Limits to anatomical accuracy of diffusion tractography using modern approaches.

Diffusion MRI fiber tractography is widely used to probe the structural connectivity of the brain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the 3-D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge at the ISBI 2018 conference. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography's inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.

Finding the baby in the bath water - evidence for task-specific changes in resting state functional connectivity evoked by training.

Resting-state functional connectivity (rsFC) between brain regions has been used for studying training-related changes in brain function during the offline period of skill learning. However, it is difficult to infer whether the observed training-related changes in rsFC measured between two scans occur as a consequence of task performance, whether they are specific to a given task, or whether they reflect confounding factors such as diurnal fluctuations in brain physiology that impact the MRI signal. Here, we sought to elucidate whether task-specific changes in rsFC are dissociable from time-of-day related changes by evaluating rsFC changes after participants were provided training in either a visuospatial task or a motor sequence task compared to a non-training condition. Given the nature of the tasks, we focused on changes in rsFC of the hippocampal and sensorimotor cortices after short-term training, while controlling for the effect of time-of-day. We also related the change in rsFC of task-relevant brain regions to performance improvement in each task. Our results demonstrate that, even in the absence of any experimental manipulation, significant changes in rsFC can be detected between two resting state functional MRI scans performed just a few hours apart, suggesting time-of-day has a significant impact on rsFC. However, by estimating the magnitude of the time-of-day effect, our findings also suggest that task-specific changes in rsFC can be dissociated from the changes attributed to time-of-day. Taken together, our results show that rsFC can provide insights about training-related changes in brain function during the offline period of skill learning. However, demonstrating the specificity of the changes in rsFC to a given task requires a rigorous experimental design that includes multiple active and passive control conditions, and robust behavioral measures.

Tensor-based morphometry using scalar and directional information of diffusion tensor MRI data (DTBM): Application to hereditary spastic paraplegia.

Tensor-based morphometry (TBM) performed using T1-weighted images (T1WIs) is a well-established method for analyzing local morphological changes occurring in the brain due to normal aging and disease. However, in white matter regions that appear homogeneous on T1WIs, T1W-TBM may be inadequate for detecting changes that affect specific pathways. In these regions, diffusion tensor MRI (DTI) can identify white matter pathways on the basis of their different anisotropy and orientation. In this study, we propose performing TBM using deformation fields constructed using all scalar and directional information provided by the diffusion tensor (DTBM) with the goal of increasing sensitivity in detecting morphological abnormalities of specific white matter pathways. Previously, mostly fractional anisotropy (FA) has been used to drive registration in diffusion MRI-based TBM (FA-TBM). However, FA does not have the directional information that the tensors contain, therefore, the registration based on tensors provides better alignment of brain structures and better localization of volume change. We compare our DTBM method to both T1W-TBM and FA-TBM in investigating differences in brain morphology between patients with complicated hereditary spastic paraplegia of type 11 (SPG11) and a group of healthy controls. Effect size maps of T1W-TBM of SPG11 patients showed diffuse atrophy of white matter. However, DTBM indicated that atrophy was more localized, predominantly affecting several long-range pathways. The results of our study suggest that DTBM could be a powerful tool for detecting morphological changes of specific white matter pathways in normal brain development and aging, as well as in degenerative disorders.

Impact of time-of-day on diffusivity measures of brain tissue derived from diffusion tensor imaging.

Diurnal fluctuations in MRI measures of structural and functional properties of the brain have been reported recently. These fluctuations may have a physiological origin, since they have been detected using different MRI modalities, and cannot be explained by factors that are typically known to confound MRI measures. While preliminary evidence suggests that measures of structural properties of the brain based on diffusion tensor imaging (DTI) fluctuate as a function of time-of-day (TOD), the underlying mechanism has not been investigated. Here, we used a longitudinal within-subjects design to investigate the impact of time-of-day on DTI measures. In addition to using the conventional monoexponential tensor model to assess TOD-related fluctuations, we used a dual compartment tensor model that allowed us to directly assess if any change in DTI measures is due to an increase in CSF/free-water volume fraction or due to an increase in water diffusivity within the parenchyma. Our results show that Trace or mean diffusivity, as measured using the conventional monoexponential tensor model tends to increase systematically from morning to afternoon scans at the interface of grey matter/CSF, most prominently in the major fissures and the sulci of the brain. Interestingly, in a recent study of the glymphatic system, these same regions were found to show late enhancement after intrathecal injection of a CSF contrast agent. The increase in Trace also impacts DTI measures of diffusivity such as radial and axial diffusivity, but does not affect fractional anisotropy. The dual compartment analysis revealed that the increase in diffusivity measures from PM to AM was driven by an increase in the volume fraction of CSF-like free-water. Taken together, our findings provide important insight into the likely physiological origins of diurnal fluctuations in MRI measurements of structural properties of the brain.

