Human white matter myelinates faster in utero than ex utero.

The formation of myelin, the fatty sheath that insulates nerve fibers, is critical for healthy brain function. A fundamental open question is what impact being born has on myelin growth. To address this, we evaluated a large (n = 300) cross-sectional sample of newborns from the Developing Human Connectome Project (dHCP). First, we developed software for the automated identification of 20 white matter bundles in individual newborns that is well suited for large samples. Next, we fit linear models that quantify how T1w/T2w (a myelin-sensitive imaging contrast) changes over time at each point along the bundles. We found faster growth of T1w/T2w along the lengths of all bundles before birth than right after birth. Further, in a separate longitudinal sample of preterm infants (N = 34), we found lower T1w/T2w than in full-term peers measured at the same age. By applying the linear models fit on the cross-section sample to the longitudinal sample of preterm infants, we find that their delay in T1w/T2w growth is well explained by the amount of time they spent developing in utero and ex utero. These results suggest that white matter myelinates faster in utero than ex utero. The reduced rate of myelin growth after birth, in turn, explains lower myelin content in individuals born preterm and could account for long-term cognitive, neurological, and developmental consequences of preterm birth. We hypothesize that closely matching the environment of infants born preterm to what they would have experienced in the womb may reduce delays in myelin growth and hence improve developmental outcomes.

Development of the Alpha Rhythm Is Linked to Visual White Matter Pathways and Visual Detection Performance.

Alpha is the strongest electrophysiological rhythm in awake humans at rest. Despite its predominance in the EEG signal, large variations can be observed in alpha properties during development, with an increase in alpha frequency over childhood and adulthood. Here, we tested the hypothesis that these changes in alpha rhythm are related to the maturation of visual white matter pathways. We capitalized on a large diffusion MRI (dMRI)-EEG dataset (dMRI n = 2,747, EEG n = 2,561) of children and adolescents of either sex (age range, 5-21 years old) and showed that maturation of the optic radiation specifically accounts for developmental changes of alpha frequency. Behavioral analyses also confirmed that variations of alpha frequency are related to maturational changes in visual perception. The present findings demonstrate the close link between developmental variations in white matter tissue properties, electrophysiological responses, and behavior.

The transition from vision to language: Distinct patterns of functional connectivity for subregions of the visual word form area.

Reading entails transforming visual symbols to sound and meaning. This process depends on specialized circuitry in the visual cortex, the visual word form area (VWFA). Recent findings suggest that this text-selective cortex comprises at least two distinct subregions: the more posterior VWFA-1 is sensitive to visual features, while the more anterior VWFA-2 processes higher level language information. Here, we explore whether these two subregions also exhibit different patterns of functional connectivity. To this end, we capitalize on two complementary datasets: Using the Natural Scenes Dataset (NSD), we identify text-selective responses in high-quality 7T adult data (N = 8), and investigate functional connectivity patterns of VWFA-1 and VWFA-2 at the individual level. We then turn to the Healthy Brain Network (HBN) database to assess whether these patterns replicate in a large developmental sample (N = 224; age 6-20 years), and whether they relate to reading development. In both datasets, we find that VWFA-1 is primarily correlated with bilateral visual regions. In contrast, VWFA-2 is more strongly correlated with language regions in the frontal and lateral parietal lobes, particularly the bilateral inferior frontal gyrus. Critically, these patterns do not generalize to adjacent face-selective regions, suggesting a specific relationship between VWFA-2 and the frontal language network. No correlations were observed between functional connectivity and reading ability. Together, our findings support the distinction between subregions of the VWFA, and suggest that functional connectivity patterns in the ventral temporal cortex are consistent over a wide range of reading skills.

QSIPrep: an integrative platform for preprocessing and reconstructing diffusion MRI data.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

Children with dyslexia show no deficit in exogenous spatial attention but show differences in visual encoding.

