic risk and shared biological mechanisms. However, how individual risk genes contribute to shared disease mechanisms and disorder-specific phenotypes remains poorly understood. BRD1 has emerged as a chromatin-associated regulator with transdiagnostic relevance across psychiatric disorders and a central role in gene regulatory networks enriched for psychiatric risk genes. To investigate the biological consequences of reduced BRD1 function in a translationally relevant system, we generated a minipig model harboring a monoallelic deletion in BRD1 and performed longitudinal neuroimaging together with behavioral and multi-omics profiling. BRD1 haploinsufficient minipigs displayed normal growth and exploratory behavior but exhibited subtle age-dependent differences in motivational behavior. Despite the absence of overt developmental abnormalities, longitudinal neuroimaging revealed genotype-associated structural differences primarily involving the cerebral cortex and caudate nucleus, suggestive of altered neurodevelopmental trajectories. Integrated multi-omics analyses revealed striking convergence across transcriptomic and metabolomic datasets, identifying coordinated perturbations of mitochondrial function, redox regulation, and phospholipid metabolism across multiple brain regions. Notably, these molecular alterations were not restricted to the central nervous system, as peripheral multi-omics profiling revealed systemic metabolic alterations, including altered phospholipid composition and glucose metabolism. Together, these findings indicate that BRD1 haploinsufficiency is associated with coordinated neurodevelopmental and metabolic alterations across brain and peripheral tissues. More broadly, this study provides systems-level insight into how a psychiatric risk gene influences interconnected neurodevelopmental and metabolic processes across multiple levels of biological organization and highlights the value of large-animal multi-omics models for translational neuropsychiatric research.

genetics↗

bioRxiv2024

Laminar fMRI in the locked-in stage of amyotrophic lateral sclerosis shows preserved activity in layer Vb of primary motor cortex

Amyotrophic lateral sclerosis (ALS) affects the cerebral cortex layer-dependently, most notably by the foremost targeting of upper motor neurons (UMNs) sited in layer Vb. Previous studies have shown a retained ability of paralysed patients to activate residual cortical motor networks, even in late-stage ALS. However, it is currently unknown whether such activation reflects a retained capacity to process sensorimotor inputs or if it is a result of actual motor output. Given the distinct function of individual cortical layers, layer-specific functional measurements may provide insight to this question. In this study, using submillimetre resolution laminar fMRI, we assessed the layer-dependent activation associated with attempted (motor) and passive (somatosensory) movements in a locked-in stage ALS patient. We found robust activation in both superficial and deep layers of primary motor cortex. The peak activation in deep layers was localised to layer Vb. These findings demonstrate preserved activity in deep output layers of M1, possibly reflecting a retained ability to engage residual UMNs despite years of paralysis. Our study underscores the capacity of laminar fMRI to discern subtle cortical activity and elucidates a promising pathway for probing in vivo human ALS pathology with unprecedented resolution.

neuroscience↗

bioRxiv2024

Tolerating B1+-inhomogeneity in MP2RAGE-based R1-mapping by calculating second contrast that permits previously problematic sequence parameters

PurposeRegarding in vivo, robust R1-mapping, the goal of the present paper is twofold. First, to verify that non-bijective mapping in MP2RAGE imaging can be resolved through a 2D look-up-table approach. Second, that the expanded parameter space from this can be used to improve B1+-inhomogeneity tolerance without other prerequisites. TheoryBy deriving a second contrast from the magnitude images of the MP2RAGE acquisition, ambiguities in the original MP2RAGE image resulting from non-bijective transfer curves can be resolved. Such ambiguities may occur when protocols are optimised, e.g., for higher B1+-inhomogeneity tolerance. A 2D look-up-table approach combines the available information to resolve these ambiguities during mapping. MethodsAt 3T, we acquired MP2RAGE images with standard acquisition parameters and (non-bijective) parameters optimised for B1+-inhomogeneity tolerance. From three subjects across multiple sessions, we assessed the B1+-inhomogeneity tolerance through excitation pulse amplitude scalings. ResultsThe R1-maps resulting from the B1+-optimised protocols showed greatly reduced B1+-effects across images, but without additional scanner time. Meanwhile these maps could only successfully be derived by a 2D look-up-table approach. ConclusionWe show that it is possible to optimise for B1+-inhomogeneity tolerance in MP2RAGE through sequence parameter settings, while still successfully estimating the R1-map with a 2D look-up-table approach. This without the need for an additional B1+-map. The increased parameter space enabled by the 2D look-up-table approach may further be used to adjust MP2RAGE acquisitions for improved scan times, SNR and/or CNR.

