Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.

Exposure to prenatal maternal distress and infant white matter neurodevelopment

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother–infant dyads. Prenatal distress was assessed at 17 and 29 weeks’ gestational age (GA). Infant structural data were collected via diffusion tensor imaging (DTI) at 42–45 weeks’ postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks’ GA was associated with increased fractional anisotropy, b = .283, t(64) = 2.319, p = .024, and with increased axial diffusivity, b = .254, t(64) = 2.067, p = .043, within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks’ GA, or earlier in gestation.

Diffusion tensor imaging for the study of early renal dysfunction in patients affected by bardet-biedl syndrome

Kidney structural abnormalities are common features of Bardet-Biedl syndrome (BBS) patients that lead to a progressive decline in renal function. Magnetic resonance diffusion tensor imaging (DTI) provides useful information on renal microstructures but it has not been applied to these patients. This study investigated using DTI to detect renal abnormalities in BBS patients with no overt renal dysfunction. Ten BBS subjects with estimated glomerular filtration rates over 60 ml/min/1.73m2 and 14 individuals matched for age, gender, body mass index and renal function were subjected to high-field DTI. Fractional anisotropy (FA), and mean, radial and axial diffusivity were evaluated from renal cortex and medulla. Moreover, the corticomedullary differentiation of each DTI parameter was compared between groups. Only cortical FA statistically differed between BBS patients and controls (p = 0.033), but all the medullary DTI parameters discriminated between the two groups with lower FA (p < 0.001) and axial diffusivity (p = 0.021) and higher mean diffusivity (p = 0.043) and radial diffusivity (p < 0.001) in BBS patients compared with controls. Corticomedullary differentiation values were significantly reduced in BBS patients. Thus, DTI is a valuable tool for investigating microstructural alterations in renal disorders when kidney functionality is preserved.

Herschel-Bulkley Model of Blood Flow through a Stenosed Artery with the Effect of Chemical Reaction on Solute Dispersion

A non-Newtonian mathematical model of blood described as a Hershel-Bulkley fluid model flowing in a stenosed artery with the effect of a chemical reaction is mathematically studied. The expressions of the shear stress, mean velocity and absolute velocity in the plug and non-plug flow field are evaluated analytically. The convective-diffusion equation is solved using the Taylor-Aris technique subject to the relevant boundary constraint in determining the concentration, relative and effective axial diffusivity. The efficiency of the dispersion process is affected by the presence of chemical reaction and stenosis in blood flow. The normalized velocity decreases as stenosis height and stenosis length increase. The relative axial diffusivity is significantly lower while the effective axial diffusivity decreases considerably as the chemical reaction rate, the height of the stenosis and the length of the stenosis increase. Besides, it is observed that as the solute disperses in the presence of stenosis, the flow quantities are lesser than in the absence of stenosis. Further, this study helps in understanding many physiological processes for instance dispersion of drugs or nutrients in the circulatory system. Also, to enhance the dispersion of a solute in blood flow through narrow arteries in the presence of chemical reaction and stenosis.

Infratentorial pathology in frontotemporal dementia: cerebellar grey and white matter alterations in FTD phenotypes

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.

Estimating intra-axonal axial diffusivity in the presence of fibre orientation dispersion

By analysing the diffusion MRI signal, we can infer information about the microscopic structure of the brain. Two parameters of interest - the intra-axonal axial diffusivity and fibre orientation dispersion - are potential biomarkers for very different aspects of the white matter microstructure, yet they are difficult to disentangle. The parameters covary such that, if one is not accurately accounted for, the other will be biased. In this work we use high b-value data to isolate the signal from the intra-axonal compartment and resolve any degeneracies with the extra-axonal compartment. In the high b-value regime, we then use a model of dispersed sticks to estimate the intra-axonal axial diffusivity and fibre orientation distribution on a voxelwise basis. Our results in in vivo, human data show an intra-axonal axial diffusivity of ~ 2.3 – 3 μm2/ms, where 3 μm2/ms is the diffusivity of free water at 37°C. The intra-axonal axial diffusivity is seen to vary considerably across the white matter. For example, in the corpus callosum we find high values in the genu and splenium, and lower values in the midbody. Furthermore, the axial diffusivity and orientation dispersion appear negatively correlated, behaviour which we show is consistent with the presence of fibre undulations but not consistent with a degeneracy between fanning fibres and axial diffusivity. Finally, we demonstrate that the parameter maps output from Neurite Orientation Dispersion and Density Imaging (NODDI) change substantially when the assumed axial diffusivity was increased from 1.7 to 2.5 or 3 μm2/ms.

Alternative Microstructural Measures to Complement Diffusion Tensor Imaging in Migraine Studies with Standard MRI Acquisition

The white matter state in migraine has been investigated using diffusion tensor imaging (DTI) measures, but results using this technique are conflicting. To overcome DTI measures, we employed ensemble average diffusion propagator measures obtained with apparent measures using reduced acquisitions (AMURA). The AMURA measures were return-to-axis (RTAP), return-to-origin (RTOP) and return-to-plane probabilities (RTPP). Tract-based spatial statistics was used to compare fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity from DTI, and RTAP, RTOP and RTPP, between healthy controls, episodic migraine and chronic migraine patients. Fifty healthy controls, 54 patients with episodic migraine and 56 with chronic migraine were assessed. Significant differences were found between both types of migraine, with lower axial diffusivity values in 38 white matter regions and higher RTOP values in the middle cerebellar peduncle in patients with a chronic migraine (p < 0.05 family-wise error corrected). Significantly lower RTPP values were found in episodic migraine patients compared to healthy controls in 24 white matter regions (p < 0.05 family-wise error corrected), finding no significant differences using DTI measures. The white matter microstructure is altered in a migraine, and in chronic compared to episodic migraine. AMURA can provide additional results with respect to DTI to uncover white matter alterations in migraine.

