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Cited by 284Advanced Neuroimaging Techniques and ApplicationsAdvanced MRI Techniques and ApplicationsFunctional Brain Connectivity Studies

NODDI in clinical research

Open access
Kamiya, Kouhei, Hori, Masaaki, Aoki, Shigeki·2020·Journal of Neuroscience Methods
DOI 10.1016/j.jneumeth.2020.108908
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Abstract

Diffusion MRI (dMRI) has proven to be a useful imaging approach for both clinical diagnosis and research investigating the microstructures of nervous tissues, and it has helped us to better understand the neurophysiological mechanisms of many diseases. Though diffusion tensor imaging (DTI) has long been the default tool to analyze dMRI data in clinical research, acquisition with stronger diffusion weightings beyond the DTI regimen is now possible with modern clinical scanners, potentially enabling even more detailed characterization of tissue microstructures. To take advantage of such data, neurite orientation dispersion and density imaging (NODDI) has been proposed as a way to relate the dMRI signal to tissue features via biophysically inspired modeling. The number of reports demonstrating the potential clinical utility of NODDI is rapidly increasing. At the same time, the pitfalls and limitations of NODDI, and general challenges in microstructure modeling, are becoming increasingly recognized by clinicians. dMRI microstructure modeling is a rapidly evolving field with great promise, where people from different scientific backgrounds, such as physics, medicine, biology, neuroscience, and statistics, are collaborating to build novel tools that contribute to improving human healthcare. Here, we review the applications of NODDI in clinical research and discuss future perspectives for investigations toward the implementation of dMRI microstructure imaging in clinical practice.

AI snapshot

Written from the paper’s full text.

TL;DR

NODDI is a three-compartment biophysical diffusion MRI model that estimates neurite density index (NDI), orientation dispersion index (ODI), and free water fraction, and this review surveys its clinical research applications across neurological and psychiatric diseases. It reports generally promising disease sensitivity and acceptable repeatability, but emphasizes unresolved model-specificity and validation limitations that keep NODDI short of routine clinical use.

Key findings

  • NODDI uses NDI/intra-neurite fraction, ODI (0 for perfectly aligned straight fibers, 1 for completely isotropic), and free water fraction; it has 5 free parameters, one fewer than DTI, and imposes constraints including fixed parallel diffusivity 1.7 µm²/ms and a tortuosity model.
  • Scan-rescan repeatability in brain is excellent for NDI and ODI, with intra-subject coefficients of variation mostly below 5%, comparable to DTI; free water fraction is less stable (10%–40% CoV). Field strength and scanner affect reproducibility.
  • Across diseases (Alzheimer’s, Parkinson’s, MS, ALS, epilepsy, ischemia, TBI, NF1, iNPH, schizophrenia, tumors, spondylotic myelopathy), NODDI often detects abnormalities more widespread than FA, e.g., reduced NDI in WM/lesions and variable ODI; however, findings are mixed and mostly cross-sectional.
  • NODDI is more specific than FA, and ODI correlates more strongly than FA with histological orientation dispersion, but specificity is only relative; the review concludes NODDI remains near the translational gap for clinical biomarker adoption.

Methods

  • Narrative review of clinical research applications of NODDI, including human studies and some preclinical/animal evidence, organized by disease and by development/aging.
  • No systematic search strategy, meta-analysis, or pooled quantitative synthesis is described in the text.
  • Main analysis is thematic synthesis of reported NODDI findings, model rationale, repeatability/reproducibility evidence, and future directions.

Limitations

  • The paper states that NODDI’s model assumptions remain debated: no consensus on compartment number; inter-compartmental exchange and non-Gaussian effects are neglected; fixed/constrained parameters can bias estimates; different constraints can change rankings; optimal fixed diffusivity may differ by age and tissue; parameter–pathology relationships are not one-to-one and pathologies coexist.
  • The paper states that most clinical studies are cross-sectional, single-center, and limited in sample size, making general conclusions about individual patient care difficult; clinical adoption requires technical, biological/clinical, and cost-effectiveness validation.
  • Evident from the text: this is a narrative review without a stated systematic search or meta-analysis, and many included findings are described as preliminary/proof-of-concept.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jneumeth.2020.108908

Cites

263 of 263 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

158 of 267 cited sources checked · 109 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    In patients with orthopedic trauma, increased f_fw and decreased NDI in WM are observed compared with controls at 2 weeks post-injury.

    “A longitudinal follow-up of patients with orthopedic trauma revealed increased f fw and decreased NDI in WM compared with controls at 2 weeks post-injury”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Palacios et al., 2018 source

      The Discussion identifies orthopedic trauma patients as the control group, not the group with these changes. It reports decreased NDI and increased free-water fraction (FISO) in patients with mTBI versus trauma controls at the early, 2-week time point. The supplied passages do not give page numbers. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    To achieve and prove specificity is extremely challenging.

    “Care is needed in the interpretation of results provided by these biophysical models, because to achieve and prove specificity is extremely challenging (for recent reviews, see (Jelescu and Budde, 2017;Novikov et al., 2018a); and Jelescu et al. in this special issue).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Jelescu and Budde, 2017 source
    • cites Novikov et al., 2018a

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

  • Premisecitation

    NDI of the parieto-occipital WM is correlated with visuospatial and visuoperceptual cognitive performance in young-onset Alzheimer's disease.

    “NDI of the parieto-occipital WM was also correlated with visuospatial and visuoperceptual cognitive performance, a marker of parietal cortex function.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Slattery et al., 2017 source
  • Premisecitation

    Field strength has significant effects on NODDI parameters.

    “However, as with DTI, care should be taken when comparing data from different scanners: field strength has significant effects on NODDI parameters (Chung et al., 2016;De Santis et al., 2019), and interscanner reproducibility has been shown to be lower than intra-scanner reproducibility, even at the same field strength (3 T) (Andica et al., 2019b).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Chung et al., 2016 source
    • cites De Santis et al., 2019 source

      The Statistical analysis section compares 3 T and 7 T protocols for the NODDI measures. Table 3 (DISCUSSION; page unavailable) reports a significant protocol effect for FR NODDI (p < 0.05), but not for ODI. The claim is therefore supported for one NODDI parameter, not NODDI parameters generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Several studies have reported non-monotonic behavior of dMRI metrics in relation to amyloid deposition in both GM and WM in human Alzheimer's disease, as well as in a rat model.

    “Several studies have reported non-monotonic behavior of dMRI metrics in relation to amyloid deposition in both GM (Montal et al., 2018) and WM (Dong et al., 2020;Wolf et al., 2015) in human Alzheimer's disease, as well as in a rat model of Alzheimer's disease (Fick et al., 2017).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Montal et al., 2018 source
    • cites Dong et al., 2020 source
    • cites Wolf et al., 2015 source
  • Classified as probably not a substantial claim. 52
  • May combine two claims. 73

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The fixed diffusivity assumption, but not the tortuosity model, is the primary cause of NODDI's incompatibility with b-tensor encoding.

