Axon morphology is modulated by the local environment and impacts the noninvasive investigation of its structure–function relationship

Andersson, Mariam; Kjer, Hans Martin; Rafael-Patiño, Jonathan; Pacureanu, Alexandra; Pakkenberg, Bente; Thiran, Jean Philippe; Ptito, Maurice; Bech, Martin; Dahl, Anders Bjorholm; Dahl, Vedrana Andersen; Dyrby, Tim B.

doi:10.1073/pnas.2012533117

Cited by 68 publications

(123 citation statements)

References 67 publications

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“…Even after eliminating orientational dispersion, it is not understood why we observe such strong along‐tract variability of the MR axon radii mapping in certain tracts (e.g., CST). Various additional confounding factors have been discussed, for example, diameter variations due to curvature or undulations of the axons (Andersson et al, 2020; Brabec, Lasič, & Nilsson, 2020; Lee, Jespersen, et al, 2020; Lee, Paioannou, Kim, Novikov and Fieremans 2020; Nilsson, Lätt, Ståhlberg, van Westen, & Hagslätt, 2012). However, in agreement with our previous hypothesis, this observation might also be explained by the lack of specificity of the high b signal to axons only.…”

Section: Discussionmentioning

confidence: 99%

“…The sixth‐order in the numerator arises from the combination of biquadratic relation between

\ln S_{c}^{⊥} ((), r)

and r (Neuman, 1974), and of the subsequent volume‐weighting that emphasizes the thickest axons by an extra quadratic factor (Alexander et al, 2010; Packer & Rees, 1972). Therefore, the effective MR radius is heavily weighted by the largest axons within the voxel or, more specifically, the largest Martin's radius in case of non‐cylindrical axons (Andersson et al, 2020).…”

Section: Theory and Methodsmentioning

confidence: 99%

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The variability of MR axon radii estimates in the human white matter

Veraart

Raven

Edwards

et al. 2021

Human Brain Mapping

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The noninvasive quantification of axonal morphology is an exciting avenue for gaining understanding of the function and structure of the central nervous system. Accurate non‐invasive mapping of micron‐sized axon radii using commonly applied neuroimaging techniques, that is, diffusion‐weighted MRI, has been bolstered by recent hardware developments, specifically MR gradient design. Here the whole brain characterization of the effective MR axon radius is presented and the inter‐ and intra‐scanner test–retest repeatability and reproducibility are evaluated to promote the further development of the effective MR axon radius as a neuroimaging biomarker. A coefficient‐of‐variability of approximately 10% in the voxelwise estimation of the effective MR radius is observed in the test–retest analysis, but it is shown that the performance can be improved fourfold using a customized along‐tract analysis.

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Section: Discussionmentioning

confidence: 99%

“…The sixth‐order in the numerator arises from the combination of biquadratic relation between

\ln S_{c}^{⊥} ((), r)

Section: Theory and Methodsmentioning

confidence: 99%

The variability of MR axon radii estimates in the human white matter

Veraart

Raven

Edwards

et al. 2021

Human Brain Mapping

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“…Our results also form a solid basis for future studies on the functional integrity of the motor transcallosal fibers in rodents. Since our approach allows to reliably investigate functional aspects of a specific cortico-cortical interhemispheric pathway, a next obvious step will be to add non-invasive microstructural mapping techniques to relate the dose-response relationships at the functional level with the microstructural properties of the transcallosal fiber tract, including post mortem histological validation [65,66]. Further, this preclinical platform can be used translationally to assess animal disease models (e.g.…”

Section: Implications and Limitationsmentioning

confidence: 99%

Profiling the transcallosal response of rat motor cortex evoked by contralateral optogenetic stimulation of glutamatergic cortical neurons

Skoven

Tomasevic

Kvitsiani

et al. 2021

Preprint

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Efficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control. We employed optogenetic stimulation to establish a framework for probing transcallosal M1-M1 interactions in rats. In male rats, we optogenetically stimulated glutamatergic neurons in right M1 and recorded the transcallosally evoked potential with chronically implanted electrodes in contralateral left M1 during dexmedetomidine anesthesia. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1. Optogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. Median N1 latencies remained stable, once stimulation elicited a reliable N1 peak and did not display a systematic shortening with increasing stimulation intensity or duration. Optogenetically stimulated glutamatergic neurons in M1 can reliably evoke a transcallosal response in anesthetized rats and can be used to characterize the relationship between "stimulation dose" and "response magnitude" (i.e., the gain function) of transcallosal M1-to-M1 glutamatergic connections. Detailed knowledge of the stimulus-response relationship is needed to optimize the efficacy of optogenetic stimulation. Since transcallosal M1-M1 interactions can also be probed non-invasively with transcranial magnetic stimulation in humans, our optogenetic stimulation approach bears translational potential for studying how unilateral M1 stimulation can induce interhemispheric plasticity.

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“…The MRI signal generated by an ensemble of protons probing the local, microscopic environment in human brain tissue contains information about microstructural tissue features such as the axonal radius [1, 2, 3, 4]. The axonal radius is a key to determine neuronal communication in the human brain because it is related to, e.g., the neuronal conduction velocity [5, 6, 7].…”

Section: Introductionmentioning

confidence: 99%

A representative reference for MRI-based human axon radius assessment using light microscopy

Mordhorst

Morozova

Papazoglou

et al. 2021

Preprint

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Non-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data on the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the frequency-weighted arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the potential error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (normalized-root-mean-square-error of reff: 7.2 %; rarith: 21.5 %) and lower bias (normalized-mean-bias-error of reff: -1.7 %; rarith: 16 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.9 % and 3 % to reff. In conclusion, the proposed method accurately estimates reff at MRI voxel resolution across a human corpus callosum sample. Further investigations are required to assess generalization to brain areas with different axon radii ensembles.

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Axon morphology is modulated by the local environment and impacts the noninvasive investigation of its structure–function relationship

Cited by 68 publications

References 67 publications

The variability of MR axon radii estimates in the human white matter

The variability of MR axon radii estimates in the human white matter

Profiling the transcallosal response of rat motor cortex evoked by contralateral optogenetic stimulation of glutamatergic cortical neurons

A representative reference for MRI-based human axon radius assessment using light microscopy

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