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

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NODDI in clinical research

Open access
Kamiya, Kouhei, Hori, Masaaki, Aoki, Shigeki·2020·Journal of Neuroscience Methods

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.

Overview

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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.

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Integrity signals

Registry

Crossref · 10.1016/j.jneumeth.2020.108908

Cites

263 of 263 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Fig. 1 Schematic illustration of the NODDI model and parameter constraints.
Fig. 1 Schematic illustration of the NODDI model and parameter constraints.CC-BY-NC-ND · From the PDF
Fig. 2 In the presence of fiber dispersion and/or crossing, selective sparing/ degeneration of axons can lead to a spurious increase of fractional anisotropy (FA), which limits the sensitivity of FA as a disease marker. NODDI may reveal the underlying neurodegeneration by separating the effect of orientation dis­ persion. NDI = neurite density index; ODI = orientation dispersion index.
Fig. 2 In the presence of fiber dispersion and/or crossing, selective sparing/ degeneration of axons can lead to a spurious increase of fractional anisotropy (FA), which limits the sensitivity of FA as a disease marker. NODDI may reveal the underlying neurodegeneration by separating the effect of orientation dis­ persion. NDI = neurite density index; ODI = orientation dispersion index.CC-BY-NC-ND · From the PDF
Fig. 3 NODDI in Parkinson's disease. Top: NODDI reveals decreased neurite density index (NDI; blue) and increased free water fraction ( f fw; red) in Parkinson's disease patients compared with healthy controls in the cortex. (Adapted and reproduced with permission from (Kamagata et al., 2017)) Bottom: Progression of Parkinson's disease-related pathology from the histology literature. (Adapted and reproduced with permission from (Braak et al., 2003)).
Fig. 3 NODDI in Parkinson's disease. Top: NODDI reveals decreased neurite density index (NDI; blue) and increased free water fraction ( f fw; red) in Parkinson's disease patients compared with healthy controls in the cortex. (Adapted and reproduced with permission from (Kamagata et al., 2017)) Bottom: Progression of Parkinson's disease-related pathology from the histology literature. (Adapted and reproduced with permission from (Braak et al., 2003)).CC-BY-NC-ND · From the PDF
Fig. 4 NODDI in the spinal cord of multiple sclerosis patients. Left: Representative images from two patients with multiple sclerosis (middle and bottom) and one healthy control (top). In the first patient (middle), decreased intra-neurite fraction (Vin, neurite density index [NDI] in the main text) is observed in areas where the anatomical image looks normal, like the right dorsal column (arrow). Widespread increase of orientation dispersion index (ODI) was observed that was not limited to lesion visible on anatomical images. Right: Contrast between lesion and normal-appearing white matter (NAWM) and histograms of voxel values. Note the bimodal distribution of Vin in NAWM, which may indicate sensitivity of Vin to neuronal damage undetectable on conventional T1- or T2-weithger images. (Reproduced with permission from (By et al., 2017)) Abbreviations: DKI = diffusion kurtosis imaging; DTI = diffusion tensor imaging; EDSS = expanded disability status scale; FA = fractional anisotropy; MK = mean kurtosis; MS = multiple sclerosis; RD = radial diffusivity; RK = radial kurtosis.
Fig. 4 NODDI in the spinal cord of multiple sclerosis patients. Left: Representative images from two patients with multiple sclerosis (middle and bottom) and one healthy control (top). In the first patient (middle), decreased intra-neurite fraction (Vin, neurite density index [NDI] in the main text) is observed in areas where the anatomical image looks normal, like the right dorsal column (arrow). Widespread increase of orientation dispersion index (ODI) was observed that was not limited to lesion visible on anatomical images. Right: Contrast between lesion and normal-appearing white matter (NAWM) and histograms of voxel values. Note the bimodal distribution of Vin in NAWM, which may indicate sensitivity of Vin to neuronal damage undetectable on conventional T1- or T2-weithger images. (Reproduced with permission from (By et al., 2017)) Abbreviations: DKI = diffusion kurtosis imaging; DTI = diffusion tensor imaging; EDSS = expanded disability status scale; FA = fractional anisotropy; MK = mean kurtosis; MS = multiple sclerosis; RD = radial diffusivity; RK = radial kurtosis.CC-BY-NC-ND · From the PDF
