Detailed connectivities have been studied in animals through invasive tracer techniques, but these invasive studies cannot be done in humans, and animal results cannot always be extrapolated to human systems. We have developed noninvasive neuronal fiber tracking for use in living humans, utilizing the unique ability of MRI to characterize water diffusion. We reconstructed fiber trajectories throughout the brain by tracking the direction of fastest diffusion (the fiber direction) from a grid of seed points, and then selected tracks that join anatomically or functionally (functional MRI) defined regions. We demonstrate diffusion tracking of fiber bundles in a variety of white matter classes with examples in the corpus callosum, geniculo-calcarine, and subcortical association pathways. Tracks covered long distances, navigated through divergences and tight curves, and manifested topological separations in the geniculo-calcarine tract consistent with tracer studies in animals and retinotopy studies in humans. Additionally, previously undescribed topologies were revealed in the other pathways. This approach enhances the power of modern imaging by enabling study of fiber connections among anatomically and functionally defined brain regions in individual human subjects.

Quantitative diffusion anisotropy images can be obtained rapidly and demonstrate subtle WM anatomy. Different histologic types of WM have significant and reproducible anisotropy differences.

We present a description, biological results and a reliability analysis for the method of diffusion tensor tracking (DTT) of white matter fiber pathways. In DTT, diffusion-tensor MRI (DT-MRI) data are collected and processed to visualize the line trajectories of fiber bundles within white matter (WM) pathways of living humans. A detailed description of the data acquisition is given. Technical aspects and experimental results are illustrated for the geniculo-calcarine tract with broad projections to visual cortex, occipital and parietal U-fibers, and the temporocalcarine ventral pathway. To better understand sources of error and to optimize the method, accuracy and precision were analyzed by computer simulations. In the simulations, noisy DT-MRI data were computed that would be obtained for a WM pathway having a helical trajectory passing through gray matter. The error vector between the real and ideal track was computed, and random errors accumulated with the square root of track length consistent with a random-walk process. Random error was most dependent on signal-to-noise ratio, followed by number of averages, pathway anisotropy and voxel size, in decreasing order. Systematic error only occurred for a few conditions, and was most dependent on the stepping algorithm, anisotropy of the surrounding tissue, and non-equal voxel dimensions. Both random and systematic errors were typically below the voxel dimension. Other effects such as track rebound and track recovery also depended on experimental conditions. The methods, biological results and error analysis herein may improve the understanding and optimization of DTT for use in various applications in neuroscience and medicine.

Diffusion tensor imaging (DTI) is amongst the simplest mathematical models available for diffusion magnetic resonance imaging, yet still by far the most used one. Despite the success of DTI as an imaging tool for white matter fibers, its anatomical underpinnings on a microstructural basis remain unclear. In this study, we used 65 myelin-stained sections of human premotor cortex to validate modeled fiber orientations and oft used microstructure-sensitive scalar measures of DTI on the level of individual voxels. We performed this validation on high spatial resolution diffusion MRI acquisitions investigating both white and gray matter. We found a very good agreement between DTI and myelin orientations with the majority of voxels showing angular differences less than 10°. The agreement was strongest in white matter, particularly in unidirectional fiber pathways. In gray matter, the agreement was good in the deeper layers highlighting radial fiber directions even at lower fractional anisotropy (FA) compared to white matter. This result has potentially important implications for tractography algorithms applied to high resolution diffusion MRI data if the aim is to move across the gray/white matter boundary. We found strong relationships between myelin microstructure and DTI-based microstructure-sensitive measures. High FA values were linked to high myelin density and a sharply tuned histological orientation profile. Conversely, high values of mean diffusivity (MD) were linked to bimodal or diffuse orientation distributions and low myelin density. At high spatial resolution, DTI-based measures can be highly sensitive to white and gray matter microstructure despite being relatively unspecific to concrete microarchitectural aspects.

Interoception, the sensing of visceral body signals, involves an interplay between neural and autonomic mechanisms. Clinical studies into this domain have focused on patients with neurological and psychiatric disorders, showing that damage to relevant brain mechanisms can variously alter interoceptive functions. However, the association between peripheral cardiac-system alterations and neurocognitive markers of interoception remains poorly understood. To bridge this gap, we examined multidimensional neural markers of interoception in patients with early stage of hypertensive disease (HTD) and healthy controls. Strategically, we recruited only HTD patients without cognitive impairment (as shown by neuropsychological tests), brain atrophy (as assessed with voxel-based morphometry), or white matter abnormalities (as evidenced by diffusion tensor imaging analysis). Interoceptive domains were assessed through (a) a behavioral heartbeat detection task; (b) measures of the heart-evoked potential (HEP), an electrophysiological cortical signature of attention to cardiac signals; and (c) neuroimaging recordings (MRI and fMRI) to evaluate anatomical and functional connectivity properties of key interoceptive regions (namely, the insula and the anterior cingulate cortex). Relative to controls, patients exhibited poorer interoceptive performance and reduced HEP modulations, alongside an abnormal association between interoceptive performance and both the volume and functional connectivity of the above regions. Such results suggest that peripheral cardiac-system impairments can be associated with abnormal behavioral and neurocognitive signatures of interoception. More generally, our findings indicate that interoceptive processes entail bidirectional influences between the cardiovascular and the central nervous systems.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease-modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples' socio-cultural background, and, more troublingly still, no gold-standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral-variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold-standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter-regional connectivity, and several graph-theory approaches. Only graph-theory analysis, based on weighted-matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph-theory as a potential gold-standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804-3822, 2017. © 2017 Wiley Periodicals, Inc.

Purpose:To use MRI diffusion-tensor tracking (DTT) to test for the presence of unknown neuronal fiber pathways interconnecting the mid-fusiform cortex and anteromedial temporal lobe in humans. Such pathways are hypothesized to exist because these regions coactivate in functional MRI (fMRI) studies of emotion-valued faces and words, suggesting a functional link that could be mediated by neuronal connections. Materials and Methods:A total of 15 normal human subjects were studied using unbiased DTT approaches designed for probing unknown pathways, including wholebrain seeding and large pathway-selection volumes. Several quality-control steps verified the results.Results: Parallel amygdalo-fusiform and hippocampo-fusiform pathways were found in all subjects. The pathways begin/end at the mid-fusiform gyrus above the lateral occipitotemporal sulcus bilaterally. The superior pathway ends/ begins at the superolateral amygdala. The inferior pathway crosses medially and ends/begins at the hippocampal head. The pathways are left-lateralized, with consistently larger cross-sectional area, higher anisotropy, and lower minimum eigenvalue (D-min) on the left, where D-min assesses intrinsic cross-fiber diffusivity independent of curvature. Conclusion:A previously-undescribed pathway system interconnecting the mid-fusiform region with the amygdala/ hippocampus has been revealed. This pathway system may be important for recognition, memory consolidation, and emotional modulation of face, object, and lexical information, which may be disrupted in conditions such as Alzheimer's disease. THE HUMAN BRAIN contains specific structural regions that support functions such as language, social cognition, memory, and abstract reasoning. These structures are likely unique or greatly expanded relative to the nonhuman primate brain. The anatomical connections involved in these functions are largely unknown in humans, as such connections cannot be directly inferred from invasive tracer studies of nonhuman primates (1,2). Diffusion tensor tracking (DTT) provides a direct measurement of white matter pathway anatomy and connectivity that previously was not possible. First introduced in fixed rat brain (3) and living humans (4), DTT was subsequently applied to reconstruct several dominant macroscopic pathways in the human brain (5-9). Extension of DTT to discover previously unknown pathways requires specific techniques and unbiased approaches.Here we use DTT to test the hypothesis that a pathway system exists in humans interconnecting the midfusiform region (MFR) with the amygdala/hippocampus. The mid-fusiform region incorporates a complex high-order cortex associated with visual object recognition, including special "objects" such as faces (in both hemispheres, more so on the right), non-face objects (in both hemispheres, more so on the left), and aspects of visual-lexical function (in the left hemisphere) (10 -20). We hypothesize the existence of these pathways based on available human functional and pathological data. In several functional MRI ...

OCD has been hypothesized to involve the failures in both cognitive and behavioral inhibitory processes. There is evidence that the hyperactivation of cortical-subcortical pathways may be involved in the failure of these inhibitory systems associated with OCD. Despite this consensus on the role of frontal-subcortical pathways in OCD, recent studies have been showing that brain regions other than the frontal-subcortical loops may be needed to understand the different cognitive and emotional deficits in OCD. Some studies have been finding evidence for decreased metabolic activity in areas such as left inferior parietal and parieto-occipital junction suggesting the possible existence of visual processing deficits. While there has been inconsistent data regarding visual processing in OCD, recent studies have been claiming that these patients have abnormal patterns of visual processing social rich stimuli, particularly emotional arousing stimuli. Thus, in this article, we hypothesize that the fronto-subcortical activation consistently found in OCD may be due to a deactivation of occipital/parietal regions associated with visual-perceptual processing of incoming social rich stimuli. Additionally, this dissociation may be more evident as the emotional intensity of the social stimulus increases.