In the search for mechanisms that contribute to dyslexia, the term "attention" has been invoked to explain performance in a variety of tasks, creating confusion since all tasks do, indeed, demand "attention." Many studies lack an experimental manipulation of attention that would be necessary to determine its influence on task performance. Nonetheless, an emerging view is that children with dyslexia have an impairment in the exogenous (automatic/reflexive) orienting of spatial attention. Here we investigated the link between exogenous attention and reading ability by presenting exogenous spatial cues in the multi-letter processing task-a task relevant for reading. The task was gamified and administered online to a large sample of children (N = 187) between 6 and 17 years. Children with dyslexia performed worse overall at rapidly recognizing and reporting strings of letters. However, we found no evidence for a difference in the utilization of exogenous spatial cues, resolving two decades of ambiguity in the field. Previous studies that claimed otherwise may have failed to distinguish attention effects from overall task performance or found spurious group differences in small samples. RESEARCH HIGHLIGHTS: We manipulated exogenous visual spatial attention using pre-cues in a task that is relevant for reading and we see robust task effects of exogenous attention. We found no evidence for a deficit in utilizing exogenous spatial pre-cues in children with dyslexia. However, children with dyslexia showed reduced recognition ability for all letter positions. Children with dyslexia were just as likely to make letter transposition errors as typical readers.

Children with developmental dyslexia have equivalent audiovisual speech perception performance but their perceptual weights differ.

As reading is inherently a multisensory, audiovisual (AV) process where visual symbols (i.e., letters) are connected to speech sounds, the question has been raised whether individuals with reading difficulties, like children with developmental dyslexia (DD), have broader impairments in multisensory processing. This question has been posed before, yet it remains unanswered due to (a) the complexity and contentious etiology of DD along with (b) lack of consensus on developmentally appropriate AV processing tasks. We created an ecologically valid task for measuring multisensory AV processing by leveraging the natural phenomenon that speech perception improves when listeners are provided visual information from mouth movements (particularly when the auditory signal is degraded). We designed this AV processing task with low cognitive and linguistic demands such that children with and without DD would have equal unimodal (auditory and visual) performance. We then collected data in a group of 135 children (age 6.5-15) with an AV speech perception task to answer the following questions: (1) How do AV speech perception benefits manifest in children, with and without DD? (2) Do children all use the same perceptual weights to create AV speech perception benefits, and (3) what is the role of phonological processing in AV speech perception? We show that children with and without DD have equal AV speech perception benefits on this task, but that children with DD rely less on auditory processing in more difficult listening situations to create these benefits and weigh both incoming information streams differently. Lastly, any reported differences in speech perception in children with DD might be better explained by differences in phonological processing than differences in reading skills. RESEARCH HIGHLIGHTS: Children with versus without developmental dyslexia have equal audiovisual speech perception benefits, regardless of their phonological awareness or reading skills. Children with developmental dyslexia rely less on auditory performance to create audiovisual speech perception benefits. Individual differences in speech perception in children might be better explained by differences in phonological processing than differences in reading skills.

Optic radiations representing different eccentricities age differently.

The neural pathways that carry information from the foveal, macular, and peripheral visual fields have distinct biological properties. The optic radiations (OR) carry foveal and peripheral information from the thalamus to the primary visual cortex (V1) through adjacent but separate pathways in the white matter. Here, we perform white matter tractometry using pyAFQ on a large sample of diffusion MRI (dMRI) data from subjects with healthy vision in the U.K. Biobank dataset (UKBB; N = 5382; age 45-81). We use pyAFQ to characterize white matter tissue properties in parts of the OR that transmit information about the foveal, macular, and peripheral visual fields, and to characterize the changes in these tissue properties with age. We find that (1) independent of age there is higher fractional anisotropy, lower mean diffusivity, and higher mean kurtosis in the foveal and macular OR than in peripheral OR, consistent with denser, more organized nerve fiber populations in foveal/parafoveal pathways, and (2) age is associated with increased diffusivity and decreased anisotropy and kurtosis, consistent with decreased density and tissue organization with aging. However, anisotropy in foveal OR decreases faster with age than in peripheral OR, while diffusivity increases faster in peripheral OR, suggesting foveal/peri-foveal OR and peripheral OR differ in how they age.