DR-TAMAS: Diffeomorphic Registration for Tensor Accurate Alignment of Anatomical Structures.

In this work, we propose DR-TAMAS (Diffeomorphic Registration for Tensor Accurate alignMent of Anatomical Structures), a novel framework for intersubject registration of Diffusion Tensor Imaging (DTI) data sets. This framework is optimized for brain data and its main goal is to achieve an accurate alignment of all brain structures, including white matter (WM), gray matter (GM), and spaces containing cerebrospinal fluid (CSF). Currently most DTI-based spatial normalization algorithms emphasize alignment of anisotropic structures. While some diffusion-derived metrics, such as diffusion anisotropy and tensor eigenvector orientation, are highly informative for proper alignment of WM, other tensor metrics such as the trace or mean diffusivity (MD) are fundamental for a proper alignment of GM and CSF boundaries. Moreover, it is desirable to include information from structural MRI data, e.g., T1-weighted or T2-weighted images, which are usually available together with the diffusion data. The fundamental property of DR-TAMAS is to achieve global anatomical accuracy by incorporating in its cost function the most informative metrics locally. Another important feature of DR-TAMAS is a symmetric time-varying velocity-based transformation model, which enables it to account for potentially large anatomical variability in healthy subjects and patients. The performance of DR-TAMAS is evaluated with several data sets and compared with other widely-used diffeomorphic image registration techniques employing both full tensor information and/or DTI-derived scalar maps. Our results show that the proposed method has excellent overall performance in the entire brain, while being equivalent to the best existing methods in WM.

Impact of time-of-day on brain morphometric measures derived from T1-weighted magnetic resonance imaging.

Measures of brain morphometry derived from T1-weighted (T1W) magnetic resonance imaging (MRI) are widely used to elucidate the relation between brain structure and function. However, the computation of T1W morphometric measures can be confounded by subject-related factors such as head motion and level of hydration. A recent study reported subtle yet significant changes in brain volume from morning to evening in a large group of patient populations as well as in healthy elderly individuals. In addition, there is a growing recognition that factors such as circadian rhythm can impact MRI measures of brain function and structure. Here, we provide a comprehensive assessment of the impact of time-of-day (TOD) on widely used measures of brain morphometry in a group of 19 healthy young adults. Our results show that (a) even in a small group of healthy adult volunteers, a highly significant reduction in apparent brain volume, from morning to evening, could be detected; (b) the apparent volume of all three major tissue compartments - gray matter, white matter, and cerebrospinal fluid - were influenced by TOD, and the magnitude of the TOD effect varied across the tissue compartments; (c) measures of cortical thickness, cortical surface area, and gray matter density computed with widely used neuroimaging software suites (i.e., FreeSurfer, FSL-VBM) were all affected by TOD, while other measures, such as curvature indices and sulcal depth, were not; and (d) the effect of TOD appeared to have a greater impact on morphometric measures of the frontal and temporal lobe than on other major lobes of the brain. Our results suggest that the TOD effect is a physiological phenomenon and that controlling for the effect of TOD is crucial for proper interpretation of apparent structural differences measured with T1W morphometry.

Clinical feasibility of using mean apparent propagator (MAP) MRI to characterize brain tissue microstructure.

Diffusion tensor imaging (DTI) is the most widely used method for characterizing noninvasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity, is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The propagator anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our ability to perform whole-brain fiber tractography. Reconstructions from subsampled data sets suggest that MAP MRI parameters can be computed from a relatively small number of DWIs acquired with high b-value and good signal-to-noise ratio in clinically achievable scan durations of less than 10min. The neuroanatomical consistency across healthy subjects and reproducibility in test-retest experiments of MAP MRI microstructural parameters further substantiate the robustness and clinical feasibility of this technique. The MAP MRI metrics could potentially provide more sensitive clinical biomarkers with increased pathophysiological specificity compared to microstructural measures derived using conventional diffusion MRI techniques.

Diffusion MRI properties of the human uncinate fasciculus correlate with the ability to learn visual associations.