    “A very recent report (Guerreri et al., 2020) suggested that the fixed diffusivity assumption, but not the tortuosity model, is the primary cause of NODDI's incompatibility with b-tensor encoding (Lampinen et al., 2017).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Guerreri et al., 2020
    • cites Lampinen et al., 2017 source

      Section 2.3 describes the fixed neurite diffusivity and the tortuosity model as linked NODDI constraints, not competing explanations. Sections 4.3 and 5 attribute the LTE–STE inconsistency to invalid constraints connecting neurite density with tissue mean diffusivity. The paper therefore does not support excluding tortuosity as a cause. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are two main approaches to extracting information from dMRI data: signal representations and biophysical models.

    “There are two main approaches to extracting information from dMRI data: signal representations and biophysical models (Jelescu and Budde, 2017;Jespersen, 2018;Novikov et al., 2018a).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Jelescu and Budde, 2017 source
    • cites Jespersen, 2018 source
    • cites Novikov et al., 2018a

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent years have seen a marked proliferation of biophysical models with the explicit aim of clinically feasible data acquisition.

    “Recent years have seen a marked proliferation of biophysical models with the explicit aim of clinically feasible data acquisition (single-diffusion encoding, b-values up to 2000-3000 s/mm 2 , diffusion time 20-100 ms) (Fieremans et al., 2011;Hansen et al., 2017;Kaden et al., 2016;Zhang et al., 2012).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Fieremans et al., 2011 source
    • cites Hansen et al., 2017 source
    • cites Kaden et al., 2016 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DTI has long been an important tool that has yielded many insights in a wide range of neurological and psychological disorders.

    “In clinical research, diffusion tensor imaging (DTI) (Basser et al., 1994) has long been an important tool that has yielded many insights in a wide range of neurological and psychological disorders (for recent reviews see (Andica et al., 2019a;Goveas et al., 2015;Pasternak et al., 2018).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Andica et al., 2019a

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

    • cites Goveas et al., 2015 source
    • cites Pasternak et al., 2018 source

      The Introduction reports DTI findings in schizophrenia, bipolar disorder, and major depressive disorder, supporting its value in psychiatric research. It says the review is limited to those conditions, so this source does not establish the claim about a wide range of neurological disorders. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Similar repeatability is reported in the cervical spinal cord, although a greater CoV for ODI and f_fw has been observed in GM.

    “Similar repeatability is also reported in the cervical spinal cord (By et al., 2017;Grussu et al., 2015;Ma et al., 2018), although a greater CoV for ODI and f fw has been observed in GM, reflecting the general challenges of dMRI in the spinal cord (e.g., small structure, magnetic field inhomogeneity, cerebrospinal fluid pulsation and physiological noise).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites By et al., 2017

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

    • cites Grussu et al., 2015 source
    • cites Ma et al., 2018

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

  • May combine two claims.

    Premisecitation

    f_fw is less stable than NDI and ODI, with a scan-rescan CoV of 10%-40%.

    “f fw is less stable than NDI and ODI, with a scan-rescan CoV of 10 %-40 % (Andica et al., 2019b;Chung et al., 2016;Granberg et al., 2017).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Andica et al., 2019b

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

    • cites Chung et al., 2016 source

      The Results (Within-Session Reproducibility; page unavailable) say that νiso, the free-water fraction, had the largest within-session CV, supporting its lower stability relative to NDI and ODI. The paper does not give a 10%–40% scan-rescan CV for νiso in the available text. The Discussion instead gives a 3.8%–40% range for between-subject NODDI CV and explicitly excludes νiso from that range. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Granberg et al., 2017 source

  • May combine two claims.

    Premisecitation

    In GM of patients with young-onset Alzheimer's disease, reductions of NDI and ODI were found in the temporal cortex and precuneus, and a smaller NDI in the cortex was associated with more severe cognitive impairment.

    “In the GM of patients with young-onset Alzheimer's disease, reductions of NDI and ODI were found in the temporal cortex and precuneus, and a smaller NDI in the cortex was associated with more severe cognitive impairment (Parker et al., 2018).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Parker et al., 2018 source

  • May combine two claims.

    Premisecitation

    Optimizing d_i based on fitting residual is helpful for revealing cortical cytoarchitecture with NODDI, though the method is still dependent on the assumption of equal diffusivities.

    “Several studies (Fukutomi et al., 2018;Genç et al., 2018) found optimizing d i, based on the fitting residual is helpful for re- vealing cortical cytoarchitecture with NODDI, though their method is still dependent on the assumption of equal diffusivities ( = d d i, e, ).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Fukutomi et al., 2018 source
    • cites Genç et al., 2018 source

      The Methods section (“Analysis of imaging data in the S259 sample”; page unavailable) says the authors adjusted NODDI’s intrinsic free-diffusivity parameter to 1.1 × 10−3 mm²/s for gray matter to analyze cortical structure. It does not say they selected that value by minimizing fitting residuals or state the claimed assumption of equal intra- and extra-neurite diffusivities. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In young-onset Alzheimer's disease, NDI is reduced in the parieto-occipital WM in both ε4+ and ε4- patients relative to controls, with the reduction more widespread in ε4+ patients.

    “With NODDI, (Slattery et al., 2017) reported reduced NDI in the parieto-occipital WM in both ε4+ and ε4-patients with young-onset Alzheimer's disease relative to controls, with the reduction more widespread in ε4+ patients.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Slattery et al., 2017 source

  • May combine two claims.

    Premisecitation

    Even within usual multi-shell acquisition (linear tensor encoding), the optimal value of d_i seems different between neonates and adults, as well as between white matter and gray matter.

    “Also, even within usual multi-shell acquisition (linear tensor encoding), the optimal value of d i, seems different between neonates and adults, as well as between white matter (WM) and gray matter (GM) (Guerrero et al., 2019).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Guerrero et al., 2019 source

  • May combine two claims.

    Premisecitation

    Extended acquisitions have been proposed toward unconstrained estimation of model parameters, but increased scan time hampers clinical application.

    “Though extended acquisitions have been proposed toward unconstrained estimation of the model parameters (Lampinen et al., 2020 et al., 2018b;Veraart et al., 2018), at present, the increased scan time hampers clinical application of these cutting-edge techniques.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Lampinen et al., 2020 source
    • cites Veraart et al., 2018 source

  • May combine two claims.

    Premisecitation

    NODDI has improved sensitivity over DTI in young-onset Alzheimer's disease, with parallel reductions of NDI and ODI in some WM regions that had no observable changes in FA.

    “(Slattery et al., 2017) also demonstrated improved sensitivity of NODDI over DTI, reporting parallel reductions of NDI and ODI in some WM regions that had no observable changes in FA.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Slattery et al., 2017 source

  • May combine two claims.

    Premisecitation

    The validity of NODDI's parameter constraints is a matter of debate, even in the normal brain, with several works pointing out incompatibility of NODDI with extended data acquisitions.

    “The validity of such constraints is a matter of debate, even in the normal brain, with several works (Lampinen et al., 2020(Lampinen et al., , 2017;;Novikov et al., 2018b) pointing out incompatibility of NODDI with extended data acquisitions.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Lampinen et al., 2020 source
    • cites Lampinen et al., 2017 source
    • cites Novikov et al., 2018b

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

  • May combine two claims.

    Premisecitation

    When applied to clinical studies, use of different constraints sometimes yields results that agree in relative trends, but such agreement is not always guaranteed and is not proof of validity.