Multidimensional analysis and detection of informative features in human brain white matter.

The white matter contains long-range connections between different brain regions and the organization of these connections holds important implications for brain function in health and disease. Tractometry uses diffusion-weighted magnetic resonance imaging (dMRI) to quantify tissue properties along the trajectories of these connections. Statistical inference from tractometry usually either averages these quantities along the length of each fiber bundle or computes regression models separately for each point along every one of the bundles. These approaches are limited in their sensitivity, in the former case, or in their statistical power, in the latter. We developed a method based on the sparse group lasso (SGL) that takes into account tissue properties along all of the bundles and selects informative features by enforcing both global and bundle-level sparsity. We demonstrate the performance of the method in two settings: i) in a classification setting, patients with amyotrophic lateral sclerosis (ALS) are accurately distinguished from matched controls. Furthermore, SGL identifies the corticospinal tract as important for this classification, correctly finding the parts of the white matter known to be affected by the disease. ii) In a regression setting, SGL accurately predicts "brain age." In this case, the weights are distributed throughout the white matter indicating that many different regions of the white matter change over the lifespan. Thus, SGL leverages the multivariate relationships between diffusion properties in multiple bundles to make accurate phenotypic predictions while simultaneously discovering the most relevant features of the white matter.

Parallel spatial channels converge at a bottleneck in anterior word-selective cortex.

In most environments, the visual system is confronted with many relevant objects simultaneously. That is especially true during reading. However, behavioral data demonstrate that a serial bottleneck prevents recognition of more than one word at a time. We used fMRI to investigate how parallel spatial channels of visual processing converge into a serial bottleneck for word recognition. Participants viewed pairs of words presented simultaneously. We found that retinotopic cortex processed the two words in parallel spatial channels, one in each contralateral hemisphere. Responses were higher for attended than for ignored words but were not reduced when attention was divided. We then analyzed two word-selective regions along the occipitotemporal sulcus (OTS) of both hemispheres (subregions of the visual word form area, VWFA). Unlike retinotopic regions, each word-selective region responded to words on both sides of fixation. Nonetheless, a single region in the left hemisphere (posterior OTS) contained spatial channels for both hemifields that were independently modulated by selective attention. Thus, the left posterior VWFA supports parallel processing of multiple words. In contrast, activity in a more anterior word-selective region in the left hemisphere (mid OTS) was consistent with a single channel, showing (i) limited spatial selectivity, (ii) no effect of spatial attention on mean response amplitudes, and (iii) sensitivity to lexical properties of only one attended word. Therefore, the visual system can process two words in parallel up to a late stage in the ventral stream. The transition to a single channel is consistent with the observed bottleneck in behavior.

White matter fascicles and cortical microstructure predict reading-related responses in human ventral temporal cortex.

Reading-related responses in the lateral ventral temporal cortex (VTC) show a consistent spatial layout across individuals, which is puzzling, since reading skills are acquired during childhood. Here, we tested the hypothesis that white matter fascicles and gray matter microstructure predict the location of reading-related responses in lateral VTC. We obtained functional (fMRI), diffusion (dMRI), and quantitative (qMRI) magnetic resonance imaging data in 30 adults. fMRI was used to map reading-related responses by contrasting responses in a reading task with those in adding and color tasks; dMRI was used to identify the brain's fascicles and to map their endpoint densities in lateral VTC; qMRI was used to measure proton relaxation time (T1), which depends on cortical tissue microstructure. We fit linear models that predict reading-related responses in lateral VTC from endpoint density and T1 and used leave-one-subject-out cross-validation to assess prediction accuracy. Using a subset of our participants (N=10, feature selection set), we find that i) endpoint densities of the arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), and vertical occipital fasciculus (VOF) are significant predictors of reading-related responses, and ii) cortical T1 of lateral VTC further improves the predictions of the fascicle model. In the remaining participants (N=20, validation set), we show that a linear model that includes T1, AF, ILF and VOF significantly predicts i) the map of reading-related responses across lateral VTC and ii) the location of the visual word form area, a region critical for reading. Overall, our data-driven approach reveals that the AF, ILF, VOF and cortical microstructure have a consistent spatial relationship with an individual's reading-related responses in lateral VTC.