Fig. 5 NODDI in temporal lobe epilepsy. A. A patient with MRI-negative left temporal lobe epilepsy. Decreased neurite density index (NDI) is observed in the temporal tip ipsilateral to the epileptogenic focus (circles). B. A patient with MRI-positive right temporal lobe epilepsy (hippocampal sclerosis). Decreased NDI and orientation dispersion index (ODI) are seen in the hippocampus (arrows). (Adapted and reproduced with permission from (Sone et al., 2018)). Abbreviations: FDGPET = fluorodeoxyglucose positron emission tomography; FLAIR = fluid-attenuated inversion recovery; T2WI = T2-weighted image.
Fig. 5 NODDI in temporal lobe epilepsy. A. A patient with MRI-negative left temporal lobe epilepsy. Decreased neurite density index (NDI) is observed in the temporal tip ipsilateral to the epileptogenic focus (circles). B. A patient with MRI-positive right temporal lobe epilepsy (hippocampal sclerosis). Decreased NDI and orientation dispersion index (ODI) are seen in the hippocampus (arrows). (Adapted and reproduced with permission from (Sone et al., 2018)). Abbreviations: FDGPET = fluorodeoxyglucose positron emission tomography; FLAIR = fluid-attenuated inversion recovery; T2WI = T2-weighted image.CC-BY-NC-ND · From the PDF
Fig. 6 NODDI in moyamoya disease. Decrease of neurite density index (NDI) and orientation dispersion index (ODI), as well as increase of free water fraction ( f fw), are observed ipsilateral to artery stenosis in the cerebrum, with concurrent decreases of cerebral blood flow (CBF) and cerebral metabolic ratio of oxygen (CMRO2) and increases of cerebral blood volume (CBV), mean transit time (MTT), and oxygen extraction fraction (OEF) (arrows). (Adapted and reproduced with permission from (Hara et al., 2019)) Abbreviations: FLAIR = fluid-attenuated inversion recovery; ICA = internal carotid artery; MRA = magnetic resonance angiography; ROI = region of interest; T1WI = T1-weighted image.
Fig. 6 NODDI in moyamoya disease. Decrease of neurite density index (NDI) and orientation dispersion index (ODI), as well as increase of free water fraction ( f fw), are observed ipsilateral to artery stenosis in the cerebrum, with concurrent decreases of cerebral blood flow (CBF) and cerebral metabolic ratio of oxygen (CMRO2) and increases of cerebral blood volume (CBV), mean transit time (MTT), and oxygen extraction fraction (OEF) (arrows). (Adapted and reproduced with permission from (Hara et al., 2019)) Abbreviations: FLAIR = fluid-attenuated inversion recovery; ICA = internal carotid artery; MRA = magnetic resonance angiography; ROI = region of interest; T1WI = T1-weighted image.CC-BY-NC-ND · From the PDF
Fig. 7 NODDI in idiopathic normal pressure hydrocephalus (iNPH). Compared with healthy controls, iNPH patients exhibited a smaller axonal water fraction ( f i ) and dispersion within the peri-ventricular portion of the corticospinal tract (purple voxels in the coronal image). The reduced axonal water fraction re­ mained unchanged after cerebrospinal fluid shunt surgery, whereas the dis­ persion showed some normalization. cos 2 is a parameter representing dis­ persion (1/3 for isotropic distribution and 1 for strictly parallel orientation) computed from the concentration parameter of the Watson distribution. Asterisks indicate significant differences ( p < 0.05). (Reproduced with per­ mission from (Kamiya et al., 2017)).
Fig. 7 NODDI in idiopathic normal pressure hydrocephalus (iNPH). Compared with healthy controls, iNPH patients exhibited a smaller axonal water fraction ( f i ) and dispersion within the peri-ventricular portion of the corticospinal tract (purple voxels in the coronal image). The reduced axonal water fraction re­ mained unchanged after cerebrospinal fluid shunt surgery, whereas the dis­ persion showed some normalization. cos 2 is a parameter representing dis­ persion (1/3 for isotropic distribution and 1 for strictly parallel orientation) computed from the concentration parameter of the Watson distribution. Asterisks indicate significant differences ( p < 0.05). (Reproduced with per­ mission from (Kamiya et al., 2017)).CC-BY-NC-ND · From the PDF