Mapping white matter damage distribution in neuromyelitis optica spectrum disorders with a multimodal MRI approach

Background: The pathogenetic mechanisms sustaining neuroinflammatory disorders may originate from the cerebrospinal fluid. Objective: To evaluate white matter damage with diffusion tensor imaging and T1/T2-weighted ratio at progressive distances from the ventricular system in neuromyelitis optica spectrum disorders and multiple sclerosis. Methods: Fractional anisotropy, mean, axial, and radial diffusivity and T1/T2-weighted ratio maps were obtained from patients with seropositive neuromyelitis optica spectrum disorders, multiple sclerosis, and healthy controls ( n = 20 each group). White matter damage was assessed as function of ventricular distance within progressive concentric bands. Results: Compared to healthy controls, neuromyelitis optica spectrum disorders patients had similar fractional anisotropy, radial and axial diffusivity, increased mean diffusivity ( p = 0.009–0.013) and reduced T1/T2-weighted ratio ( p = 0.024–0.037) in all bands. In multiple sclerosis, gradient of percentage lesion volume and intra-lesional mean and axial diffusivity were higher in periventricular bands. Compared to healthy controls, multiple sclerosis patients had reduced fractional anisotropy ( p = 0.001–0.043) in periventricular bands, increased mean ( p < 0.001), radial ( p < 0.001–0.004), and axial diffusivity ( p = 0.002–0.008) and preserved T1/T2-weighted ratio in all bands. Conclusion: White matter damage is higher at periventricular level in multiple sclerosis and diffuse in neuromyelitis optica spectrum disorders. Fractional anisotropy preservation, associated with increased mean diffusivity and reduced T1/T2-weighted ratio may reflect astrocyte damage.

T169. SEMANTIC PROCESSING IN RELATION TO ANATOMICAL INTEGRITY OF THE VENTRAL LANGUAGE STREAM IN SCHIZOPHRENIA SPECTRUM DISORDERS

Background Semantic processing anomalies, clinically reflected by disorganized speech are a core symptom of schizophrenia. In the light of accumulating evidence on its prominent role in semantic processing, aberrant structural integrity of the ventral language stream may reflect impaired semantic processing in schizophrenia spectrum disorders (SSD). Methods Comparison of white matter tract integrity in SSD patients and healthy controls using diffusion tensor imaging combined with probabilistic fiber tractography. For the ventral language stream, we assessed the inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus, and uncinate fasciculus. The arcuate fasciculus and corticospinal tract were used as control tracts. In SSD patients, the relationship between semantic processing impairments and tract integrity was analyzed separately. Three-dimensional tract reconstructions were performed in 45/44 SSD patients/controls (“Bern sample”) and replicated in an independent sample of 24/24 SSD patients/controls (“Basel sample”). Results Multivariate analyses of fractional anisotropy, mean, axial, and radial diffusivity of the left IFOF showed significant differences between SSD patients and controls (p&lt;0.001, ηp2=0.23) in the Bern sample. In SSD, axial diffusivity of the left IFOF was inversely correlated with semantic processing impairments (r=-0.579, p&lt;0.0001). In the Basel sample, significant group differences for the left IFOF were replicated (p&lt;0.01, ηp2=0.29), while the correlation between axial diffusivity of the left IFOF and semantic processing decline (r=-0.376, p=0.09) showed a statistical trend. No significant effects were found for the dorsal language stream. Discussion This work provides direct evidence for the importance of the integrity of the ventral language stream, in particular the left IFOF, in semantic processing deficits in SSD.

White matter changes in chronic and episodic migraine: a diffusion tensor imaging study

Background White matter alterations have been observed in patients with migraine. However, no microstructural white matter alterations have been found particularly in episodic or chronic migraine patients, and there is limited research focused on the comparison between these two groups of migraine patients. Methods Fifty-one healthy controls, 55 episodic migraine patients and 57 chronic migraine patients were recruited and underwent brain T1-weighted and diffusion-weighted MRI acquisition. Using Tract-Based Spatial Statistics (TBSS), fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were compared between the different groups. On the one hand, all migraine patients were compared against healthy controls. On the other hand, patients from each migraine group were compared between them and also against healthy controls. Correlation analysis between clinical features (duration of migraine in years, time from onset of chronic migraine in months, where applicable, and headache and migraine frequency, where applicable) and Diffusion Tensor Imaging measures was performed. Results Fifty healthy controls, 54 episodic migraine and 56 chronic migraine patients were finally included in the analysis. Significant decreased axial diffusivity (p < .05 false discovery rate and by number of contrasts corrected) was found in chronic migraine compared to episodic migraine in 38 white matter regions from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas. Significant positive correlation was found between time from onset of chronic migraine and mean fractional anisotropy in the bilateral external capsule, and negative correlation between time from onset of chronic migraine and mean radial diffusivity in the bilateral external capsule. Conclusions These findings suggest global white matter structural differences between episodic migraine and chronic migraine. Patients with chronic migraine could present axonal integrity impairment in the first months of chronic migraine with respect to episodic migraine patients. White matter changes after the onset of chronic migraine might reflect a set of maladaptive plastic changes.