neuroscience↗

bioRxiv2023

The laminar pattern of proprioceptive activation in human primary motor cortex

The primary motor cortex (M1) has traditionally been viewed as a motor output generator. However, its vital role in proprioceptive somatosensation is increasingly being recognized. Yet, our understanding of proprioceptive somatosensation in M1 at the laminar scale is limited, largely due to methodological challenges. Empirical findings in primates and rodents suggest a pronounced role of superficial cortical layers, but the involvement of deep layers has yet to be examined in humans. Submillimeter resolution fMRI has emerged in recent years, paving the way for the study of layer-dependent activity in humans (laminar fMRI). In the present study, laminar fMRI was employed to investigate the laminar pattern of proprioceptive somatosensation on M1 deep layer activation using passive finger movements as proprioceptive stimulation. Significant M1 deep layer activation was observed in response to proprioceptive stimulation across 10 healthy subjects using vascular space occupancy (VASO) at 7T. For further validation, two additional subjects were scanned using a balanced steady-state free precession (bSSFP) sequence with ultrahigh (0.3 mm) in-plane resolution, yielding converging results. These results were interpreted in the light of previous laminar fMRI studies and the active inference account of motor control. We suggest that a considerable proportion of M1 deep layer activation is due to proprioceptive influence and that deep layers of M1 constitute a key component in proprioceptive circuits.

neuroscience↗

bioRxiv2022

Feasibility of 3T layer-dependent fMRI with GE-BOLD using NORDIC and phase regression

IntroductionFunctional MRI with spatial resolution in the submillimeter domain enables measurements of activation across cortical layers in humans. This is valuable as different types of cortical computations, e.g., feedforward versus feedback related activity, take place in different cortical layers. Layer-dependent fMRI (L-fMRI) studies have almost exclusively employed 7T scanners to overcome the reduced signal stability associated with small voxels. However, such systems are relatively rare and only a subset of those are clinically approved. In the present study, we examined the feasibility of L-fMRI at 3T using NORDIC denoising. Methods5 healthy subjects were scanned on a Siemens MAGNETOM Prisma 3T scanner. To assess across-session reliability, each subject was scanned in 3-8 sessions on 3-4 consecutive days. A 3D gradient echo EPI (GE-EPI) sequence was used for BOLD acquisitions (voxel size 0.82 mm isotopic, TR = 2.2 s) using a block designed finger tapping paradigm. NORDIC denoising was applied to the magnitude and phase time series to overcome limitations in tSNR and the denoised phase time series were subsequently used to correct for large vein contamination through phase regression. Results and conclusionNORDIC denoising resulted in temporal signal-to-noise ratio (tSNR) values comparable to or higher than commonly observed at 7T. Layer-dependent activation profiles could thus be extracted robustly, within and across sessions, from regions of interest located in the hand knob of the primary motor cortex (M1). Phase regression led to substantially reduced superficial bias in obtained layer profiles, although residual macrovascular contribution remained. We believe the present results support the feasibility of L-fMRI at 3T, which might help make L-fMRI available to a much wider community.

neuroscience↗

bioRxiv2019

Language beyond the language system: dorsal visuospatial pathways support processing of demonstratives and spatial language during naturalistic fast fMRI

Spatial demonstratives are powerful linguistic tools used to establish joint attention. Identifying the meaning of semantically underspecified expressions like \"this one\" hinges on the integration of linguistic and visual cues, attentional orienting and pragmatic inference. This synergy between language and extralinguistic cognition is pivotal to language comprehension in general, but especially prominent in demonstratives.\n\nIn this study, we aimed to elucidate which neural architectures enable this intertwining between language and extralinguistic cognition using a naturalistic fMRI paradigm. In our experiment, 28 participants listened to a specially crafted dialogical narrative with a controlled number of spatial demonstratives. A fast multiband-EPI acquisition sequence (TR = 388ms) combined with finite impulse response (FIR) modelling of the hemodynamic response was used to capture signal changes at word-level resolution.\n\nWe found that spatial demonstratives bilaterally engage a network of parietal areas, including the supramarginal gyrus, the angular gyrus, and precuneus, implicated in information integration and visuospatial processing. Moreover, demonstratives recruit frontal regions, including the right FEF, implicated in attentional orienting and reference frames shifts. Finally, using multivariate similarity analyses, we provide evidence for a general involvement of the dorsal (\"where\") stream in the processing of spatial expressions, as opposed to ventral pathways encoding object semantics.\n\nOverall, our results suggest that language processing relies on a distributed architecture, recruiting neural resources for perception, attention, and extra-linguistic aspects of cognition in a dynamic and context-dependent fashion.

neuroscience↗