Keywords: Tractography, Tractography & Fibre Modelling, preoperative planning, ODF-fingerprinting, pyramidal tract, corticospinal tract, brain tumor, BOLD activation, task fMRI

Motivation: Tractography enables preoperative visualization of major neural pathways altered or displaced by a brain tumor; however, it often fails to reconstruct the cortical terminations of corticospinal tracts due to the complex bending and branching formations of fibers.

Goal(s): We aim to improve tracking of corticospinal tracts in their most challenging regions of hand and face projections to the motor cortex. 

Approach: We refine reconstruction of fibers inside corticospinal tracts by incorporating ODF-Fingerprinting into the tracking pipeline. 

Results: With ODF-Fingerprinting, we increased the overlap between the reconstructed corticospinal tracts and the cortical regions activated during task-based functional MRI involving hand and face movement.

Impact: Our improved reconstruction can help decrease the incidence of postoperative deficits by identifying the structural neural connections that need to be spared during tumor resection.

Keywords: Microstructure, Dementia, Lewy bodies, NODDI, DTI, Amyloid, Tau

Motivation: The influence of Alzheimer’s disease (AD) copathologies on white matter neurite changes in dementia with Lewy bodies (DLB) remains unclear.

Goal(s): To delineate the severity of neurite abnormalities and their associations with amyloid and tau PET imaging in DLB.

Approach: We compared Neurite Orientation Dispersion and Density Imaging metrics in the DLB spectrum (DLBs, n=45) against controls (n=45), and evaluated their correlations with amyloid-β ([11C]-PiB) and tau ([18F]-Flortaucipir) PET.

Results: The DLBs exhibited widespread white matter injury relative to controls. Elevated tau deposition, but not amyloid-β burden, was significantly associated with neurite abnormalities, predominantly involving the temporal and limbic white matter tracts.

Impact: These findings demonstrate the impact of AD copathologies on widespread neurite abnormalities in people with DLB, underscoring the importance of further elucidating the mechanisms underlying amyloid-β and tau deposition, and evaluating anti-AD disease-modifying interventions for DLB.

Keywords: Tractography, Brain Connectivity

Motivation: Models of propagation of neurodegeneration encode hypotheses on the mechanisms of pathology spread via the brain’s connectome. However, they fail to accurately capture pathology patterns, partly due to errors in tractography-estimated connectomes.

Goal(s): We use this link between pathology and connectivity to help resolve errors in connectivity estimation. Specifically, we use disease-related pathology to jointly estimate brain connectivity and pathology propagation. 

Approach: We introduce a new algorithm to use an estimate of the false-positive potential (FPP) of each connection to constrain the pathology-informed connectome-optimisation.

Results: Combining FPP and pathology-informed optimisation yields substantial improvement to both the connectome and the connectome-based prediction of pathology.

Impact: By jointly estimating pathology and the connectome, we advance both disease understanding and understanding of structural connectivity. The work is a first demonstration of the general idea of using pathology to inform on brain connectivity.

Keywords: Microstructure, Diffusion Tensor Imaging, oscillating gradient, diffusion time, spinal cord, multiple sclerosis

Motivation: Spinal cord MRI has both diagnostic and prognostic value for multiple sclerosis (MS) patients. Several quantitative MRI biomarkers show high sensitivity to characterize MS lesions but lack pathological specificity. Time-dependent DWI may reveal microstructural features and pathological variations in MS.

Goal(s): To explore diffusion time-dependence in the cervical spinal cord and its potential to quantify pathology of MS

Approach: Optimized oscillating gradient spin-echo (OGSE) DTI were performed for healthy volunteers (N=18) and MS patients (N=17).

Results: Diffusivities show time-dependence in the dorsal-columns and lateral-funiculis of healthy controls. The increase of RD in MS lesions is larger than healthy WM when diffusion time decreases.

Impact: The time-dependence of diffusivities in the cervical spinal cord of healthy volunteers and MS patients are observed using optimized OGSE DWI sequences on a clinical scanner. This may reveal further insight into the microstructural differences and pathological variations in MS.

