Effects of Psilocybin on Mouse Brain Microstructure.

Diffusion tensor imaging (DTI) has been used to explore changes in the brain of subjects with human immunodeficiency virus (HIV) infection. However, DTI notoriously suffers from low specificity. Neurite orientation dispersion and density imaging (NODDI) is a compartmental model able to provide specific microstructural information with additional sensitivity/specificity. In this study we use both the NODDI and the DTI models to evaluate microstructural differences between 35 HIV-positive patients and 20 healthy controls. Diffusion-weighted imaging was acquired using three b-values (0, 1000 and 2500 s/mm2). Both DTI and NODDI models were fitted to the data, obtaining estimates for fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), neurite density index (NDI) and orientation dispersion index (ODI), after which we performed group comparisons using Tract-based spatial statistics (TBSS). While significant group effects were found in in FA, MD, RD, AD and NDI, NDI analysis uncovered a much wider involvement of brain tissue in HIV infection as compared to DTI. In region-of interest (ROI)-based analysis, NDI estimates from the right corticospinal tract produced excellent performance in discriminating the two groups (AUC = 0.974, sensitivity = 90%; specificity =97%).

BackgroundObesity is a risk factor for dementia. However, results from studies associating obesity to volume in the hippocampus and parahippocampal gyrus, regions underpinning memory, are inconsistent. Null findings could be due to the insensitivity of volumetric MRI to detect early neurodegenerative change. The neurite orientation dispersion and density imaging (NODDI) model provides unique information about neurite microstructure that may be relevant to the earliest stages of neurodegeneration. In cognitively healthy participants, we used NODDI to examine if body mass index (BMI) and waist circumference (WC) were related to the microstructure of the hippocampus and parahippocampal gyrus and white matter (WM) tracts linking these gray matter (GM) regions to the brain (i.e., hippocampal cingulum, uncinate fasciculus, and fornix).MethodParticipants were enrolled in the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core, had T‐1 weighted and multi‐shell diffusion MRI, and lacked history of stroke and cognitive impairment (Table 1). Microstructure was assessed using neurite density (NDI) and orientation dispersion (ODI) indices obtained from the NODDI model. Higher NDI indicates higher neurite density; higher ODI reflects lower neurite coherence and greater neurite dispersion. N=383 had NODDI indices, height, weight and covariate data. Waist circumference (WC) (n=382) was dichotomized according to sex‐specific thresholds for cardiovascular/diabetes disease risk (females >88cm; males >102cm). Linear regression tested the relationship of BMI and WC to NDI and ODI in regions of interest controlling for age, sex, education, diabetes, hypertension, depression, and APOE4 carrier status.ResultIndividuals with higher BMI and in the higher‐risk WC category had significantly lower hippocampal ODI and fornix NDI when adjusting for covariates (Table 2, Figure 1). Higher BMI was also related to higher uncinate fasciculus ODI.ConclusionIncreased adiposity was related to lower neurite dispersion in the hippocampus and lower neurite density in the fornix. BMI alone was associated with lower neurite coherence in the uncinate fasciculus. These results suggest that increased adiposity may be related to less complex neurite microstructure in regions important for memory. Additional research is needed to determine if adiposity‐related microstructural differences in GM and WM are related to memory decline and presage future development of dementia.

One third of patients with medically refractory focal epilepsy have normal-appearing MRI scans. This poses a problem as identification of the epileptogenic region is required for surgical treatment. This study performs a multimodal voxel-based analysis (VBA) to identify brain abnormalities in MRI-negative focal epilepsy. Data was collected from 69 focal epilepsy patients (42 with discrete lesions on MRI scans, 27 with no visible findings on scans), and 62 healthy controls. MR images comprised T1-weighted, fluid-attenuated inversion recovery (FLAIR), fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging, and neurite density index (NDI) from neurite orientation dispersion and density imaging. These multimodal images were coregistered to T1-weighted scans, normalized to a standard space, and smoothed with 8 mm FWHM. Initial analysis performed voxel-wise one-tailed t-tests separately on grey matter concentration (GMC), FLAIR, FA, MD, and NDI, comparing patients with epilepsy to controls. A multimodal non-parametric combination (NPC) analysis was also performed simultaneously on FLAIR, FA, MD, and NDI. Resulting p-maps were family-wise error rate corrected, threshold-free cluster enhanced, and thresholded at p < 0.05. Sensitivity was established through visual comparison of results to manually drawn lesion masks or seizure onset zone (SOZ) from stereoelectroencephalography. A leave-one-out cross-validation with the same analysis protocols was performed on controls to determine specificity. NDI was the best performing individual modality, detecting focal abnormalities in 38% of patients with normal MRI and conclusive SOZ. GMC demonstrated the lowest sensitivity at 19%. NPC provided superior performance to univariate analyses with 50% sensitivity. Specificity in controls ranged between 96 and 100% for all analyses. This study demonstrated the utility of a multimodal VBA utilizing NPC for detecting epileptogenic lesions in MRI-negative focal epilepsy. Future work will apply this approach to datasets from other centres and will experiment with different combinations of MR sequences.