    “When applied to clinical studies, the use of different constraints sometimes yields results that agree in their relative trends (Huber et al., 2019;Jelescu et al., 2015;Kamiya et al., 2017), but such agreement is not always guaranteed and is not proof of validity.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Huber et al., 2019 source

      The Results (Biological underpinnings of reading-diffusion correlations; page unavailable) report that measures from two models, NODDI and WMTI, both correlated with reading skill in children, supporting an example of agreement in relative trends. The paper does not establish that differing model constraints generally yield agreement across clinical studies. The caution after the citations is not clearly attributed to Huber et al. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Jelescu et al., 2015 source
    • cites Kamiya et al., 2017 source

  • May combine two claims.

    Premisecitation

    In a mouse model of tau pathology, NDI in WM and hippocampus was reduced, and NDI in GM was positively correlated with the level of hyperphosphorylated tau protein.

    “In a mouse model of tau pathology, NDI in WM and hippocampus was reduced, and NDI in GM was positively correlated with the level of hyperphosphorylated tau protein (Colgan et al., 2016).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Colgan et al., 2016 source

      The Results (Hippocampus and Corpus callosum; page unavailable) report lower NDI in the tau-model mice, supporting the reduction in hippocampus and white matter. The Results (Cortex and Hippocampus; page unavailable) report correlations between NDI and tau burden in grey matter, but do not establish the claimed positive direction; they report higher cortical NDI but lower hippocampal NDI in the model mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In temporal lobe epilepsy (TLE), NDI is reduced in the temporal lobes, with more prominent abnormalities in the hemisphere ipsilateral to the epileptogenic focus.

    “In temporal lobe epilepsy (TLE), the most common epilepsy in adults, reduction of NDI was found in the temporal lobes, with more prominent abnormalities in the hemisphere ipsilateral to the epileptogenic focus (Sone et al., 2018;Winston et al., 2020).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Sone et al., 2018 source
    • cites Winston et al., 2020 source

  • Classified as probably not a substantial claim.

    Premisecitation

    NDI maps yielded a clearer depiction of focal cortical dysplasia than other imaging approaches (T1-/T2-weighted images and DTI maps).

    “(Winston et al., 2014) reported that NDI maps yielded a clearer depiction of FCD than other imaging approaches (i.e., T1-/T2-weighted images and DTI maps).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Winston et al., 2014 source

  • May combine two claims.

    Premisecitation

    In postmortem human spinal cord, decreased ODI in MS lesions and excellent agreement between ODI and its histological counterpart were observed.

    “In postmortem human spinal cord, (Grussu et al., 2017) observed decreased ODI in MS lesions and an excellent agreement between ODI and its histological counterpart.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Grussu et al., 2017 source

  • May combine two claims.

    Premisecitation

    NODDI has potential usefulness for discriminating Parkinson's disease from other Parkinsonian disorders, with greater abnormalities in progressive supranuclear palsy and multiple system atrophy than in Parkinson's disease.

    “The potential usefulness of NODDI for discriminating Parkinson's disease from the other Parkinsonian disorders has also been suggested (Mitchell et al., 2019), with NODDI showing greater abnormalities in progressive supranuclear palsy and multiple system atrophy than in Parkinson's disease.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Mitchell et al., 2019 source

  • May combine two claims.

    Premisecitation

    Reduced NDI was seen in larger areas than FA in ALS, suggesting greater sensitivity of NODDI over DTI.

    “They also reported that reduced NDI was seen in larger areas than was FA, suggesting a greater sensitivity of NODDI over DTI, and that reduced ODI within the precentral gyrus was correlated with disease duration, presumably representing reduced dendritic density and branching.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Broad et al., 2019 source

  • May combine two claims.

    Premisecitation

    In MS, NDI in WM is reduced compared with healthy controls in MR-visible lesions, and to a lesser degree in normal-appearing WM, and NDI reveals more prominent and widespread abnormalities than FA.

    “These studies generally agree that NDI in WM is reduced compared with healthy controls in MR-visible lesions, and to a lesser degree in normal-appearing WM, and that NDI reveals more prominent and widespread abnormalities than FA (Fig. 4).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Collorone et al., 2019

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

    • cites De Santis et al., 2019 source

      The Effect size section reports reduced NODDI restricted fraction in MS lesions and normal-appearing white matter, while FA differences did not survive the post-hoc test. This supports the comparison with FA, but the claim is too broad across protocols: the NODDI difference in normal-appearing white matter was not significant at 7 T. The paper does not establish that the abnormalities were more widespread beyond the tissue regions it tested. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Granberg et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Because tractography, network analysis, and NODDI each have limitations, caution is required when interpreting NODDI connectomics data.

    “Tractography and network analysis both have their own limitations (Jeurissen et al., 2019;Sotiropoulos and Zalesky, 2019), which, in combination with the limitations of NODDI, means that caution is required when interpreting the data.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Jeurissen et al., 2019 source
    • cites Sotiropoulos and Zalesky, 2019 source

  • May combine two claims.

    Premisecitation

    Tuberous sclerosis patients exhibited smaller NDI compared with controls throughout the WM, although no correlation was observed with severity of mental retardation or epilepsy.

    “The tuberous sclerosis patients also exhibited smaller NDI compared with controls throughout the WM, although no correlation was observed with severity of mental retardation or epilepsy.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Taoka et al., 2020 source

      The Results (Quantitative analysis; page unavailable) report reduced Ficv, a measure of neurite density, across widespread white-matter regions—not throughout all white matter. The Results (Correlations of clinical symptoms; page unavailable) found no statistically significant correlations with mental retardation or epilepsy, although the Discussion describes slight associations with mental-retardation severity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NDI in the CST distal to a stroke lesion is not different from the contralateral side in the subacute phase and is decreased in the chronic phase.

    “NDI in this region was not different from the contralateral side in the subacute phase, and was decreased in the chronic phase, presumably representing the course of Wallerian degeneration (Mastropietro et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Mastropietro et al., 2019 source

  • May combine two claims.

    Premisecitation

    Reduced NDI is observed in TLE patients with no structural MRI abnormalities, though to a lesser extent than in MRI-positive TLE.

    “Notably, (Sone et al., 2018) observed reduced NDI in patients with TLE in whom experienced radiologists did not find abnormalities on structural MRI, albeit to a lesser extent than in patients with MRI-positive TLE (Fig. 5).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sone et al., 2018 source

  • May combine two claims.

    Premisecitation

    Increased f_fw in the substantia nigra was observed by Mitchell et al. 2019 but not by Kamagata et al. 2016.

    “In addition, increased f fw in the substantia nigra, which is consistent with accumulated evidence (Burciu et al., 2017(Burciu et al., , 2016) ) from free water imaging (Pasternak et al., 2009), was observed by (Mitchell et al., 2019) but not by (Kamagata et al., 2016).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Mitchell et al., 2019 source
    • cites Kamagata et al., 2016 source

  • May combine two claims.

    Premisecitation

    In athletes at 9-120 months after their last concussion, increased NDI and decreased ODI are observed compared with controls.

    “Interestingly, a study of the long-term effects of sports-related concussion reported increased NDI and decreased ODI in athletes at 9-120 months after their last concussion compared with controls”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Churchill et al., 2017 source

  • May combine two claims.

