Neurite orientation dispersion and density imaging of mouse brain microstructure

Calculated NODDI metrics are parametrically dependent on the Din value.

“Since obtaining the ground truth of Din value is still challenging, the calculated NODDI metrics are parametrically dependent on this value (Jelescu et al. 2016; Lampinen et al. 2017).”

• cites Jelescu et al. 2016 sourceSupported
• cites Lampinen et al. 2017 sourceSupported

• AssumptionRests on an assumption: The default Din value in the NODDI toolbox is 0.6 × 10−3 mm2/s.

Applying parallel imaging and SMS techniques to studies in the mouse brain is challenging due to the small coil size and limited space in the probe.

“Applying these techniques to studies in the mouse brain is challenging due to the small coil size (supplemental figure 1) and the limited space in the probe (Johnson et al. 2012; Petiet et al. 2008; Larkman and Nunes 2007).”

• cites Johnson et al. 2012 sourceCould not verify

  Methods §2.2 describes a 30-mm solenoid RF coil used for rat-brain imaging, and the Introduction discusses mouse atlases. Neither passage addresses whether small coils or limited probe space make parallel imaging or SMS challenging in mouse-brain studies (searched: parallel imaging, SMS, coil size, probe space). (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites Petiet et al. 2008 sourceCould not verify

  The Discussion (page unavailable) discusses limits on imaging multiple embryos, identifying the homogeneous magnetic-field volume and gradient-coil volume as constraints. Our copy does not address whether small coil size or limited probe space makes parallel imaging or SMS challenging in mouse-brain studies; searches for those techniques, coil size, and probe space found no supporting passage. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Larkman and Nunes 2007 sourceNot checked — no full text of the source

The NODDI model assumes the neurite orientation distribution using a single Watson distribution without accounting for fiber crossings.

“In addition, NODDI model assumes the neurite orientation distribution using a single Watson distribution without accounting for fiber crossings, the current results may be improved with multiple Bingham distributions or spherical mean technique (SMT) (Kaden et al. 2016; Tariq et al. 2016).”

• cites Kaden et al. 2016 sourceSupported
• cites Tariq et al. 2016 sourceNot checked — no full text of the source

NODDI could be a sensitive biomarker to probe different stages of white matter pathology between acute and chronic demyelination.

“It may suggest that NODDI could be sensitive biomarkers to probe the different stages of white matter pathology between acute demyelination and chronic demyelination (Matsushima and Morell 2001).”

• cites Matsushima and Morell 2001 sourceCould not verify

  The paper’s discussion of the cuprizone model describes the time course of demyelination and remyelination in mice, but does not assess an imaging biomarker. Searches for NODDI and for acute versus chronic demyelination found no passage supporting the attributed claim about NODDI’s sensitivity. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Total density of axons was not significantly different in densities of total neurofilament profiles throughout cuprizone treatment up to 12 weeks in the corpus callosum.

“Xie et al. found the axon diameter values were reduced after 4 weeks of cuprizone and the axonal atrophy persisted at 12 weeks of cuprizone treatment, however, the total density of axons were not significantly different in the densities of total neurofilament profiles throughout cuprizone treatment up to 12 weeks in the corpus callosum (Xie et al. 2010).”

• cites Xie et al. 2010 sourceSupported

NODDI may overestimate the free-water content in cerebral white matter.

“As NODDI depicts a single and fixed intrinsic diffusivity over the whole brain, which may hold the potential to overestimate the free-water content in the cerebral white matter (Kaden et al. 2016).”

• cites Kaden et al. 2016 sourceSupported

Compression factors up to 8× could further reduce the acquisition time to 15.8 hours.

“Since this work was started, we have demonstrated that compression factors up to 8× can be used with limited impact on the conventional DTI metrics which could further reduce the acquisition time to 15.8 hr (Wang et al. 2018a).”