Keywords: DWI/DTI/DKI, Diffusion Tensor Imaging

Motivation: Cisplatin-Induced cognitive impairment, resulting from chemotherapeutic agents, is typically addressed through pharmacological treatments absent of effective rehabilitation therapy. 

Goal(s): Aim to investigate the therapeutic efficacy of Low-Intensity Focused Ultrasound (LIFUS), with a specific emphasis on the hippocampus, using an established animal model. 

Approach: We scrutinized the behavioral and cerebral alterations in rats with cisplatin chemotherapy, utilizing pre- and post-treatment behavioral phenotypes and diffusion weighted imaging (DTI) with a 9.4T MRI scanner. 

Results: Our findings revealed significant differences in indicators of biological behavior and DTI across specific brain regions in the LIFUS-treated group, suggesting that LIFUS holds potential in reversing brain damage.

Impact: Our research helps to understand brain plasticity changes after LIFUS treatment with cisplatin chemotherapy, providing the theoretical support for future clinical intervention in chemotherapy related cognitive impairment.

Keywords: Tractography, Parkinson's Disease

Motivation: Cholinergic denervation underlying clinical manifestations in Parkinson’s disease (PD) is complicated. 

Goal(s): To clarify motor vs non-motor correlates of cholinergic denervation in PD and identify potential novel therapeutic targets.

Approach: We evaluated for significant associations between projections of the nucleus basalis of Meynert and pedunculopontine nucleus and motor/non-motor scores using correlational tractography in a case-control PD cohort.

Results: Intracellular and extracellular diffusivity demonstrated significant correlations with motor, cognitive and sleep assessment scores in patients. Significantly reduced intra- and extracellular diffusivity of the PPN-cholinergic-motor projection were seen. The cholinergic projections were dichotomized where the most correlated segments innervated ventral posterolateral thalamic nuclei.

Impact: The motor and non-motor correlates of cholinergic denervation show potential as objective clinical markers to characterize the PD spectrum while mapping of the cholinergic projection with highest correlation could identify substructure areas as novel stimulation target. 

Keywords: Tractography, Brain Connectivity, nociceptive pain pathway, chronic pain, anxiety, Parabrachial nucleus, Center amygdala, ball and sticks model, msmt-csd, probabilistic diffusion tractography

Motivation: The parabrachial nucleus (PBN) to the central amygdala (CeA) is a critical pathway for multiple types of aversive, unconditional threat behaviors including chronic pain states in animals. However, there do not exist connectivity studies on this pathway in the human brain by diffusion tractography.

Goal(s): Study of connectivity between PBN and CeA by diffusion tractography.

Approach: Probabilistic tractography with the ball-and-stick model (FSL) and multi-shell, multi-tissue constrained spherical deconvolution, and fixel-based analysis (MRTRIX).

Results: The study showed the existence of a PBN-CeA pathway in the human brain. Average streamline density of this pathway differs across the subjects while the cross section is comparable.

Impact: This study has discovered that a PBN-CeA pathway exists in both hemispheres of the human brain, which is consistent with our previous functional connectivity study. This finding will open up new avenues of research on fear conditioning, anxiety, and pain.

Keywords: Microstructure, Gray Matter, Neurodegeneration

Motivation: Findings of this study help clarify the microstructural substrate of network-based gray matter (GM) atrophy and improve current understanding of network concepts in multiple sclerosis (MS).

Goal(s): The goal of this study was to assess network behavior of microstructural alterations in atrophy-prone GM.

Approach: We leveraged high gradient diffusion MRI to probe GM at the mesoscopic scale by using the SANDI (Soma and Neurite Density Imaging) method.

Results: Our results demonstrated decreased cell body density in atrophy-prone GM of MS, which correlates with clinical disability. Further, covariance of localized GM microstructural alteration suggests that neuronal loss may relate in part to network-based effects.