The uncinate fasciculus (UF) is a cortico-cortico white matter pathway that links the anterior temporal and the orbitofrontal cortex (OFC). In the monkey, transection of the UF causes significant impairments in learning conditional visual-visual associations, while object discrimination remains intact, suggesting an important role for the UF in mediating the learning of complex visual associations. Whether this functional role extends to the human UF has not been tested directly. Here, we used diffusion tensor magnetic resonance imaging (dMRI) and behavioral experiments to examine the relation between learning visual associations and the structural properties of the human UF. In a group of healthy adults, we segmented the UF and the inferior longitudinal fasciculus (ILF) and derived dMRI measures of the structural properties of the two pathways. We also used a behavioral experiment adapted from the monkey studies to characterize the ability of these individuals to learn to associate a person's face with a group of specific scenes (conditional visual-visual association). We then tested whether the variability in the dMRI measures of the two pathways correlated with variability in the ability to rapidly learn the face-place associations. Our study suggests that in the human, the left UF may be important for mediating the rapid learning of conditional visual-visual associations whereas the right UF may play an important role in the immediate retrieval of visual-visual associations. These results provide preliminary evidence suggesting similarities and differences in the functional role of the UF in monkeys compared to humans. The findings presented here contribute to our understanding of the functional role of the UF in humans and the functional neuroanatomy of the brain networks involved in visual cognition.

Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited.

Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.

Global motion perception deficits in autism are reflected as early as primary visual cortex.

Individuals with autism are often characterized as 'seeing the trees, but not the forest'-attuned to individual details in the visual world at the expense of the global percept they compose. Here, we tested the extent to which global processing deficits in autism reflect impairments in (i) primary visual processing; or (ii) decision-formation, using an archetypal example of global perception, coherent motion perception. In an event-related functional MRI experiment, 43 intelligence quotient and age-matched male participants (21 with autism, age range 15-27 years) performed a series of coherent motion perception judgements in which the amount of local motion signals available to be integrated into a global percept was varied by controlling stimulus viewing duration (0.2 or 0.6 s) and the proportion of dots moving in the correct direction (coherence: 4%, 15%, 30%, 50%, or 75%). Both typical participants and those with autism evidenced the same basic pattern of accuracy in judging the direction of motion, with performance decreasing with reduced coherence and shorter viewing durations. Critically, these effects were exaggerated in autism: despite equal performance at the long duration, performance was more strongly reduced by shortening viewing duration in autism (P < 0.015) and decreasing stimulus coherence (P < 0.008). To assess the neural correlates of these effects we focused on the responses of primary visual cortex and the middle temporal area, critical in the early visual processing of motion signals, as well as a region in the intraparietal sulcus thought to be involved in perceptual decision-making. The behavioural results were mirrored in both primary visual cortex and the middle temporal area, with a greater reduction in response at short, compared with long, viewing durations in autism compared with controls (both P < 0.018). In contrast, there was no difference between the groups in the intraparietal sulcus (P > 0.574). These findings suggest that reduced global motion perception in autism is driven by an atypical response early in visual processing and may reflect a fundamental perturbation in neural circuitry.

Emerging structure-function relations in the developing face processing system.

To evaluate emerging structure-function relations in a neural circuit that mediates complex behavior, we investigated age-related differences among cortical regions that support face recognition behavior and the fiber tracts through which they transmit and receive signals using functional neuroimaging and diffusion tensor imaging. In a large sample of human participants (aged 6-23 years), we derived the microstructural and volumetric properties of the inferior longitudinal fasciculus (ILF), the inferior fronto-occipital fasciculus, and control tracts, using independently defined anatomical markers. We also determined the functional characteristics of core face- and place-selective regions that are distributed along the trajectory of the pathways of interest. We observed disproportionately large age-related differences in the volume, fractional anisotropy, and mean and radial, but not axial, diffusivities of the ILF. Critically, these differences in the structural properties of the ILF were tightly and specifically linked with an age-related increase in the size of a key face-selective functional region, the fusiform face area. This dynamic association between emerging structural and functional architecture in the developing brain may provide important clues about the mechanisms by which neural circuits become organized and optimized in the human cortex.

On evidence, biases and confounding factors: Response to commentaries.

In a critical review (Thomas and Baker, 2012), we argued for caution in evaluating reports of training-dependent adult structural plasticity measured with MRI. Here, we respond to the commentaries on our review, clarifying our position and addressing some of the specific criticisms raised.

Teaching an adult brain new tricks: a critical review of evidence for training-dependent structural plasticity in humans.

A growing number of structural neuroimaging studies have reported significant changes in gray matter density or volume and white matter microstructure in the adult human brain following training. Such reports appear consistent with animal studies of training-dependent structural plasticity showing changes in, for example, dendritic spines. However, given the microscopic nature of these changes in animals and the relatively low spatial resolution of MRI, it is unclear that such changes can be reliably detected in humans. Here, we critically evaluate the robustness of the current evidence in humans, focusing on the specificity, replicability, and the relationship of the reported changes with behavior. We find that limitations of experimental design, statistical methods, and methodological artifacts may underlie many of the reported effects, seriously undermining the evidence for training-dependent structural changes in adult humans. The most robust evidence, showing specificity of structural changes to training, task and brain region, shows changes in anterior hippocampal volume with exercise in elderly participants. We conclude that more compelling evidence and converging data from animal studies is required to substantiate structural changes in the adult human brain with training, especially in the neocortex.