Neurobiological underpinnings of rapid white matter plasticity during intensive reading instruction.

Diffusion MRI is a powerful tool for imaging brain structure, but it is challenging to discern the biological underpinnings of plasticity inferred from these and other non-invasive MR measurements. Biophysical modeling of the diffusion signal aims to render a more biologically rich image of tissue microstructure, but the application of these models comes with important caveats. A separate approach for gaining biological specificity has been to seek converging evidence from multi-modal datasets. Here we use metrics derived from diffusion kurtosis imaging (DKI) and the white matter tract integrity (WMTI) model along with quantitative MRI measurements of T1 relaxation to characterize changes throughout the white matter during an 8-week, intensive reading intervention (160 total hours of instruction). Behavioral measures, multi-shell diffusion MRI data, and quantitative T1 data were collected at regular intervals during the intervention in a group of 33 children with reading difficulties (7-12 years old), and over the same period in an age-matched non-intervention control group. Throughout the white matter, mean 'extra-axonal' diffusivity was inversely related to intervention time. In contrast, model estimated axonal water fraction (AWF), overall diffusion kurtosis, and T1 relaxation time showed no significant change over the intervention period. Both diffusion and quantitative T1 based metrics were correlated with pre-intervention reading performance, albeit with distinct anatomical distributions. These results are consistent with the view that rapid changes in diffusion properties reflect phenomena other than widespread changes in myelin density. We discuss this result in light of recent work highlighting non-axonal factors in experience-dependent plasticity and learning.

Development of the visual white matter pathways mediates development of electrophysiological responses in visual cortex.

The latency of neural responses in the visual cortex changes systematically across the lifespan. Here, we test the hypothesis that development of visual white matter pathways mediates maturational changes in the latency of visual signals. Thirty-eight children participated in a cross-sectional study including diffusion magnetic resonance imaging (MRI) and magnetoencephalography (MEG) sessions. During the MEG acquisition, participants performed a lexical decision and a fixation task on words presented at varying levels of contrast and noise. For all stimuli and tasks, early evoked fields were observed around 100 ms after stimulus onset (M100), with slower and lower amplitude responses for low as compared to high contrast stimuli. The optic radiations and optic tracts were identified in each individual's brain based on diffusion MRI tractography. The diffusion properties of the optic radiations predicted M100 responses, especially for high contrast stimuli. Higher optic radiation fractional anisotropy (FA) values were associated with faster and larger M100 responses. Over this developmental window, the M100 responses to high contrast stimuli became faster with age and the optic radiation FA mediated this effect. These findings suggest that the maturation of the optic radiations over childhood accounts for individual variations observed in the developmental trajectory of visual cortex responses.

Bridging sensory and language theories of dyslexia: Toward a multifactorial model.

Competing theories of dyslexia posit that reading difficulties arise from impaired visual, auditory, phonological, or statistical learning mechanisms. Importantly, many theories posit that dyslexia reflects a cascade of impairments emanating from a single "core deficit". Here we report two studies evaluating core deficit and multifactorial models. In Study 1, we use publicly available data from the Healthy Brain Network to test the accuracy of phonological processing measures for predicting dyslexia diagnosis and find that over 30% of cases are misclassified (sensitivity = 66.7%; specificity = 68.2%). In Study 2, we collect a battery of psychophysical measures of visual motion processing and standardized measures of phonological processing in 106 school-aged children to investigate whether dyslexia is best conceptualized under a core-deficit model, or as a disorder with heterogenous origins. Specifically, by capitalizing on the drift diffusion model to analyze performance on a visual motion discrimination experiment, we show that deficits in visual motion processing, perceptual decision-making, and phonological processing manifest largely independently. Based on statistical models of how variance in reading skill is parceled across measures of visual processing, phonological processing, and decision-making, our results challenge the notion that a unifying deficit characterizes dyslexia. Instead, these findings indicate a model where reading skill is explained by several distinct, additive predictors, or risk factors, of reading (dis)ability.