Impact: Decreased cell body density in atrophy-prone gray matter in multiple sclerosis is correlated with clinical disability and exhibits network behavior. Findings may support future development of quantitative non-invasive methods for sensitive monitoring of disease progression to enable prompt clinical intervention.

Keywords: DWI/DTI/DKI, Brain, Ageing | White Matter | Microstructure | Brain Ageing | Polygenic Risk | Magnetic Resonance Imaging | Diffusion MRI

Motivation: White matter microstructural (WMM) changes are a crucial feature of ageing and disease development. There is yet no comprehensive mapping of such changes.

Goal(s): Providing an overview of WMM changes at different spatial scales, and relationship of these changes to polygenic risk scores (PGRS) of developing psychiatric disorders and Alzheimer's disease.

Approach: WMM metrics were estimated using multiple diffusion approaches, associated with age and PGRS, and ageing changes (inter-scan interval:2.44±0.73 years) assessed at different spatial scales.

Results: We find spatially distributed WMM-changes and PGRS-associations across the brain (most age-sensitive: central and cerebellar WMM). Brain longitudinal changes reflected disorder PGRS better than cross-sectional measures.

Impact: The manuscript details for the first time longitudinal WMM changes in a large longitudinal sample (UK Biobank, N=2,676), and provides the currently most comprehensive overview of PGRS associations with WMM change and WMM (using an additional cross-sectional validation sample, N=31,056).

Keywords: Microstructure, Diffusion/other diffusion imaging techniques

Motivation: Our primary aim is to enhance non-invasive tissue-microstructure characterization as a diagnostic paradigm through advanced MRI methods.

Goal(s): We explore microscopic tortuosity in human white-matter using the Non-uniform Oscillating-Gradient Spin-Echo (NOGSE) contrast in a clinical 3T MRI-scanner.

Approach: The NOGSE contrast was obtained by subtracting distinct OGSE acquisitions, allowing the discrimination of signals from molecules within specific brain compartments.

Results: We found restriction-sizes consistent with human histological findings, and evidence that the dominant signals originate from extra-axonal spaces, supporting microscopic tortuosity effects. This compartment-size specific contrast opens a path for diagnosis based on quantitative imaging.

Impact: We characterize microscopic-tortuosity mechanisms in human-brain white-matter through the Non-uniform Oscillating-Gradient Spin-Echo contrast, which targets the signal of confined molecules in specific microscopic-sizes. This novel contrast, demonstrated at 3T-MRI, promises a quantitative tissue-microstructure paradigm for medical diagnosis of diseases.

Keywords: Tractography, White Matter, microstructure, brain, adolescents, MS

Motivation: It is unknown if the fornix (main output tract of the hippocampus) is affected in pediatric multiple sclerosis (MS), which would suggest its early involvement.

Goal(s): Are the volume and diffusion metrics of the fornix affected in pediatric MS as it is in adult MS, and does fornix injury precede damage to the hippocampus?

Approach: Fornix diffusion tensor imaging and whole-brain MPRAGE were acquired from pediatric MS patients and controls. The fornix was identified with tractography.

Results: Pediatric MS showed a much (29%) smaller fornix with abnormal diffusion metrics indicative of early injury, but had no difference in hippocampus volume, compared to controls.

Impact: Diffusion tractography identifies marked injury to the fornix, a small white matter tract important for cognition, in children and adolescents with multiple sclerosis, while the hippocampus volume is unaffected, implicating the fornix as an early brain target in this disease.

Keywords: Diffusion Modeling, Signal Representations

Motivation: Diffusion-weighted MRI (dMRI) has significantly enhanced our ability to investigate the brain's microstructure, but analysis in pathology remains difficult.

Goal(s): This study introduces a voxelwise approach to concurrently estimate the Orientation Distribution Function (ODF) and response function for fiber orientation analysis and tractography.

Approach: The proposed blind deconvolution method models the kernel as a sum of axially-symmetric Gaussian functions, defined in spherical harmonics. It is evaluated through simulations and in-vivo experiments in healthy volunteers and glioma patients, demonstrating its efficacy in ODF estimation and data fitting.