    Premisecitation

    In moyamoya disease, NODDI parameters in GM and WM are correlated with hemodynamic activities measured by 15O-gas PET and with neurocognitive dysfunction.

    “In patients with moyamoya disease, a disease characterized by progressive occlusion of the circle of Willis, NODDI parameters in GM and WM were correlated with hemodynamic activities measured with 15 O-gas positron-emission tomography, as well as neurocognitive dysfunction”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hara et al., 2019 source
    • cites Hara et al., 2018 source

      The Conclusions (page unavailable) report a correlation between NODDI and neuropsychological performance in adult moyamoya disease, and describe white-matter and cortical NODDI differences. The Statistical Analysis section (page unavailable) describes correlations with cognitive scores, but our copy does not report a correlation between NODDI parameters and hemodynamic activity measured by 15O-gas PET. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    After surgery for idiopathic normal pressure hydrocephalus, the orientation parameter shows partial normalization, whereas the reduced axonal water fraction remains unchanged.

    “After surgery, the orientation parameter showed partial normalization, whereas the reduced axonal water fraction remained unchanged (Kamiya et al., 2017) (Fig. 7).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kamiya et al., 2017 source

  • May combine two claims.

    Premisecitation

    Individuals with a history of TBI are at higher risk for dementia, neurodegenerative diseases, psychiatric illness, and mortality, indicating long-term progression of sub-clinical pathology that manifests in late adulthood.

    “Furthermore, individuals with a history of TBI are at higher risk for dementia, neurodegenerative diseases, psychiatric illness, and even mortality, indicating long-term progression of sub-clinical pathology that manifests only in late adulthood (Smith et al., 2013;Wilson et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Smith et al., 2013 source

      The Introduction and “Single TBI” section support increased risk of later dementia and neurodegenerative disease, particularly after moderate to severe TBI. “Repetitive mild TBI” reports neuropsychiatric symptoms in selected cases and higher neurodegenerative mortality in former NFL players, but does not establish a general increased risk of psychiatric illness or mortality for everyone with a TBI history. The “Histological features” section also describes pathology appearing within hours of injury, so the claim that it manifests only in late adulthood is not supported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Wilson et al., 2017 source

      The sections on neurodegenerative disease after single TBI and stroke and other neurological disorders after TBI report links with dementia, neurodegenerative disease, and neuropsychiatric illness; the Conclusions and future directions report higher mortality. But the paper does not establish that these outcomes all result from sub-clinical pathology manifesting only in late adulthood: it describes that mechanism as a possibility and also reports young-onset dementia and elevated mortality in younger people. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The degree of post-operative improvement in idiopathic normal pressure hydrocephalus varies greatly among individuals, and quantitative metrics capable of predicting treatment response have been sought.

    “The degree of post-operative improvement varies greatly among individuals, and therefore quantitative metrics capable of predicting treatment response have been sought (Halperin et al., 2015).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Halperin et al., 2015 source

  • May combine two claims.

    Premisecitation

    In neurofibromatosis type 1, no significant differences are observed for ODI, f_fw, myelin water fraction, or intra- or extra-neurite water fraction.

    “No significant differences were observed for ODI, f fw , myelin water fraction, or intra-or extra-neurite water fraction.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Billiet et al., 2014 source

      The dMRI Results report no significant differences in ODI or isotropic fluid fraction (FISO), and the multi-exponential T2 Results report none in myelin water fraction or combined intra- and extracellular water fraction (IEWF). The comparison is specifically between unidentified bright objects and normal-appearing white matter in children with NF1. The paper does not report separate intra- or extra-neurite water fractions; calling its combined IEWF measure those fractions is not supported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    With NODDI, axonal water fraction and orientation dispersion are both smaller within the CST of patients with idiopathic normal pressure hydrocephalus.

    “With NODDI, axonal water fraction and orientation dispersion were both smaller within the CST of patients”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kamiya et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depending on anatomical location, UBOs may be associated with cognitive deficits in neurofibromatosis type 1.

    “Studies have suggested that, depending on their anatomical location (e.g., thalamus), UBOs may be associated with cognitive deficits (Hyman et al., 2007;Moore et al., 1996).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Hyman et al., 2007 source
    • cites Moore et al., 1996 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The observed NDI increase during interferon alpha therapy has been interpreted as representing the inflammatory process.

    “the observed NDI increase has been interpreted as representing the inflammatory process.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Haroon et al., 2014 source

      The Abstract and Discussion report increased glutamate measured as Glu/Cr during IFN-alpha treatment and discuss possible inflammatory mechanisms. Our copy does not report an NDI increase or interpret NDI as representing inflammation (searched: NDI, neurite density index). (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Capuron et al., 2007 source

  • May combine two claims.

    Premisecitation

    In WM, NDI has a positive correlation with age, but the increase is non-linear and more rapid during early life.

    “In WM, NDI has a positive correlation with age, but the increase is non-linear and more rapid during early life (Dean et al., 2016;Jelescu et al., 2015;Lynch et al., 2020) (Fig. 9B).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Dean et al., 2016 source
    • cites Jelescu et al., 2015 source
    • cites Lynch et al., 2020 source

  • May combine two claims.

    Premisecitation

    DTI has consistently shown reduced FA in the compressed spinal cord, but the correlation of FA with symptoms and postoperative recovery remains controversial.

    “Although DTI has consistently shown reduced FA in the compressed spinal cord, the correlation of FA with symptoms and postoperative recovery remains controversial (Jones et al., 2013;Rajasekaran et al., 2017).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Jones et al., 2013 source

      The Correlation with Initial Clinical Assessment Scores section reports lower FA with poorer neurologic function in patients with cervical spondylotic myelopathy. The Relation to Surgical Outcome section reports an association between baseline FA and improvement on one postoperative measure, but not on the Nurick or mJOA scales; the Conclusions call the results preliminary. This supports uncertainty about postoperative prediction, but the paper does not establish that correlations with symptoms and recovery are broadly controversial or that reduced FA has been shown consistently across studies. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Rajasekaran et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Higher intelligence in healthy young to middle-aged individuals is associated with lower cortical ODI.

    “However, (Genç et al., 2018) have reported that higher intelligence in healthy young to middle-aged individuals was associated with lower cortical ODI”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Genç et al., 2018 source

  • May combine two claims.

    Premisecitation

    Reduced ODI in the frontal cortices and increased ODI in the parietal cortices and striatum are reported in young-adult binge drinkers.

    “Reduced ODI in the frontal cortices and increased ODI in the parietal cortices and the striatum have been reported from a study in young-adult binge drinkers (Morris et al., 2018).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Morris et al., 2018 source

  • May combine two claims.

    Premisecitation

    Lower NDI in WM is associated with poorer mathematics performance but not with reading performance across children born very preterm and full term.

    “Another study found that lower NDI in WM was associated with poorer mathematics performance-but not with reading performance-across children born very preterm and full term (Collins et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Collins et al., 2019 source

  • May combine two claims.

    Premisecitation

    In patients receiving interferon alpha treatment with confirmed inflammatory cytokine response, ODI remained unchanged although NDI was increased.