Fig. 8 NODDI in brain tumors. The peritumoral T2-weighted hyperintense regions of different tumors exhibit different characteristics on NODDI maps. A greater extra-neurite fraction ( f e ) in glioblastoma (left) and a greater free water fraction ( f fw ) in metastatic brain tumor (right). (Adapted and reproduced with permission from (Kadota et al., 2018)) Abbreviations: ADC = apparent diffusion coefficient; f i = intra-neurite fraction; Gd T1w = contrast-enhanced T1-weighted image; T2w = T2-weighted image.
Fig. 8 NODDI in brain tumors. The peritumoral T2-weighted hyperintense regions of different tumors exhibit different characteristics on NODDI maps. A greater extra-neurite fraction ( f e ) in glioblastoma (left) and a greater free water fraction ( f fw ) in metastatic brain tumor (right). (Adapted and reproduced with permission from (Kadota et al., 2018)) Abbreviations: ADC = apparent diffusion coefficient; f i = intra-neurite fraction; Gd T1w = contrast-enhanced T1-weighted image; T2w = T2-weighted image.CC-BY-NC-ND · From the PDF
Fig. 9 NODDI in brain development and aging. A. Life-span trajectories of NODDI and DTI parameters in the callosal fibers from 7 to 84 years of age. (Adapted and reproduced with permission from (Slater et al., 2019)) B. Trajectories of parameters in the genu of callosum during the first 3 years of life. (Adapted and reproduced with permission from (Jelescu et al., 2015)) cos 2 is a parameter representing dispersion (1/3 for isotropic distribution and 1 for strictly parallel orientation) computed from the concentration parameter of the Watson distribution. C. Association with postmenstrual age within the cortical gray matter of newborns (Re­ produced with permission from (Batalle et al., 2019)) Abbreviations: CC = corpus callosum; FA = fractional anisotropy; fintra = intra-neurite fraction; fiso = isotropic fraction (free water fraction [ f fw] in the main text); ICVF = intra-cellular volume fraction (neurite density index [NDI] in the main text); MD = mean diffusivity; ODI = orientation dispersion index; PMA = postmenstrual age; WMTI = white matter tract integrity (another white matter model proposed in (Fieremans et al., 2011)).
Fig. 9 NODDI in brain development and aging. A. Life-span trajectories of NODDI and DTI parameters in the callosal fibers from 7 to 84 years of age. (Adapted and reproduced with permission from (Slater et al., 2019)) B. Trajectories of parameters in the genu of callosum during the first 3 years of life. (Adapted and reproduced with permission from (Jelescu et al., 2015)) cos 2 is a parameter representing dispersion (1/3 for isotropic distribution and 1 for strictly parallel orientation) computed from the concentration parameter of the Watson distribution. C. Association with postmenstrual age within the cortical gray matter of newborns (Re­ produced with permission from (Batalle et al., 2019)) Abbreviations: CC = corpus callosum; FA = fractional anisotropy; fintra = intra-neurite fraction; fiso = isotropic fraction (free water fraction [ f fw] in the main text); ICVF = intra-cellular volume fraction (neurite density index [NDI] in the main text); MD = mean diffusivity; ODI = orientation dispersion index; PMA = postmenstrual age; WMTI = white matter tract integrity (another white matter model proposed in (Fieremans et al., 2011)).CC-BY-NC-ND · From the PDF
Fig. 10 Imaging biomarker roadmap. (Connor et al., 2017).
Fig. 10 Imaging biomarker roadmap. (Connor et al., 2017).CC-BY-NC-ND · From the PDF

Verification

Claims the paper makes

64 Supported · 46 Partly supported · 43 No full text of the sources · 31 Own interpretation · 18 No basis given · 10 Sources not found · 9 Supported so far · 2 Not supported · 2 Not checked yet · 1 Couldn’t confirm · accuracy not yet measured

Show all 117 claims

  • Probably not a substantial claim. 52
  • It may state two separate claims as one. 73
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

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Metadata

Authors
Kamiya, K., Hori, M., & Aoki, S.
Affiliations
  • Toho University (JP)
  • Juntendo University (JP)
Corresponding author
Kamiya, Kouhei
Venue
Journal of Neuroscience Methods
Publisher
Elsevier BV
Published
2020-12
Volume
346
Pages
108908
ISSN
0165-0270 (ISSN-L)
OpenAlex
W3049304068
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
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

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