• cites Wang et al. 2018a sourcePartly supported

  The Methods (CS Reconstruction) confirm an acceleration factor of 8×. But Methods (Animal Preparation) report 11.6 hours at that factor, and the Discussion (Tradeoffs between spatial resolution and angular resolution) says about 11 hours—not 15.8 hours. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

Only NDI from the NODDI model correlated with histological measurements of hyperphosphorylated tau protein levels.

“Colgan et al. demonstrated that only NDI from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein and NODDI may provide greater specificity to pathology in Alzheimer’s disease (Colgan et al. 2016).”

• cites Colgan et al. 2016 sourceSupported

NODDI may provide greater specificity to pathology in Alzheimer's disease.

“Colgan et al. demonstrated that only NDI from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein and NODDI may provide greater specificity to pathology in Alzheimer’s disease (Colgan et al. 2016).”

• cites Colgan et al. 2016 sourceSupported

Compression factors up to 8× can be used with limited impact on conventional DTI metrics.

“Since this work was started, we have demonstrated that compression factors up to 8× can be used with limited impact on the conventional DTI metrics which could further reduce the acquisition time to 15.8 hr (Wang et al. 2018a).”

• cites Wang et al. 2018a sourceSupported

NODDI depicts a single and fixed intrinsic diffusivity over the whole brain.

“As NODDI depicts a single and fixed intrinsic diffusivity over the whole brain, which may hold the potential to overestimate the free-water content in the cerebral white matter (Kaden et al. 2016).”

• cites Kaden et al. 2016 sourceSupported

• AssumptionRests on an assumption: The default Din value in the NODDI toolbox is 0.6 × 10−3 mm2/s.

There is a significant correlation between myelin density estimated by absolute tissue density from NODDI (ABTIN) and myelin density obtained from electron microscopy in the mouse corpus callosum.

“There is significant correlation between myelin density estimated by absolute tissue density from NODDI (ABTIN) and myelin density obtained from electron microscopy in the mouse corpus callosum (Sepehrband et al. 2015).”

• cites Sepehrband et al. 2015 sourceSupported

Demyelinated areas have extensive infiltration and amplification of cells that distort the normal tissue structure in the acute demyelination cuprizone model.

“It’s reported that demyelinated areas have extensive infiltration and amplification of cells that distort the normal tissue structure in acute demyelination cuprizone model (Aggarwal et al. 2012; Sun et al. 2006).”

• cites Aggarwal et al. 2012 sourceSupported
• cites Sun et al. 2006 sourceNot checked — no full text of the source

Both NODDI metrics are highest in cortical layer I.

“For example, both NODDI metrics are highest in layer I, which is a molecular layer enriched in the largely symmetrical apical dendritic tufts of cortical pyramidal neurons and the thalamocortical and cortico-cortical axons that innervate them, with only a sparsely distributed population of neuronal cell bodies.”

Modification of the fixed parameter Din in the NODDI model produced considerable systematic changes in the outcome metrics.

“Modification of the fixed parameters, Din, in the NODDI model produced considerable systematic changes in the outcome metrics”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.
• AssumptionRests on an assumption: Ex vivo diffusivities are significantly lower than in vivo measurements.

There is an apparent contrast change in the NDI images.

“However, there is an apparent contrast change in the NDI images.”

Higher resolution images show greater definition of laminar and sublaminar features in neuronal and molecular layers of the hippocampus.

“For example, ODI images in panels b and c show greater definition of laminar and sublaminar features in neuronal and molecular layers of the hippocampus (yellow arrows in Figure 2b).”

Subsampled NDI shows less deviations from pseudo ground-truth than ODI images.

“In general, subsampled NDI shows less deviations from pseudo ground-truth than ODI images (Figure 8k–r).”

Including higher b value helps compare ODI and fiber orientation distributions directly.

“Including higher b value also helps to compare the ODI and fiber orientation distributions directly (Figure 6), where more crossing fibers are found in higher ODI regions.”

Stratum lucidum of the hippocampus shows slightly higher NDI than the surrounding sublaminae.

“Stratum lucidum of the hippocampus (SLu), the track of the mossy fiber projections, shows slightly higher NDI than the surrounding sublaminae.”