Results: This novel approach presents better modeling of pathology and offers promising results for white matter analysis.

Impact: We introduce a blind deconvolution method for brain microstructure analysis with DWI that concurrently estimates a voxelwise ODF and kernel. This method can aid tractography and provide new image contrasts in the presence of pathology.

Keywords: DWI/DTI/DKI, Diffusion/other diffusion imaging techniques, Tract-Based Spatial Statistics;neurodevelopmental disorder;children

Motivation: The diagnosis of global developmental delay (GDD) heavily relies on clinical scale assessments, which are highly subjective and present challenges for early diagnosis and intervention. 

Goal(s): The purpose of this study was to investigate the changes in white matter microstructure in children with GDD.

Approach: We used a diffusional kurtosis imaging (DKI)-based TBSS approach to analyze the whole brain. 

Results: Our findings indicate abnormalities in multiple white matter brain regions among children with GDD. Additionally, DKI parameters were found to be correlated with clinical developmental levels. 

Impact: The DKI can offer quantitative parameter values for assessing microstructural changes in the brain of GDD, making it a promising diagnostic tool.

Keywords: DWI/DTI/DKI, White Matter

Motivation: Currently, brain charts index gray matter brain volume from T1-weighted MRI, whose sensitivity is limited to millimeter resolution, thereby unable to probe early signs of aging and pathology at the cellular level.

Goal(s): To introduce normative data for diffusion MRI (dMRI) and apply it to multiple sclerosis (MS) patients to evaluate sensitivity and accuracy.

Approach: We created normative data using diffusion tensor, diffusion kurtosis, and standard model imaging metrics in white matter. Then, assessed MS subjects by comparing to these normative data.

Results: dMRI metrics from MS patients deviate from normative data, suggesting brain charts may be used to benchmark brain health.

Impact: This study is the first step to achieve a brain-age framework from clinically feasible dMRI scans that provides meaningful insight into microstructural processes underlying brain aging and disease– possibly enabling quantitative assessment of treatment response to future disease-modifying therapies.

Keywords: Microstructure, Ischemia, MKI MKA mismatch isotropic kurtosis anisotropic kurtosis

Motivation: Diffusion-weighted imaging (DWI) is widely used in the early detection of stroke, providing valuable information on the infarct core and ischemic penumbra. The mismatch between DWI and more advanced dMRI enhances the accuracy of stroke lesion characterization.

Goal(s): Our goal is to explore whether advanced tensor-valued diffusion MRI (dMRI) can yield sensitive microstructural readouts and evaluate the mismatch between anisotropic and isotropic kurtosis as a potential biomarker for stroke.

Approach: We performed tensor-valued dMRI in a middle cerebral artery occlusion (MCAO) rodent model. 

Results: The tensor-valued diffusion MRI demonstrated significant mean diffusivity, mean kurtosis, anisotropic kurtosis, and isotropic kurtosis lesion mismatch.

Impact: Tensor-valued diffusion MRI reveals the isotropic and anisotropic in kurtosis/diffusion lesion mismatch in an animal model of acute stroke, the tensor-valued dMRI may help characterize different microstructural features of acute stroke lesions for precision medicine.

Keywords: Microstructure, Multiple Sclerosis

Motivation: Representing axons as impermeable sticks is a cornerstone of white matter modeling, e.g. for the Standard Model and related models. However, the validity of this framework in pathology remains unknown.

Goal(s): Validate the modeling assumption of axons as impermeable sticks in multiple sclerosis white matter.

Approach: We analyze the functional form of the orientationally-averaged signal as a function of b-value up to b=10,000 s/mm².

Results: We find that normal-appearing white matter, T1 black-holes, and T1-hypointense lesions show distinct deviations from the healthy tissue power-law b^-1/2 signal scaling. Simulations reveal these deviations may be specific markers for microglia inflammation and unmyelinated leaky axons.