Enabling global processing in simultanagnosia by psychophysical biasing of visual pathways.

A fundamental aspect of visual cognition is our disposition to see the 'forest before the trees'. However, damage to the posterior parietal cortex, a critical brain region along the dorsal visual pathway, can produce a neurological disorder called simultanagnosia, characterized by a debilitating inability to perceive the 'forest' but not the 'trees' (i.e. impaired global processing despite intact local processing). This impairment in perceiving the global shape persists even though the ventral visual pathway, the primary recognition pathway, is intact in these patients. Here, we enabled global processing in patients with simultanagnosia using a psychophysical technique, which allowed us to bias stimuli such that they are processed predominantly by the intact ventral visual pathway. Our findings reveal that the impairment in global processing that characterizes simultanagnosia stems from a disruption in the processing of low-spatial frequencies through the dorsal pathway. These findings advance our understanding of the relationship between visuospatial attention and perception and reveal the neural mechanism mediating the disposition to see the 'forest before the trees'.

The anatomy of the callosal and visual-association pathways in high-functioning autism: a DTI tractography study.

There is increasing recognition that many of the core behavioral impairments that characterize autism potentially emerge from poor neural synchronization across nodes comprising dispersed cortical networks. A likely candidate for the source of this atypical functional connectivity in autism is an alteration in the structural integrity of intra- and inter-hemispheric white matter (WM) tracts that form large-scale cortical networks. To test this hypothesis, in a group of adults with high-functioning autism (HFA) and matched control participants, we used diffusion tensor tractography to compare the structural integrity of three intra-hemispheric visual-association WM tracts, the inferior longitudinal fasciculus (ILF), the inferior fronto-occipito fasciculus (IFOF) and the uncinate fasciculus (UF), with the integrity of three sub-portions of the major inter-hemispheric fiber tract, the corpus callosum. Compared with the control group, the HFA group evinced an increase in the volume of the intra-hemispheric fibers, particularly in the left hemisphere, and a reduction in the volume of the forceps minor (F-Mi) and body of the corpus callosum. The reduction in the volume of the F-Mi also correlated with an increase in repetitive and stereotypical behavior as measured by the Autism Diagnostic Interview. These findings suggest that the abnormalities in the integrity of key inter- and intra-hemispheric WM tracts may underlie the atypical information processing observed in these individuals.

Normal movement selectivity in autism.

It has been proposed that individuals with autism have difficulties understanding the goals and intentions of others because of a fundamental dysfunction in the mirror neuron system. Here, however, we show that individuals with autism exhibited not only normal fMRI responses in mirror system areas during observation and execution of hand movements but also exhibited typical movement-selective adaptation (repetition suppression) when observing or executing the same movement repeatedly. Movement selectivity is a defining characteristic of neurons involved in movement perception, including mirror neurons, and, as such, these findings argue against a mirror system dysfunction in autism.

Reduced structural connectivity in ventral visual cortex in congenital prosopagnosia.

Using diffusion tensor imaging and tractography, we found that a disruption in structural connectivity in ventral occipito-temporal cortex may be the neurobiological basis for the lifelong impairment in face recognition that is experienced by individuals who suffer from congenital prosopagnosia. Our findings suggest that white-matter fibers in ventral occipito-temporal cortex support the integrated function of a distributed cortical network that subserves normal face processing.

Reduction in white matter connectivity, revealed by diffusion tensor imaging, may account for age-related changes in face perception.

An age-related decline in face processing, even under conditions in which learning and memory are not implicated, has been well documented, but the mechanism underlying this perceptual alteration remains unknown. Here, we examine whether this behavioral change may be accounted for by a reduction in white matter connectivity with age. To this end, we acquired diffusion tensor imaging data from 28 individuals aged 18 to 86 years and quantified the number of fibers, voxels, and fractional anisotropy of the two major tracts that pass through the fusiform gyrus, the pre-eminent face processing region in the ventral temporal cortex. We also measured the ability of a subset of these individuals to make fine-grained discriminations between pairs of faces and between pairs of cars. There was a significant reduction in the structural integrity of the inferior fronto-occipital fasciculus (IFOF) in the right hemisphere as a function of age on all dependent measures and there were also some changes in the left hemisphere, albeit to a lesser extent. There was also a clear age-related decrement in accuracy of perceptual discrimination, especially for more challenging perceptual discriminations, and this held to a greater degree for faces than for cars. Of greatest relevance, there was a robust association between the reduction of IFOF integrity in the right hemisphere and the decline in face perception, suggesting that the alteration in structural connectivity between the right ventral temporal and frontal cortices may account for the age-related difficulties in face processing.