The quantitative mappings from CS at 50 μm are visually comparable with the fully sampled results at 100 μm from NODDI models.

“The quantitative mappings from CS (right panels) are visually comparable with the FS results (left panels) from NODDI models”

Other brain regions show enrichments in ODI and/or NDI without obvious correlates in either LFB or NeuN histological preparations; these include the lateral nucleus of the amygdala, the hypothalamus, and certain nuclear divisions of the thalamus.

“Other brain regions show enrichments in ODI and/or NDI without obvious correlates in either the LFB or NeuN histological preparations; these include the lateral nucleus of the amygdala, the hypothalamus, and certain nuclear divisions of the thalamus.”

When Din is lower than 0.6, apparent artifacts are shown at hippocampus regions in both NDI and Viso images.

“When Din is lower than 0.6, apparent artifacts are shown at hippocampus regions in both NDI and Viso images.”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.
• AssumptionRests on an assumption: Ex vivo diffusivities are significantly lower than in vivo measurements.

Use of only 3 shells yields correspondence nearly comparable to that of the best selection of 4 shells.

“Finally, use of only 3 shells (figure 7e, 7k, 7q, 7v, 7aa) yields correspondence nearly comparable to that of best selection of 4 shells.”

Plots of correspondence using 4 shells with equally spaced b values (1000, 3000, 5000, 7000 s/mm2) demonstrate good agreements.

“In contrast, plots of correspondence using 4 shells (figure 7u and 7z) with equally spaced b values (1000, 3000, 5000, 7000 s/mm2), demonstrate good agreements.”

NDI and ODI images with more than 64 diffusion gradient directions are visually comparable to the pseudo ground-truth results.

“NDI and ODI images with more than 64 diffusion gradient directions are visually comparable to the pseudo ground-truth results.”

Cortical layer V displays higher values of ODI and NDI.

“Similarly, cortical layer V, which features a relatively low density of neuronal cell bodies and a high density of neuritic elements, displays higher values of ODI and NDI.”

NDI images show less dependence on angular resolution than ODI images.

“NDI images always shows less dependence on the angular resolution than ODI images (Figure 9k–l) and larger deviation is found with lower angular resolution (red arrows for external capsule, yellow arrows for neocortex).”

The contrast between the corpus callosum and surrounding GM is almost absent in the NDI image after 13 weeks cuprizone administration.

“The contrast between the corpus callosum and surrounding GM is almost absent in the NDI image after 13 weeks cuprizone administration.”

The NDI metric is particularly sensitive to microstructural variations in the corpus callosum in the cuprizone model of demyelination.

“Furthermore, we demonstrated that the NDI metric is particularly sensitive to microstructural variations in the corpus callosum in the cuprizone model of demyelination.”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.

The 3-shell (1000, 4000, 8000 s/mm2 with 48 DWIs in each shell) dataset yields correspondence nearly comparable to that of pseudo ground truth.

“The 3-shell (1000, 4000, 8000 s/mm2 with 48 DWIs in each shell) dataset yields correspondence nearly comparable to that of pseudo ground truth”

Significant artifacts are evident in both ODI and NDI in the external capsule and hippocampus when fitting with the 4 highest b value shells (5000, 6000, 7000, 8000 s/mm2).

“Significant artifacts are evident in both ODI and NDI in the external capsule and hippocampus in figure 7c and 7i, i.e. when fitting with the 4 highest b value shells (5000, 6000, 7000, 8000 s/mm2), probably due to less accurate estimation of the free water diffusivity derived from lower b values (figure 7o).”

Similar results are observed in different cortical areas.

“The similar results are observed in different cortical areas (Bregma 0.74 mm, supplemental figure 8).”

The fitting results are suboptimal with lower angular resolution.

“As one might expect, the fitting results are suboptimal with lower angular resolution.”

NDI shows lower values in the pyramidal cell layer of the hippocampus and the granule cell layer of the dentate gyrus, corresponding to higher neuron contents in NeuN images.