Impact: We assess the validity of the modeling assumption of water diffusion along impermeable axons in multiple sclerosis tissue. Pathological processes such as microglial inflammation or demyelination show different behaviors in this experimental regime, highlighting the potential for an imaging biomarker.

Keywords: Diffusion Modeling, Diffusion Tensor Imaging, Migraine

Motivation: About 25% of female migraine patients suffer from menstrual-related migraine, which has been poorly studied.

Goal(s): To identify white matter alterations across the migraine cycle in patients with episodic menstrual-related migraine without aura.

Approach: Diffusion MRI allows to assess alterations in the brain tissue microenvironment. Moreover, including the free-water contribution in the diffusion signal can give information about biological mechanisms, such as inflammation, and more directly expose the tissue alterations by removing free water contamination.

Results: Significant differences were found in the diffusion parameters of the white matter tracts of the menstrual-related migraine patients.

Impact: We found significant alterations in the diffusion parameters of the white matter tracts of episodic menstrual-related migraine patients across migraine cycle using standard diffusion tensor imaging (DTI) and Free-Water corrected DTI.

Keywords: Simulation/Validation, Microstructure, Monte-Carlo, Histology

Motivation: Analytical biophysical diffusion MRI (dMRI) models fail to capture the full complexity
of diffusion processes.

Goal(s): We propose a Monte Carlo (MC) simulation framework enabling the numerical implementation
of biophysical models with unprecedented fidelity to histology.

Approach: Our framework enables simulating diffusion within cancer environments reconstructed
from histology. It provides paired examples of dMRI signals and histological properties, which can be
used to build numerical microstructure parameter estimators.

Results: Our approach enables more accurate estimation of key properties such as cell size compared
to fitting of classical multi-compartment analytical models.

Impact: We propose a Monte Carlo (MC) simulation framework enabling the implementation of biophysicalmodels with unprecedented fidelity to histology. The framework improves microstructure inference compared to standard analytical fitting, and may provide more robust biomarkers in diseases such ascancer.

Keywords: Microstructure, Diffusion/other diffusion imaging techniques

Motivation: Addressing the unmet need for non-invasive non-alcoholic steatohepatitis (NASH) diagnosis.

Goal(s): Assessing MRI cytometry’s potential for quantifying alterations in cell sizes and cell densities linked to inflammation, a critical factor in NASH diagnosis.

Approach: Histology-based simulations were used to assess MRI cytometry's performance across various SNR levels in normal and NASH liver tissues. Additionally, used MRI cytometry to distinguish healthy liver from NASH with a clinical 3T scanner.

Results: Both simulations and in vivo data revealed increased cell density and reduced cell sizes in inflammatory areas compared to steatosis and healthy liver tissues.

Impact: Findings of this study establish a strong foundation for future investigations into the role of non-invasive assessment of liver cellular characteristics in diagnosing NASH, with the ultimate goal of reducing the necessity for liver biopsy.

Keywords: Microstructure, Diffusion/other diffusion imaging techniques, Tumor

Motivation: Pretherapeutic characterization of the aggressive macrotrabecular-massive (MTM) subtype hepatocellular carcinoma (HCC) may promote the implementation of precision treatment and improvement of prognosis. 

Goal(s): To investigate the value of multiple advanced diffusion models in identifying the MTM subtype of HCC preoperatively.

Approach: DWI of twelve b-values (0-2000 s/mm²) were performed in 70 patients with HCC. Multiple diffusion-derived parameters were extracted and compared between MTM and non-MTM HCC. The predictive efficacy of various diffusion parameters was assessed.

Results: CTRW_α exhibited the highest predictive performance with an AUC of 0.861 among individual parameters, a combination of parameters could improve the AUC to 0.912. 

Impact: MTM is a distinct subtype of HCC and is associated with aggressive biological behavior, but it might be a suitable candidate for immunotherapy. Our result demonstrated that non-Gaussian diffusion parameters could serve as promising biomarkers for predicting MTM preoperatively.