    “For example, in patients receiving interferon alpha treatment in whom an inflammatory cytokine response was confirmed by blood test, ODI remained unchanged, although NDI was increased (Dowell et al., 2019).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Dowell et al., 2019 source

      The Results sections on inflammatory cytokine response and acute NODDI effects report a blood-measured cytokine response and no significant change in ODI. However, they also report no significant increase in NDI after IFN-α; most of the listed NDI means were slightly lower at 4 hours. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Infants with congenital heart disease exhibit smaller NDI and greater ODI in WM compared with controls, as well as smaller ODI in cortical GM.

    “Compared with controls, infants with congenital heart disease exhibited smaller NDI and greater ODI in WM (Karmacharya et al., 2018), as well as smaller ODI in cortical GM (Kelly et al., 2019)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Karmacharya et al., 2018 source
    • cites Kelly et al., 2019 source

  • May combine two claims.

    Premisecitation

    Both lower NDI and greater ODI are correlated with poorer neurodevelopmental outcomes.

    “Both lower NDI and greater ODI were correlated with poorer neurodevelopmental outcomes (Kelly et al., 2016;Mürner-Lavanchy et al., 2018;Young et al., 2019).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Kelly et al., 2016 source
    • cites Mürner-Lavanchy et al., 2018 source
    • cites Young et al., 2019 source

      The Discussion reports that, among children born very preterm, lower NDI was associated with poorer intelligence and visuomotor skills, but intelligence was associated with NDI rather than ODI. Greater ODI was associated with lower intellectual scores in the full-term group; in that group, higher—not lower—NDI was also associated with lower scores. The claim combines associations observed in different groups as though both applied together. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The default fixed diffusivity value of 1.7 μm2/ms is likely suboptimal for neonatal brain and GM, and the age-dependence of NDI and ODI is affected by the choice of fixed diffusivity value.

    “Focusing on the fixed diffusivity assumption, (Guerrero et al., 2019) have suggested that the default value of 1.7 μm 2 /ms is likely suboptimal for neonates brain and GM, and that the age-dependence of NDI and ODI is affected by the choice of fixed diffusivity value.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Guerrero et al., 2019 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chronic neuroinflammation plays a major role in neurodegeneration that occurs in aging and in a broad range of diseases including Alzheimer's disease, Parkinson's disease, MS, ALS, stroke, TBI, and psychiatric diseases.

    “Accumulating evidence suggests a major role of chronic neuroinflammation in the neurodegeneration that occurs in aging and in a broad range of diseases including Alzheimer's disease, Parkinson's disease, MS, ALS, stroke, TBI, and psychiatric diseases (Amor et al., 2010;Glass et al., 2010;Vikhreva et al., 2016).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Amor et al., 2010 source

      The Abstract and Conclusions describe chronic immune activation as a feature of many neurodegenerative diseases, and the paper discusses the listed neurological conditions, including ALS. The Introduction mentions an aging population but does not establish a role for chronic neuroinflammation in neurodegeneration caused by aging; the passages found also do not address psychiatric diseases. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Glass et al., 2010 source

      The Introduction and Conclusion support a role for sustained neuroinflammation in the progression of Alzheimer’s, Parkinson’s, ALS, and MS, while noting that inflammation may amplify pathology rather than initiate disease. The Alzheimer’s Disease section identifies AD as age-related, but the cited passages do not establish the broader claim about neurodegeneration in aging, stroke, traumatic brain injury, or psychiatric diseases. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Vikhreva et al., 2016 source

  • May combine two claims.

    Premisecitation

    T2s are likely different among compartments and are affected by pathologies like neuroinflammation, demyelination, and intramyelinic edema.

    “For example, T2s are likely different among compartments (Lampinen et al., 2020;Veraart et al., 2018) and are affected by pathologies like neuroinflammation (Stanisz et al., 2004), demyelination (Bartzokis, 2004;Lin et al., 2018), and intramyelinic edema (Harkins et al., 2013).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Lampinen et al., 2020 source
    • cites Veraart et al., 2018 source
    • cites Stanisz et al., 2004 source

  • May combine two claims.

    Interpretationcitation

    The negative correlation between NDI in posterior callosal connections and reading skill is in line with studies reporting higher FA in this region in individuals with reading difficulties and with the hypothesis that left lateralization of reading-related functions is diminished in struggling readers.

    “Although the negative correlation may look counterintuitive, it is in line with a number of studies reporting higher FA within this region in individuals with reading difficulties and the hypothesis that left lateralization of reading-related functions is diminished in struggling readers (Dougherty et al., 2007;Finn et al., 2014).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Dougherty et al., 2007 source
    • cites Finn et al., 2014 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For translation into the clinic, an imaging biomarker needs to pass multiple steps in three parallel tracks: technical validation, biological/clinical validation, and cost-effectiveness.

    “For translation into the clinic, an imaging biomarker needs to pass multiple steps in three parallel tracks: technical validation (precision, accuracy, and realizability), biological/clinical validation (performance in measuring relevant biological properties or predicting clinical outcomes), and cost-effectiveness (Connor et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Connor et al., 2017 source

  • May combine two claims.

    Premisecitation

    Cortical development between 25 and 38 weeks is dominated by an increase of ODI, whereas between 38 and 47 weeks it is dominated by an increase of NDI.

    “Later, (Batalle et al., 2019) reported that cortical development between 25 and 38 weeks is dominated by an increase of ODI, whereas between 38 and 47 weeks it is dominated by an increase of NDI”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Batalle et al., 2019 source

  • May combine two claims.

    Premisecitation

    Preliminary applications of NODDI and the g-ratio framework include studies of brain maturation during childhood, effects of age and gender in young-to-late adulthood, and effects of diseases like MS and cervical spondylotic myelopathy.

    “Preliminary applications of NODDI and the g-ratio framework include studies of brain maturation during childhood (Dean et al., 2016;Geeraert et al., 2019), the effects of age and gender in young-to-late adulthood (Berman et al., 2018;Cercignani et al., 2017;Slater et al., 2019), and the effects of diseases like MS (Hagiwara et al., 2019;Stikov et al., 2015;Yu et al., 2019) and cervical spondylotic”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Dean et al., 2016 source
    • cites Geeraert et al., 2019 source
    • cites Berman et al., 2018 source

  • May combine two claims.

    Premisecitation

    A few studies have adopted multi-parameter analysis with NODDI, although most have been limited to combinations with other dMRI measures.

    “A few studies have adopted this type of multi-parameter analysis with NODDI (Andica et al., 2020;Churchill et al., 2019Churchill et al., , 2017)), although most have been limited to combinations with other dMRI measures.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Andica et al., 2020 source

      The Methods (Linked independent component analysis) confirm that this study combined NODDI with DTI and VBM measures in a multi-parameter analysis. Because VBM measures white-matter volume, this study was not limited to other dMRI measures; the cited paper also does not establish that most such studies were so limited. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Churchill et al., 2019 source
    • cites Churchill et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several groups have investigated the use of MRI g-ratio as weights in connectomics studies.

    “Several groups have been even more ambitious and have investigated the use of MRI g-ratio as weights in connectomics studies (Kamagata et al., 2019;Mancini et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Kamagata et al., 2019 source
    • cites Mancini et al., 2018 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One rapidly growing field is joint modeling of diffusion and relaxation.