“NDI shows lower values in the pyramidal cell layer of the hippocampus (Py), the granule cell layer of the dentate gyrus in the hippocampus (GrDG), corresponding to higher neuron contents in NeuN images.”

Larger deviation is found with lower angular resolution, especially with only 48 diffusion gradient directions.

“Larger deviation is found with lower angular resolution, especially with only 48 diffusion gradient directions (Figure 8r).”

The layers of the neocortex show striking variation in both ODI and NDI images.

“In addition, the layers of the neocortex, which are evident in NeuN staining, show striking variation in both ODI and NDI images.”

Use of only 2 shells leads to a significant dispersion, particularly in the NDI.

“Use of only 2 shells (figure 7f and 7l) leads to a significant dispersion, particularly in the NDI.”

The fiber orientation in the corpus callosum is consistent regardless of cuprizone administration.

“The fiber orientation in the corpus callosum is consistent regardless of cuprizone administration (yellow arrows, Figure 11c, 11f, and 11i).”

The SNR at b of 8000 s/mm2 is about 12.9 at 50 μm isotropic resolution.

“The SNR at b of 8000 s/mm2 is about 12.9 at 50 μm isotropic resolution.”

When Din is larger than 1.0, the ODI values in some cortex region rise to 1.

“When Din is larger than 1.0, the ODI values in some cortex region rise to 1 (supplemental figures 4, 5).”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.
• AssumptionRests on an assumption: Ex vivo diffusivities are significantly lower than in vivo measurements.

NDI is sensitive to microstructural variations in the corpus callosum using a well-established demyelination cuprizone model.

“Furthermore, we found that NDI is sensitive to microstructural variations in the corpus callosum using a well-established demyelination cuprizone model.”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.

The ODI image highlights multiple discrete, high intensity features in the 50 μm image that are not resolved at 100 μm.

“Thus, the ODI image highlights multiple discrete, high intensity features in the 50 μm image that are not resolved at 100 μm.”

NDI and ODI images with 64 or higher diffusion gradient directions are visually comparable to the 3-shell dataset with 144 DWIs.

“NDI and ODI images with 64 or higher diffusion gradient directions are visually comparable to the 3-shell dataset with 144 DWIs.”

A protocol with three b values of 1000, 4000, and 8000 s/mm2 and angular sampling between 64 and 128 yields good agreement with the foundation set with reasonable scan time.

“By comparing combinations of b values and angular samples to the comprehensive scan (8 b values, 384 angular samples at 50 μm resolution) we can judiciously choose acquisition parameters (three b values of 1000, 4000, 8000 s/mm2, and angular sampling between 64–128) that yield good agreement with the foundation set with reasonable scan time.”

NDI is sensitive to microstructural white matter variations in the cuprizone model.

“The finding that NDI is sensitive to microstructural white matter variations in the cuprizone model also renders this technique useful for applications in mouse models of white matter disorders.”

There is good agreement between NDI and NeuN.

“In this study, the good agreement between NDI and NeuN suggests high resolution NODDI could be a biomarker for characterizing the microstructure in the brain.”

• AssumptionRests on an assumption: Major white matter tracts contain largely axons that are tightly bundled into compact parallel fascicles, corresponding to higher neurite density.
• AssumptionRests on an assumption: GrDG and Py have densely packed cell bodies with relatively low neuropil volume and therefore show low axon/dendrite density.

Heavy myelinated white matter bundles show lower ODI than the neocortex and hippocampus.

“The relative homogeneity of fiber alignment in heavy myelinated white matter bundles shows lower ODI than the neocortex and hippocampus, which demonstrates good agreement between LFB staining and ODI in these white matter structures.”

• AssumptionRests on an assumption: Major white matter tracts contain largely axons that are tightly bundled into compact parallel fascicles, corresponding to higher neurite density.

Significant demyelination was found in both acute and chronic stages of cuprizone treatment from LFB staining of myelin.

“Since significant demyelination was found in both acute and chronic stages of treatment from the evaluation of the LFB staining of myelin, the marked NDI variation in the corpus callosum may not only cause by the demyelination itself.”