Context effects on phoneme categorization in children with dyslexia.

Research shows that, on average, children with dyslexia behave less categorically in phoneme categorization tasks. This study investigates three subtle ways that struggling readers may perform differently than their typically developing peers in this experimental context: sensitivity to the frequency distribution from which speech tokens are drawn, bias induced by previous stimulus presentations, and fatigue during the course of the task. We replicate findings that reading skill is related to categorical labeling, but we do not find evidence that sensitivity to the stimulus frequency distribution, the influence of previous stimulus presentations, and a measure of task engagement differs in children with dyslexia. It is, therefore, unlikely that the reliable relationship between reading skill and categorical labeling is attributable to artifacts of the task design, abnormal neural encoding, or executive function. Rather, categorical labeling may index a general feature of linguistic development whose causal relationship to literacy remains to be ascertained.

Evaluating arcuate fasciculus laterality measurements across dataset and tractography pipelines.

The arcuate fasciculi are white-matter pathways that connect frontal and temporal lobes in each hemisphere. The arcuate plays a key role in the language network and is believed to be left-lateralized, in line with left hemisphere dominance for language. Measuring the arcuate in vivo requires diffusion magnetic resonance imaging-based tractography, but asymmetry of the in vivo arcuate is not always reliably detected in previous studies. It is unknown how the choice of tractography algorithm, with each method's freedoms, constraints, and vulnerabilities to false-positive and -negative errors, impacts findings of arcuate asymmetry. Here, we identify the arcuate in two independent datasets using a number of tractography strategies and methodological constraints, and assess their impact on estimates of arcuate laterality. We test three tractography methods: a deterministic, a probabilistic, and a tractography-evaluation (LiFE) algorithm. We extract the arcuate from the whole-brain tractogram, and compare it to an arcuate bundle constrained even further by selecting only those streamlines that connect to anatomically relevant cortical regions. We test arcuate macrostructure laterality, and also evaluate microstructure profiles for properties such as fractional anisotropy and quantitative R1. We find that both tractography choice and implementing the cortical constraints substantially impact estimates of all indices of arcuate laterality. Together, these results emphasize the effect of the tractography pipeline on estimates of arcuate laterality in both macrostructure and microstructure.

Categorical phoneme labeling in children with dyslexia does not depend on stimulus duration.

It is established that individuals with dyslexia are less consistent at auditory phoneme categorization than typical readers. One hypothesis attributes these differences in phoneme labeling to differences in auditory cue integration over time, suggesting that the performance of individuals with dyslexia would improve with longer exposure to informative phonetic cues. Here, the relationship between phoneme labeling and reading ability was investigated while manipulating the duration of steady-state auditory information available in a consonant-vowel syllable. Children with dyslexia obtained no more benefit from longer cues than did children with typical reading skills, suggesting that poor task performance is not explained by deficits in temporal integration or temporal sampling.

Evaluating g-ratio weighted changes in the corpus callosum as a function of age and sex.

Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI-based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences. To estimate the g-ratio we used a model (Stikov et al., 2011; Duval et al., 2017) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al., 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al., 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum. Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age.

Tractography optimization using quantitative T1 mapping in the human optic radiation.