    “One rapidly growing field is joint modeling of diffusion and relaxation (Gong et al., 2020;Lampinen et al., 2020;Veraart et al., 2018) (see also Hutter et al. in this special issue).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Gong et al., 2020 source
    • cites Lampinen et al., 2020 source
    • cites Veraart et al., 2018 source

  • May combine two claims.

    Findingnone given

    Most disease studies of NODDI reported to date have been cross-sectional and have included a limited sample size from a single center.

    “As with other advanced imaging techniques, most of the disease studies reported to date have been cross-sectional and have included a sample of limited size from a single center.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Biophysical models aim at specificity by parametrizing the dMRI signal as a function of biophysically meaningful parameters.

    “In contrast, biophysical models aim at specificity by parametrizing the dMRI signal as a function of biophysically meaningful parameters (e.g., axon density).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    There are two main reasons for introducing a new imaging technique to the study of a disease: to improve sensitivity to target pathologies and to provide better explanations for observed abnormalities.

    “There are two main reasons for introducing a new imaging technique to the study of a disease: to improve sensitivity to target pathologies and to provide better explanations for observed abnormalities.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Models are often based on assumptions that are not yet proven even in the normal brain.

    “As the models are often based on assumptions that are not yet proven even in the normal brain, users must be aware of the risk of being misled in their interpretations of the data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The validity of model assumptions is currently under debate.

    “The validity of model assumptions is currently under debate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The signal representation approach aligns with improving sensitivity to target pathologies, with the caveat that it comes with no obvious biological interpretation.

    “The signal representation approach aligns with the first reason, to improve sensitivity to target pathologies, with the caveat that this approach comes with no obvious biological interpretation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    NODDI has been proposed as a way to relate the dMRI signal to tissue features via biophysically inspired modeling.

    “neurite orientation dispersion and density imaging (NODDI) has been proposed as a way to relate the dMRI signal to tissue features via biophysically inspired modeling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2012 source

  • May combine two claims.

    Premisecitation

    In Parkinson's disease, reduced NDI and ODI have been observed in the substantia nigra and putamen compared with controls, and these reductions were predominant on the contralateral side.

    “With NODDI, reduced NDI and ODI have been observed in the substantia nigra and putamen of patients with Parkinson's disease compared with controls, and these reductions were predominant on the side corresponding to symptoms (contralateral) (Kamagata et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kamagata et al., 2016 source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Research to investigate the clinical usefulness of NODDI can still be justified despite remaining ambiguity about model assumptions.

    “Despite the remaining ambiguity about model assumptions, research to investigate the clinical usefulness of NODDI can still be justified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    NODDI may provide useful biomarkers if the effect of disease is far greater than the bias introduced by the constraints.

    “NODDI may provide useful biomarkers if the effect of disease is far greater than the bias introduced by the constraints.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    As the one true model has not been identified, results of NODDI, and any other model, are more or less phenomenological fit parameters that probably represent mixes of microstructural features rather than unambiguous quantifications of specific tissue properties.

    “As the one true model has not been identified, results of NODDI, and any other model, are more or less phenomenological fit parameters that probably represent mixes of microstructural features rather than unambiguous quantifications of specific tissue properties.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The debates on specificity and model validity have caused confusion among clinicians who are not familiar with modeling.

    “The debates on specificity and model validity have caused confusion among clinicians who are not familiar with the art of modeling and who wonder whether it is okay to use NODDI in their research.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Usual multi-shell dMRI data has limited information that allows estimation of only a handful of parameters.

    “Important to note is that usual multi-shell dMRI data has limited information that allows estimation of only a handful of parameters.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    NODDI has 5 free parameters (NDI, ODI, f_fw, and polar and azimuthal angles of the principal direction of the bundle), which is one less than DTI.

    “With regard to the degree of freedom, NODDI has 5 free parameters (NDI, ODI, f fw , and polar and azimuthal angles of the principal direction of the bundle), which is one less than DTI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The range of pathologies may be too diverse to be adequately captured with a single model, and models need to be validated in the target disease, not only in the healthy state.

    “The range of pathologies may be too diverse to be adequately captured with a single model, and models need to be validated in the target disease, not only in the healthy state.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Apparent diffusion coefficient is a mix of a multitude of microstructural effects.

    “Remember, apparent diffusion coefficient, virtually the only dMRI metric that has gained a presence in clinical practice, is a mix of a multitude of microstructural effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Relationships between model parameters and pathologies (e.g., atrophy and loss of axons, demyelination, microglial activation) are not one-to-one, and different pathologies tend to coexist rather than occur in isolation.

    “Besides, the relationships between the model parameters and pathologies (e.g., atrophy and loss of axons, demyelination, microglial activation) are not one-to-one, and in reality different pathologies tend to coexist rather than occur in isolation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a study of mild cognitive impairment, the mild cognitive impairment group had relatively greater ODI and smaller NDI than controls, although DTI was more sensitive to the group differences.

    “In a study of mild cognitive impairment, the mild cognitive impairment group had relatively greater ODI and smaller NDI than controls, although DTI was more sensitive to the group differences (Q.Wen et al., 2019b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Q.Wen et al., 2019b

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

  • May combine two claims.

    Premisecitation

    In a comparison of healthy controls, mild cognitive impairment, and Alzheimer's disease, NDI was the most sensitive to group differences, and NDI, ODI, and f_fw were all correlated with cognitive score.

    “Another study, which compared healthy controls, subjects with mild cognitive impairment, and patients with Alzheimer's disease, reported that NDI was the most sensitive to group differences, and that NDI, ODI, and f fw were all correlated with cognitive score (Fu et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fu et al., 2019

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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Dependence on assumptions applies to all proposed biophysical models and does not necessarily undermine the value of NODDI.

    “We also emphasize dependence on assumptions applies to all of the proposed biophysical models and does not necessarily undermine the value of NODDI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most widespread and successful clinical application of dMRI to date is the detection of acute ischemic infarction.

    “The most widespread and successful clinical application of dMRI to date is the detection of acute ischemic infarction (Moseley et al., 1990).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moseley et al., 1990 source

  • May combine two claims.

    Premisecitation

    A weak negative correlation between NDI and dendritic markers was found, which is counter-intuitive to the name 'neurite density index'.

    “In addition, this work found a weak negative correlation between NDI and dendritic markers, which is counter-intuitive to the name 'neurite density index'.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crombe et al., 2018 source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    There is an argument that the focal cortical dysplasias presented in Winston et al. 2014 and Rostampour et al. 2018 are readily detectable on conventional T1-/T2-weighted images.

    “Yet, there is an argument that those FCDs presented in (Winston et al., 2014) and (Rostampour et al., 2018) are readily detectable on conventional T1-/T2-weighted images (Chougar et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chougar et al., 2018 source

  • May combine two claims.

    Premisecitation

    Idiopathic normal pressure hydrocephalus is primarily a disorder of cerebrospinal fluid dynamics that leads to cerebral dyshomeostasis, hypoperfusion, and hypometabolism.

    “In addition, iNPH is primarily a disorder of cerebrospinal fluid dynamics that leads to cerebral dyshomeostasis, hypoperfusion, and hypometabolism (Bräutigam et al., 2019)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bräutigam et al., 2019 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Volume reduction and abnormal activation of the left superior temporal gyrus are associated with auditory hallucination in schizophrenia.

    “volume reduction and abnormal activation of the left superior temporal gyrus are reported to be associated with auditory hallucination in schizophrenia (Allen et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Allen et al., 2007 source

  • May combine two claims.

    Premisecitation

    In athletes with concussion, reduced NDI in WM is present in the early symptomatic phase and persists at return-to-play.

    “A longitudinal study in athletes with concussion (Churchill et al., 2019) showed reduced NDI in WM in the early symptomatic phase of injury, and this decrease persisted at the time of return-to-play.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Churchill et al., 2019 source

  • May combine two claims.

    Premisecitation

    In athletes with concussion, increased ODI and decreased FA are observed at both the early symptomatic phase and return-to-play.

    “In addition, increased ODI as well as decreased FA were also observed at both the early symptomatic phase and return-to-play.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Churchill et al., 2019 source

  • May combine two claims.

    Interpretationreasoning

    Despite concerns about model assumptions in the acute phase, NODDI has shown the ability to track brain alterations caused by ischemia and may be useful for predicting chronic disabilities.

    “Overall, despite the issue of the validity of the model assumptions, especially in the acute phase, NODDI has shown the ability to track brain alterations caused by ischemia and it may be a potentially useful means of predicting chronic disabilities.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In schizophrenia, axon disruption with concurrent reduced myelin levels and oligodendrocyte abnormalities has been postulated as a key pathology based on imaging and postmortem studies.

    “In schizophrenia, a severe mental illness characterized by positive (e.g., hallucinations and delusions) and negative (e.g., anhedonia and flat affect) symptoms, axon disruption with concurrent reduced myelin levels and oligodendrocyte abnormalities has been postulated as a key pathology based on both imaging and postmortem studies (Davis et al., 2003;Vikhreva et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Davis et al., 2003 source
    • cites Vikhreva et al., 2016 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Reported results and hypothetical interpretations of NODDI in TBI indicate the need to account for variabilities in time after injury, injury biomechanics, and individual pre-injury baseline.

    “Overall, the reported results and hypothetical interpretations of NODDI in TBI indicate the need to account for variabilities in time after injury, injury biomechanics, and individual pre-injury baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some damaged axons recover with remyelination, whereas others progress to irreversible axonal fragmentation and disconnection.

    “Some damaged axons show recovery with remyelination, whereas others progress into the irreversible stage characterized by axonal fragmentation and disconnection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Armstrong et al., 2016 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In idiopathic normal pressure hydrocephalus, neurodegeneration is thought to be a consequence rather than a pathogenetic factor, and it remains uncertain to what degree neurodegeneration explains symptoms.

    “therefore, neurodegeneration is thought to be a consequence rather than a pathogenetic factor, and it remains uncertain as to what degree neurodegeneration explains the symptoms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bräutigam et al., 2019 source

  • May combine two claims.

    Premisecitation

    In a longitudinal follow-up, NDI recovers to values comparable with the non-compressed level at 6 months after surgery, with concurrent recovery of neurological score.

    “In a longitudinal follow-up, NDI recovered to values comparable with the non-compressed level at 6 months after surgery, with concurrent recovery of neurological score (Iwama et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Iwama et al., 2020 source

  • May combine two claims.

    Premisecitation

    Gliomas and metastases tend to exhibit a higher extra-neurite fraction and a higher f_fw, respectively.

    “with gliomas and metastases tending to exhibit a higher extra-neurite fraction and a higher f fw , respectively (Fig. 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Caverzasi et al., 2016 source
    • cites Kadota et al., 2018

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

  • May combine two claims.

    Premisecitation

    NODDI reveals regional variation in WM maturation, consistent with known asynchrony of myelination and fiber development; maturation generally proceeds from posterior to anterior, and primary motor and sensory regions develop earlier than higher-order areas.

    “NODDI has also revealed a regional variation in WM maturation, which is consistent with the known asynchrony of myelination and fiber development; maturation generally proceeds from posterior to anterior, and primary motor and sensory regions develop earlier than areas of higher order functions (Brody et al., 1987;Yakolev and Lecours, 1967).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brody et al., 1987 source
    • cites Yakolev and Lecours, 1967

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

  • May combine two claims.

    Interpretationnone given

    Application of NODDI in clinical research has mostly reported promising results that dMRI biophysical models can be potentially useful for improving patient stratification and prediction of neurological functions.

    “Application of NODDI in clinical research has mostly reported promising results that dMRI biophysical models can be potentially useful for improving patient stratification and prediction of neurological functions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    The clinical value of NODDI needs to be evaluated in comparison with more accessible measures other than dMRI, with critical consideration given to cost effectiveness.

    “In addition, the clinical value of NODDI needs to be evaluated in comparison with more accessible measures other than dMRI, with critical consideration given to cost effectiveness (Rao and Levin, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rao and Levin, 2012 source

  • May combine two claims.

    Premisereasoning

    NODDI is a simplified model but is already complex compared with the current clinical standard, apparent diffusion coefficient.

    “Although NODDI is a simplified model, it is already complex compared with the current clinical standard, apparent diffusion coefficient which is simply the average of diffusivities measured along three orthogonal axes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    In the vast majority of NODDI clinical studies, disease-related effects were in directions that are biologically plausible, although this does not assure specificity to tissue pathology.

    “In the vast majority of studies, disease-related effects were in directions that are biologically plausible, although this does not assure specificity to the tissue pathology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Even if the NODDI model is correct, assigning a certain cellular structure to a certain compartment is somewhat ambiguous.

    “After all, even if the model was correct, assigning a certain cellular structure to a certain compartment is somewhat ambiguous.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Because dMRI parameters are indirect measures of tissue features and the underlying microstructure can only be speculated, hard-thinking about possible confounding effects is always required to interpret model parameters.

    “Because dMRI parameters are indirect measures of tissue features and the underlying microstructure can only be speculated, hard-thinking about possible confounding effects is always required to interpret model parameters.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Impaired recognition of facial emotion expression in persons with autism spectrum disorder is linked with reduced NDI and ODI in the corpus callosum and cortical regions associated with viewing of a human face.

    “Recently, impaired recognition of facial emotion expression in persons with autism spectrum disorder was reported to be linked with reduced NDI and ODI in the corpus callosum and cortical regions associated with viewing of a human face (Yasuno et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yasuno et al., 2020 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Even if an imaging tool does not pass all criteria to become part of clinical routine, evidence accumulated during technical and biological/clinical validation can still show its usefulness in basic research.

    “It is important to note, however, that even if an imaging tool does not pass all the criteria to become part of clinical routine, the evidence accumulated during technical and biological/clinical validation can still show the usefulness of the tool in the basic research setting.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    NODDI needs to be compared with representations that suffice to explain the data, such as DKI.

    “Therefore, NODDI needs to be compared with the representations that suffice to explain the data, such as DKI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In preterm infants, between soon after birth and term-equivalent age, ODI increases in the cortex and NDI increases in the thalamus.

    “In GM, (Eaton-Rosen et al., 2015) compared two time-points in infants born preterm (soon after birth and at term-equivalent age) and observed an increase of ODI in the cortex and an increase of NDI in the thalamus during the two time-points.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Eaton-Rosen et al., 2015 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ODI may be sensitive to microglial density due to increased occupancy in the extra-neurite space, and therefore could be a potential marker of neuroinflammation.