There is good agreement between LFB staining and ODI in heavy myelinated white matter structures.

“The relative homogeneity of fiber alignment in heavy myelinated white matter bundles shows lower ODI than the neocortex and hippocampus, which demonstrates good agreement between LFB staining and ODI in these white matter structures.”

• AssumptionRests on an assumption: Major white matter tracts contain largely axons that are tightly bundled into compact parallel fascicles, corresponding to higher neurite density.

A 3-shell acquisition with 64 angular samples at 50 μm resolution can be completed in 24.7 hours.

“A 3-shell acquisition with 64 angular samples at 50 μm resolution can be completed in 24.7 hrs.”

The NODDI protocol demonstrated unique tissue contrasts in the mouse brain.

“The NODDI protocol demonstrated unique tissue contrasts in the mouse brain.”

The high values of ODI in cortical layer V presumably reflect the rich abundance and, on average, isotropic distribution of basal dendrites of the large pyramidal neurons characteristic of this cortical layer.

“The high values of ODI in cortical layer V presumably reflects the rich abundance and, on average, isotropic distribution of basal dendrites of the large pyramidal neurons that are a characteristic feature of this cortical layer.”

The good agreement between NDI and ODI with subsequent histochemical analysis of myelin and neuronal density highlights that NODDI could provide new insight into the microstructure of the brain.

“The good agreement between neurite density index (NDI) and the orientation dispersion index (ODI) with the subsequent histochemical analysis of myelin and neuronal density highlights that NODDI could provide new insight into the microstructure of the brain.”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.

Higher b value is useful for resolving crossing fibers in the central nervous system.

“In addition, higher b value is useful for resolving the crossing fibers in CNS (Vu et al. 2015).”

• cites Vu et al. 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A three-shell acquisition strategy covering low, medium, and high b values with at least angular resolution of 64 is essential for ex vivo NODDI experiments.

“A three-shell acquisition strategy covering low, medium, and high b values with at least angular resolution of 64 is essential for ex vivo NODDI experiments.”

• AssumptionThe authors state this as an assumption: The NODDI model assumes three types of microstructural environments: intra-neurite, extra-neurite, and CSF compartments.

The use of compressed sensing has allowed the authors to acquire a foundational dataset that can serve as a high resolution reference template.

“The use of compressed sensing has allowed us to acquire a foundational dataset that can be served as a high resolution reference template.”

• AssumptionRests on an assumption: NODDI metrics derived from high spatial and angular resolution diffusion MRI using the fixed mouse brain as a reference template have not yet been reported due in part to the extremely long scan time required.

The artifacts with the 4 highest b value shells are probably due to less accurate estimation of the free water diffusivity derived from lower b values.

“probably due to less accurate estimation of the free water diffusivity derived from lower b values (figure 7o).”

Extending NODDI to microscopic studies of cytoarchitecture and myeloarchitecture is challenging due to the relatively long scan time for high spatial resolution.

“Extending NODDI to microscopic studies of cytoarchitecture and myeloarchitecture are challenging due to the relatively long scan time for high spatial resolution (Kleinnijenhuis et al. 2013b; Crombe et al. 2018).”

• cites Kleinnijenhuis et al. 2013bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Crombe et al. 2018 sourceNot checked — no full text of the source

DTI metrics such as FA and MD may not be directly related to specific aspects of tissue structure because the DTI model does not consider hindered and restricted diffusion properties in tissue.

“However, these parameters may not be directly related to specific aspects of tissue structure because DTI model does not consider the hindered and restricted diffusion properties in the tissue (Zhang et al. 2012a; Basser et al. 1994).”

• cites Zhang et al. 2012a sourceNot checked — no full text of the source
• cites Basser et al. 1994 sourceNot checked — no full text of the source

Higher b value is useful for resolving the crossing fibers in CNS.

“In addition, higher b value is useful for resolving the crossing fibers in CNS (Vu et al. 2015).”

• cites Vu et al. 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

NODDI parameters reveal additional features that correspond with the appearance of demyelination evident in the LFB staining in the cuprizone treated animals.