Posttraumatic stress disorder (PTSD) can be a source of significant social and daily distress in autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, people with ASD are at an increased risk of adverse childhood experiences (ACEs), which can result in abnormal neuronal development. However, whether or how ACEs influence abnormal neural development and PTSD symptoms in ASD has not been fully elucidated. Thirty-nine TD individuals and 41 individuals with ASD underwent T1-weighted magnetic resonance imaging and neurite orientation dispersion and density imaging (NODDI), with axonal and dendritic densities assessed in terms of the orientation dispersion index and neurite density index (NDI), respectively. Voxel-based analyses were performed to explore the brain regions associated with PTSD symptoms, and the relationships between the severity of ACEs and PTSD symptoms and NODDI parameters in the extracted brain regions were examined. There was a significant positive association between PTSD symptom severity and NDI in the bilateral supplementary motor area; right superior frontal, left supramarginal, and right superior temporal gyrus; and right precuneus in the ASD group, but not in the TD group. ACE severity was significantly associated with NDI in the right superior frontal and left supramarginal gyrus and right precuneus in the ASD group. Moreover, NDI in the right precuneus mainly predicted the severity of PTSD symptoms in the ASD group, but not the TD group. These results suggest that ACE-associated higher neurite density is of clinical importance in the pathophysiology of PTSD symptoms in ASD.

BackgroundCortical grey matter (CGM) and superficial white matter (SWM) undergo pathological changes, but standard MRI spatial resolutions make interpreting disease‐related effects at their interface challenging. We present findings from a study investigating the grey/white interface in typical amnestic Alzheimer’s disease (tAD), posterior cortical atrophy (PCA) and healthy controls using ultra‐high‐resolution quantitative MRI measures sensitive to microstructural properties.MethodEleven participants (Table 1) were scanned at 7T using multi‐echo FLASH (0.5mm isotropic resolution with prospective motion correction) and diffusion MRI (dMRI) (1.25mm isotropic resolution). The hMRI toolbox produced multi‐parametric mapping (MPM) measures: R1, R2* and Proton Density (PD) (Vaculciakova et al., 2021https://doi.org/10.1002/mrm.29253). dMRI processing included denoising and correcting for Gibbs ringing, eddy currents, susceptibility artifacts and motion. Metrics from dMRI were fractional anisotropy (FA), and mean diffusivity (MD), as well as tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) from Neurite Orientation Dispersion and Density Imaging (NODDI). A deep learning segmentation approach estimated the grey/white boundary (Billot et al., 2021, arXiv:2107.09559). MPM and dMRI measures were sampled from the CGM into the SWM at 0.5mm increments in regions of interest (Harvard‐Oxford cortical atlas). Tissue‐weighted (tw) averages were calculated for NDI and ODI. Metrics were visualized across the grey/white interface using boxplots.ResultFigures 1‐2 show MPM and dMRI measures in the precuneus (dashed lines indicate group medians). Qualitatively, most tAD and PCA participants had lower R1 and R2* than controls, most prominently 0.5mm into the SWM (Figure 1). PD appeared higher in tAD and PCA patients across the grey/white interface. Qualitatively, most tAD and PCA participants had lower TF and higher MD in the CGM, where twNDI and FA appeared lower than controls across grey/white interface (Figure 2). Most tAD and PCA had qualitatively lower twODI in CGM and a flatter slope across the grey/white interface compared to controls.ConclusionMacromolecular (R1, R2* and twNDI) and iron content (R2*) MR measures at 7T appear reduced in tAD and PCA across the grey/white interface, whereas neurite organisational complexity (twODI) may become more homogeneous. Ongoing study will assess if these findings are consistent with further participants.