    “Recently, using an animal model and computer simulation, (Yi et al., 2019) showed that ODI may be sensitive to microglial density (due to increased occupancy in the extra-neurite space) and therefore could be a potential marker of neuroinflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yi et al., 2019

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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    NODDI was originally developed for examining the adult brain, and evidence is scarce on its applicability in infants and younger children.

    “NODDI was originally developed for examining the adult brain and evidence is scarce on its applicability in infants and younger children.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    One possible explanation for the slow dissemination of dMRI microstructure models is that the diagnostic power of microstructure imaging does not yet have enough accumulated evidence to convince clinicians of its value.

    “One possible explanation for the slow dissemination is that the diagnostic power of microstructure imaging does not yet have enough accumulated evidence to convince clinicians of its value.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    At present, it is not known what biophysical phenomena have dominant effects on the dMRI signal, especially in disease states.

    “At present, we are not sure what biophysical phenomena have dominant effects on the dMRI signal, especially in disease states.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Difficulty in translation to actual clinical practice is not unique to dMRI; it is a universal issue for all kinds of biomarkers.

    “Difficulty in translation to actual clinical practice is not unique to dMRI; it is a universal issue for all kinds of biomarkers (Poste, 2011;Sung et al., 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Poste, 2011 source
    • cites Sung et al., 2003 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aging is associated with axonal degeneration characterized by accumulation of organelles and increase of neurofilaments in axoplasm, myelin splitting and degeneration, increase of cellular debris, and proliferation and activation of glial cells.

    “For example, aging is associated with axonal degeneration characterized by accumulation of organelles and increase of neurofilaments in axoplasm, myelin splitting and degeneration, increase of cellular debris, and proliferation and activation of glial cells (Peters, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Peters, 2003 source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    NODDI has achieved great success as a first-generation biophysical model designed for use in clinical settings, as demonstrated by studies reporting sensitivity to disease-related effects and biologically plausible interpretations of the dMRI data.

    “As a first-generation biophysical model designed for use in clinical settings, NODDI has achieved great success, as demonstrated by studies reporting sensitivity to disease-related effects and biologically plausible interpretations of the dMRI data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These aging processes are thought to result in increased hindrance of diffusion in both intra- and extra-axonal spaces.

    “These processes are thought to result in increased hindrance of diffusion in both intra-and extra-axonal spaces.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Imaging sensitive to glial cells could be of large clinical importance in the future because glial cells are the targets of several emerging therapeutic strategies.

    “Imaging sensitive to glial cells could be of large clinical importance in the future because glial cells are the targets of several emerging therapeutic strategies (Hirsch and Hunot, 2009;Wilbanks et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hirsch and Hunot, 2009 source
    • cites Wilbanks et al., 2019 source

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Intensive application of a tool in clinical studies is not enough for it to cross the translational gap, and proof of specificity, technical validation, and cost effectiveness are likely to become bottlenecks for the clinical application of NODDI.

    “It should be noted that intensive application of a tool in clinical studies is not enough for it to cross the translational gap, and proof of specificity, technical validation, and cost effectiveness are likely to become bottlenecks for the clinical application of NODDI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    NODDI represents a significant step toward application of microstructure imaging in real-world clinical practice.

    “Although substantial work remains to be done, we believe that NODDI represents a significant step toward application of microstructure imaging in realworld clinical practice.”
    Quote in the paperNot a substantial claim
109 of 109

  • The authors state this as an assumption.

    Diffusion within each NODDI compartment is well described by a Gaussian distribution.

    “NODDI belongs to a family of models that assume diffusion within each compartment is well described by a Gaussian distribution (i.e., diffusion tensor ellipsoid).”

  • The authors state this as an assumption.

    The intra-neurite compartment can be modeled as a collection of infinitely thin 'sticks' with negligible perpendicular diffusivity.

    “The intra-neurite compartment represents axons, and possibly dendritic processes, that are often referred to together as neurites, and is modeled as a collection of infinitely thin 'sticks' (signal attenuation due to diffusion in the perpendicular direction is negligible, d 0 i, μm 2 /ms) (Kroenke et al., 2004).”

  • The authors state this as an assumption.

    The free water compartment is represented by isotropic diffusion with diffusivity 3 μm²/ms.

    “The free water compartment is represented by isotropic diffusion with the diffusivity = d 3 fw μm 2 /ms.”

  • The authors state this as an assumption.

    The orientation distribution function is constrained to the Watson distribution.

    “In NODDI, the orientation distribution function is constrained to the Watson distribution, an axially symmetric distribution characterized by a single parameter.”

  • The authors state this as an assumption.

    The parallel diffusivity of intra- and extra-neurite compartments is fixed at 1.7 μm²/ms and equal (tortuosity model).

    “In addition, for the sake of stable estimation, the following constraints are imposed: (i) = = d d 1.7 µm /ms i, e ) e, i e, (tortuosity model; (Szafer et al., 1995)).”

  • The paper relies on this without support.

    Data acquisition with stronger diffusion weightings beyond the normal DTI regimen, with b-values up to 2000-3000 s/mm2, is feasible in clinical settings with modern scanners.

    “However, with modern scanners, data acquisition with stronger diffusion weightings beyond the normal DTI regimen, with b-values up to 2000-3000 s/mm 2 , is now feasible in clinical settings and it is expected that these data will further improve our understanding of the brain and diseases.”

  • The paper relies on this without support.

    Axonal injury is the primary neuropathology in TBI, and a proxy for axon density derived from dMRI is promising for detecting it.

    “Although there is no established imaging tool capable of detecting the neuronal damage in TBI (Eierud et al., 2014), axonal injury is generally believed to be the primary neuropathology and so a proxy for axon density derived from dMRI is thought promising.”

  • The paper relies on this without support.

    Pre-operative prediction of surgical outcome in cervical spondylotic myelopathy is difficult or almost impossible.

    “In addition, pre-operative prediction of surgical outcome is difficult or almost impossible.”
8 of 8

Cites

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18 of the 281 references couldn’t be matched to a known paper.

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Related

Authors
Kamiya, K., Hori, M., & Aoki, S.
Affiliations
  • Toho University (JP)
  • Juntendo University (JP)
Corresponding author
Kamiya, Kouhei
ORCID
Venue
Journal of Neuroscience Methods
Publisher
Elsevier BV
Published
2020-12
Volume
346
Pages
108908
ISSN
0165-0270 (ISSN-L)
DOI
10.1016/j.jneumeth.2020.108908
OpenAlex
W3049304068
Semantic Scholar
4423ed0011e278c09c71720daeabdd56c94e251e
Cited by
283
References
281
Citations by year
2026: 40 · 2025: 67 · 2024: 73 · 2023: 49 · 2022: 35 · 2021: 18 · 2020: 1
FWCI
11.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience Methods (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Japan Agency for Medical Research and Development
  • Japan Society for the Promotion of Science
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
NODDI, diffusion MRI, microstructure modeling, clinical application, diffusion tensor imaging, tissue microstructure, clinical translation
MeSH terms
Brain, Humans, Neurites, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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