“However, NODDI parameters reveal additional features that correspond with the appearance of demyelination evident in the LFB staining in the cuprizone treated animals.”

This relatively high SNR may improve the performance of the NODDI model.

“This relatively high SNR may improve the performance of the NODDI model.”

Use of 3 shells with equally spaced b values is a potential protocol for routine use.

“These last two points suggest that use of 3 shells with equally spaced b values as a potential protocol for routine use.”

The study acquired a foundation set that allowed systematic understanding of the tradeoff in number of shells, b value, and angular samples.

“We have acquired a foundation set that has allowed us to systematically understand the tradeoff in number of shells, b value, and angular samples.”

NDI variations are unlikely to be purely attributed to axon damage.

“Furthermore, it’s unlikely that the NDI variations in is purely attributed to axon damage, since the NDI is lower than the surrounding GM in acute demyelination (CUPZ5) but then elevates in chronic demyelination mice (CUPZ13).”

The main orientation/alignment of the diffusion tensor corresponds with the orientation of axons and dendrites in both neocortex and hippocampus.

“The main orientation/alignment of the diffusion tensor corresponds with the orientation of the axons and dendrites in both neocortex and hippocampus, which suggested that high resolution diffusion MRI holds the potential to detect intrinsic cortical architecture with high sensitivity (Assaf 2018).”

• cites Assaf 2018 sourceNot checked — no full text of the source

Marked NDI variation in the corpus callosum may not only be caused by demyelination itself.

“Since significant demyelination was found in both acute and chronic stages of treatment from the evaluation of the LFB staining of myelin, the marked NDI variation in the corpus callosum may not only cause by the demyelination itself.”

Swelling due to infiltration of immune cells in the cuprizone model may play an important role in the dramatic NDI decrease after 5 weeks cuprizone administration.

“This swelling due to infiltration of immune cells in the cuprizone model may play an important role for the dramatic NDI decrease after 5 weeks cuprizone administration.”

High resolution NODDI could be a biomarker for characterizing brain microstructure.

“In this study, the good agreement between NDI and NeuN suggests high resolution NODDI could be a biomarker for characterizing the microstructure in the brain.”

• AssumptionRests on an assumption: Major white matter tracts contain largely axons that are tightly bundled into compact parallel fascicles, corresponding to higher neurite density.
• AssumptionRests on an assumption: GrDG and Py have densely packed cell bodies with relatively low neuropil volume and therefore show low axon/dendrite density.

NDI is useful for applications in mouse models of white matter disorders.

“The finding that NDI is sensitive to microstructural white matter variations in the cuprizone model also renders this technique useful for applications in mouse models of white matter disorders.”

Subtle dynamics between 5 and 13 weeks cuprizone treatment could reflect microanatomical changes in the response of glial constituents and immune-related activity in the demyelinating corpus callosum.

“These subtle dynamics between 5 and 13 weeks cuprizone treatment could reflect microanatomical changes in the response of glial constituents (microgliosis and/or astrogliosis) and immune-related activity in the demyelinating corpus callosum.”

The dataset with 384 diffusion encoding gradients with 8 shells at 50 μm provides a pseudo ground truth.

“The dataset with 384 diffusion encoding gradients with 8 shells at 50 μm provides a pseudo ground truth, however, a relatively high-throughput protocol, derived from the analysis of this dataset including three b values and 64–128 angular samples may be applied for population studies.”

The study extended the spatial resolution in NODDI for whole mouse brain to 50 μm.

“To summarize, we have extended the spatial resolution in NODDI for whole mouse brain to 50 μm.”

High resolution diffusion MRI holds the potential to detect intrinsic cortical architecture with high sensitivity.

“The main orientation/alignment of the diffusion tensor corresponds with the orientation of the axons and dendrites in both neocortex and hippocampus, which suggested that high resolution diffusion MRI holds the potential to detect intrinsic cortical architecture with high sensitivity (Assaf 2018).”

• cites Assaf 2018 sourceNot checked — no full text of the source