Diffusion MRI tractography is essential for reconstructing white-matter projections in the living human brain. Yet tractography results miss some projections and falsely identify others. A challenging example is the optic radiation (OR) that connects the thalamus and the primary visual cortex. Here, we tested whether OR tractography can be optimized using quantitative T1 mapping. Based on histology, we proposed that myelin-sensitive T1 values along the OR should remain consistently low compared with adjacent white matter. We found that complementary information from the T1 map allows for increasing the specificity of the reconstructed OR tract by eliminating falsely identified projections. This T1-filtering outperforms other, diffusion-based tractography filters. These results provide evidence that the smooth microstructural signature along the tract can be used as constructive input for tractography. Finally, we demonstrate that this approach can be applied in a case of multiple sclerosis, and generalized to the HCP-available MRI measurements. We conclude that multimodal MRI microstructural information can be used to eliminate spurious tractography results in the case of the OR.

Aging-Resilient Associations between the Arcuate Fasciculus and Vocabulary Knowledge: Microstructure or Morphology?

UNLABELLED: Vocabulary knowledge is one of the few cognitive functions that is relatively preserved in older adults, but the reasons for this relative preservation have not been well delineated. We tested the hypothesis that individual differences in vocabulary knowledge are influenced by arcuate fasciculus macrostructure (i.e., shape and volume) properties that remain stable during the aging process, rather than white matter microstructure that demonstrates age-related declines. Vocabulary was not associated with age compared to pronounced age-related declines in cognitive processing speed across 106 healthy adults (19.92-88.29 years) who participated in this neuroimaging experiment. Fractional anisotropy in the left arcuate fasciculus was significantly related to individual variability in vocabulary. This effect was present despite marked age-related differences in a T1-weighted/T2-weighted ratio (T1w/T2w) estimate of myelin that were observed throughout the left arcuate fasciculus and associated with age-related differences in cognitive processing speed. However, atypical patterns of arcuate fasciculus morphology or macrostructure were associated with decreased vocabulary knowledge. These results suggest that deterioration of tissue in the arcuate fasciculus occurs with normal aging, while having limited impact on tract organization that underlies individual differences in the acquisition and retrieval of lexical and semantic information. SIGNIFICANCE STATEMENT: Vocabulary knowledge is resilient to widespread age-related declines in brain structure that limit other cognitive functions. We tested the hypothesis that arcuate fasciculus morphology, which supports the development of reading skills that bolster vocabulary, could explain this relative preservation. We disentangled (1) the effects of age-related declines in arcuate microstructure (mean diffusivity; myelin content estimate) that predicted cognitive processing speed but not vocabulary, from (2) relatively stable arcuate macrostructure (shape/volume) that explained significant variance in an age-independent association between fractional anisotropy and vocabulary. This latter result may reflect differences in fiber trajectory and organization that are resilient to aging. We propose that developmental sculpting of the arcuate fasciculus determines acquisition, storage, and access of lexical information across the adult lifespan.

The corticospinal tract profile in amyotrophic lateral sclerosis.

This work evaluates the potential in diagnostic application of a new advanced neuroimaging method, which delineates the profile of tissue properties along the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS), by means of diffusion tensor imaging (DTI). Twenty-four ALS patients and twenty-four demographically matched healthy subjects were enrolled in this study. The Automated Fiber Quantification (AFQ), a tool for the automatic reconstruction of white matter tract profiles, based on a deterministic tractography algorithm to automatically identify the CST and quantify its diffusion properties, was used. At a group level, the highest non-overlapping DTI-related differences were detected in the cerebral peduncle, posterior limb of the internal capsule, and primary motor cortex. Fractional anisotropy (FA) decrease and mean diffusivity (MD) and radial diffusivity (RD) increases were detected when comparing ALS patients to controls. The machine learning approach used to assess the clinical utility of this DTI tool revealed that, by combining all DTI metrics measured along tract between the cerebral peduncle and the corona radiata, a mean 5-fold cross validation accuracy of 80% was reached in discriminating ALS from controls. Our study provides a useful new neuroimaging tool to characterize ALS-related neurodegenerative processes by means of CST profile. We demonstrated that specific microstructural changes in the upper part of the brainstem might be considered as a valid biomarker. With further validations this method has the potential to be considered a promising step toward the diagnostic utility of DTI measures in ALS. Hum Brain Mapp 38:727-739, 2017. © 2016 Wiley Periodicals, Inc.