White matter is fundamental for efficient information transfer and thus crucial for intelligence. Previous studies demonstrated associations between fractional anisotropy and intelligence, but it remains unclear whether this relation is due to greater axon density, parallel, homogenous fiber orientation distributions, or greater myelination, as all influence fractional anisotropy. Using neurite orientation dispersion and density imaging and myelin water fraction imaging, we analyzed the microstructural architecture of intelligence in 500 healthy young adults. We were also interested whether specific white matter indices mediate the pathway linking genetic disposition for intelligence to phenotype. For the first time, we conducted mediation analyses investigating whether neurite density index, orientation dispersion index, and myelin water fraction of 64 white matter tracts mediate the effects of polygenic scores for intelligence on general intelligence (g). Our results showed that neurite density index, but not orientation dispersion index or myelin water fraction of white matter tracts, was significantly associated with g and that neurite density index of six fiber tracts mediated the relation between genetic variability and g. These findings are a crucial step toward decoding the neurogenetic underpinnings of general intelligence, as they identify that neurite density of specific fiber tracts relates polygenic variation to g, whereas orientation dispersion and myelination did not.

Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM. Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI. ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM. C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.

Detection of structural abnormalities of cortical and subcortical gray matter in patients with MRI-negative refractory epilepsy using neurite orientation dispersion and density imaging

The use of diffusional kurtosis imaging and neurite orientation dispersion and density imaging of the brain in major depressive disorder

Age-dependent differences in brain tissue microstructure assessed with neurite orientation dispersion and density imaging

BackgroundPlasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood‐based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations.MethodWe included Mayo Clinic Study of Aging (MCSA) participants (ages 60‐95 years) with diagnoses or CU (n = 356) or MCI (n = 60), and Alzheimer’s Dementia Research Center (ADRC) participants with dementia (n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4‐Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log‐transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume.ResultThe Table displays demographic data. Figures 1 & 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus (p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions (p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions.ConclusionNODDI‐derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.

BackgroundIsolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF).MethodWe included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests.ResultCompared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance (T = 2.0, p < 0.05, Figure 2).ConclusionOur study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

Demyelinating diseases constitute the most frequent cause of non-traumatic neurological disability in the pediatric population. Conventional MRI, while sensitive to focal white matter injury, lacks specificity to discern between edema, demyelination and axonal loss. This study aimed to employ advanced MRI biomarkers-specifically macromolecular tissue volume (MTV) and neurite orientation dispersion and density imaging (NODDI)-derived metrics-to assess myelin integrity (myelin volume fraction, MVF), axonal density (neurite density index, NDI), and the g-ratio in pediatric patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Thirty-nine pediatric patients (MS, n = 15; NMOSD, n = 6; MOGAD, n = 11), including 7 age-matched heathy controls, underwent 3 Tesla MRI as part of a cross-sectional study. Multi-echo gradient echo and multi-shell diffusion sequences were acquired to compute MTV and NODDI metrics. Lesional and normal-appearing white matter (NAWM) were segmented, and imaging metrics (MVF, NDI, and g-ratio) were compared across groups. Correlations between imaging biomarkers and clinical measures were also examined. MS demonstrated significantly higher lesional g-ratio than MOGAD (p = 0.02) and NMOSD (p = 0.02) and lower MVF than NMOSD (p = 0.006), indicating greater relative myelin loss. NAWM partitioning identified higher deep-NAWM ODI in MS patients than controls (p = 0.04). Within the MS cohort, 25ftW was associated with g-ratio, MVF, and NDI measures for both whole-brain and deep NAWM. Advanced MRI biomarkers provide a more nuanced characterization of microstructural alterations in pediatric demyelinating diseases. The distinct imaging profiles-highlighting greater demyelination in MS versus MOGAD and NMOSD-support the utility of these metrics for targeted clinical management and therapeutic stratification. Future longitudinal studies are warranted to further validate their role in monitoring disease progression and treatment response.

IntroductionFetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI).Materials and methodsParticipants: Youth with PAE (n = 34) and typically-developing Controls (n = 31) ages 8–17 years at enrollment. Participants underwent formal evaluation of growth and facial dysmorphology. Participants also completed two study visits (17 months apart on average), both of which involved cognitive testing and an MRI scan (data collected on a Siemens Prisma 3 T scanner). Age-related changes in the orientation dispersion index (ODI) and the neurite density index (NDI) were examined across five corpus callosum (CC) regions defined by tractography.ResultsWhile linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE.DiscussionPreliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important.

White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16–21 years) and eight healthy controls (aged 15–20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms.