Biology subjects

Winkler, A. M.

Publications and source records attributed to Winkler, A. M..

10 recordsLinked to original sources

bioRxiv2026

Targeting Nitric Oxide Synthase 2 Reverses Learning Deficits in an Oligodendrocyte-Focused Model of Costello Syndrome

Oligodendrocyte (OL) functions greatly improve information processing in the brain; consequently, compromised OL biology negatively impacts brain function in various diseases. Young-adult Costello Syndrome (CS) patients present with learning disabilities and regression of psychomotor skills in correlation with abnormal brain white matter, delayed myelination, and dysmyelination. This suggests the involvement of OLs and myelin in abnormal brain physiology during and beyond development; however, the neuropathophysiology of CS remains poorly understood. Replacing the endogenous HRas gene with the CS-causing HRasG12V mutant gene in adult OLs (pHRasG/+ mice) induces structural myelin abnormalities; nonetheless, any functional impact is unknown. Here we show robust learning - but not memory - deficits in pHRasG/+ males and modest, delayed learning issues in females. Learning phenotypes are transient, likely involving compensatory responses from the OL lineage and microglia. Diffusion-weighted magnetic resonance imaging revealed regional time- and sex-dependent compromised myelin microstructure, coinciding with the peak of learning issues. Remarkably, transcripts associated with inflammation/immune function are upregulated and pharmacological control of nitric oxide synthase 2 restores learning in male pHRasG+/- mice. Our study supports the notion that abnormal nitric oxide signaling in mature OLs affects learning, suggests a chronic impact of glia-myelin mechanisms in CS neuropathology, and proposes molecular targets with therapeutic potential.

neuroscience↗

bioRxiv2026

The methodological foundations of lesion network mapping remain sound

Lesion network mapping (LNM) and related techniques have been used in over 200 studies, primarily to test whether anatomically distributed lesions that cause the same symptom fall within a common brain network. A recent article1 challenges the specificity and validity of this technique, suggesting that lesion network maps primarily reflect intrinsic properties of the normative connectome rather than lesion-symptom relationships. However, the data and procedures in van den Heuvel et al. do not reflect those used in most LNM studies. Further, the main conclusions were based on similarity between maps, but similarity does not imply the absence of meaningful differences. In contrast, LNM provides evidence for meaningful differences using specificity testing. Exemplary analyses of 1090 lesion locations from 34 prior LNM studies do not support van den Heuvels concerns and confirm the lesion-deficit specificity of LNM. While we encourage further methodological investigation, the analyses of van den Heuvel et al. do not invalidate prior LNM findings or future applications.

neuroscience↗

bioRxiv2022

Widespread, depth-dependent microstructural damage in the cortex of children with drug resistant focal epilepsy: A quantitative T1 and T2 mapping study

ObjectiveTissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes, treatment-related side-effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilised quantitative MRI, which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. MethodsTo assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy [age-range=4-18 years] and 46 typically-developing children [age-range=2-18 years]. We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically-defined abnormalities (MRI-positive) and healthy controls, and tested if this could classify patients without reported radiological abnormalities (MRI-negative). ResultsWe uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 62% at 100% specificity on held-out MRI-negative patients. SignificanceThese findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically-identified abnormalities, and potentially evident pre-symptomatically. Key PointsO_LIWe assessed cortical microstructure in children with focal epilepsy C_LIO_LIQuantitative T1 and T2 relaxometry (qT1 and qT2) was measured in the neocortex C_LIO_LIPatients showed extensive qT1/qT2 increases and intracortical organization changes C_LIO_LIAlterations may appear during cerebral development, prior to disease onset C_LI

neuroscience↗

bioRxiv2022

tDCS induced GABA change is associated with the simulated electric field in M1, an effect mediated by grey matter volume in the MRS voxel

Background and ObjectiveTranscranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. MethodsData from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual MPRAGE images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. ResultsIn M1, higher mean E-field magnitude was associated with greater tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = -3.55, p =0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. ConclusionsOur data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects. HighlightsO_LIWe study the link between individually simulated electric field dose and tDCS-induced change in GABA in the cortex. C_LIO_LIThe electric field strength in the brain correlates with a decrease in GABA in the motor cortex. C_LIO_LIThe correlation between the electric field and GABA change is modulated by the amount of grey matter in the MRS voxel. C_LIO_LIWe find no association between the electric field and GABA in the temporal cortex. C_LI

neuroscience↗

bioRxiv2021

Structural and functional asymmetry of the neonatal cerebral cortex

Features of brain asymmetry have been implicated in a broad range of cognitive processes; however, their origins are still poorly understood. Using a new left-right symmetric, spatiotemporal cortical surface atlas, we investigated cortical asymmetries in 442 healthy term-born neonates using structural and functional magnetic resonance images from the Developing Human Connectome Project. Cortical asymmetries observed in the term cohort were contextualised in two ways: by comparing them against cortical asymmetries observed in 103 preterm neonates scanned at term-equivalent age, and by comparing structural asymmetries against those observed in 1110 healthy young adults from the Human Connectome Project. Our results demonstrate that the neonatal cortex is markedly asymmetric in both structure and function, and while associations with preterm birth and biological sex were minimal, significant differences exist between birth and adulthood. Although these changes may represent experience-dependent developmental milestones, longitudinal studies across the lifespan are required to fully address these hypotheses.

neuroscience↗

bioRxiv2020

Multimodal imaging brain markers in early adolescence are linked with a physically active lifestyle

The World Health Organization (WHO) promotes physical exercise and a healthy lifestyle as means to improve youth development. However, relationships between physical lifestyle and brain development are not fully understood. Here, we asked whether a brain - physical latent mode of covariation underpins the relationship between physical activity, fitness, and physical health measures with multimodal neuroimaging markers. In 50 12-year old school pupils (26 females), we acquired multimodal whole-brain MRI, characterizing brain structure, microstructure, function, myelin content, and blood perfusion. We also acquired physical variables measuring objective fitness levels, 7-days physical activity, body-mass index, heart rate, and blood pressure. Using canonical correlation analysis we unravel a latent mode of brain - physical covariation, independent of demographics, school, or socioeconomic status. We show that MRI metrics with greater involvement in this mode also showed spatially extended patterns across the brain. Specifically, global patterns of greater grey matter perfusion, volume, cortical surface area, greater white matter extra-neurite density, and resting state networks activity, covaried positively with measures reflecting a physically active phenotype (high fit, low sedentary individuals). Showing that a physically active lifestyle is linked with systems-level brain MRI metrics, these results suggest widespread associations relating to several biological processes. These results support the notion of close brain-body relationships and underline the importance of investigating modifiable lifestyle factors not only for physical health but also for brain health early in adolescence. Significance statementAn active lifestyle is key for healthy development. In this work, we answer the following question: How do brain neuroimaging markers relate with young adolescents level of physical activity, fitness, and physical health? Combining advanced whole-brain multimodal MRI metrics with computational approaches, we show a robust relationship between physically active lifestyles and spatially extended, multimodal brain imaging derived phenotypes. Suggesting a wider effect on brain neuroimaging metrics than previously thought, this work underlies the importance of studying physical lifestyle, as well as other brain - body relationships in an effort to foster brain health at this crucial stage in development.

neuroscience↗

bioRxiv2019

Ultra-high field imaging reveals increased whole brain connectivity underpins cognitive strategies that attenuate pain

We investigate how the attenuation of pain with cognitive interventions affects the strength of cortical connections by pursuing a whole brain approach. While receiving tonic cold pain, 20 healthy participants were asked to utilise three different pain attenuation strategies. During a 7T fMRI recording, participants were asked to rate their pain after each single trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity of the cortical data. Across all conditions, we found that a higher performance of pain attenuation was predominantly associated with higher functional connectivity. Of note, we observed an association between low pain and high connectivity for regions that belong to the core areas of pain processing, i.e. the insular and cingulate cortices. For one of the cognitive strategies (safe place), the performance of pain attenuation was explained by diffusion tensor imaging metrics of increased white matter integrity. Impact StatementIn a single trial analysis, the more effective attempts to attenuate pain in three different conditions are associated with general higher functional connectivity across the entire brain.

neuroscience↗

bioRxiv2019

Multiple testing correction over contrasts for brain imaging

The multiple testing problem arises not only when there are many voxels or vertices in an image representation of the brain, but also when multiple contrasts of parameter estimates (that is, hypotheses) are tested in the same general linear model. Here we argue that a correction for this multiplicity must be performed to avoid excess of false positives. Various methods have been proposed in the literature, but few have been applied to brain imaging. Here we discuss and compare different methods to make such correction in different scenarios, showing that one classical and well known method is invalid, and argue that permutation is the best option to perform such correction due to its exactness and flexibility to handle a variety of common imaging situations.

neuroscience↗

bioRxiv2019

Skill acquisition increases myelination and strengthens functional connectivity in the sensorimotor circuit of the adult rat

The effects of skill acquisition on whole-brain structure and functional networks have been extensively investigated in humans but have yet to be explored in rodents. Forelimb reaching training in rodents results in well-established focal functional and structural reorganization within the motor cortex (M1) and cerebellum, indicating distributed alterations in both structure and function. However, it is unclear how local alterations in structure and function relate to distributed learning-related changes across motor networks. Here we trained adult rats in skilled reaching and used multimodal whole-brain in vivo MRI to assess both structural and functional plasticity over time.\n\nWe detected increases in a myelin-related MRI metric in white matter, cortical areas, and to a lesser extent in the cerebellum, paralleled by strengthened functional connectivity between M1 and cerebellum, possibly reflecting a decrease in cerebellum inhibition over M1. Skill learning therefore leads to myelin increases in pathways that connect sensorimotor regions, and in functional connectivity increases between areas involved in motor learning, all of which correlate with performance. These findings closely mirror previous reports of network-level changes following motor learning in humans and underlines the correspondence between human and rodent brain circuits for motor learning, despite important differences in the anatomy of physiology of movement circuits between species.

neuroscience↗

bioRxiv2017

Fast and Powerful Genome Wide Association Analysis of Dense Genetic Data with High Dimensional Imaging Phenotypes

Genome wide association (GWA) analysis of brain imaging phenotypes can advance our understanding of the genetic basis of normal and disorder-related variation in the brain. GWA approaches typically use linear mixed effect models to account for non-independence amongst subjects due to factors such as family relatedness and population structure. The use of these models with high-dimensional imaging phenotypes presents enormous challenges in terms of computational intensity and the need to account multiple testing in both the imaging and genetic domain. Here we present method that makes mixed models practical with high-dimensional traits by a combination of a transformation applied to the data and model, and the use of a non-iterative variance component estimator. With such speed enhancements permutation tests are feasible, which allows inference on powerful spatial tests like the cluster size statistic.

genetics↗