Surface-based tracking for short association fibre tractography.

It is estimated that in the human brain, short association fibres (SAF) represent more than half of the total white matter volume and their involvement has been implicated in a range of neurological and psychiatric conditions. This population of fibres, however, remains relatively understudied in the neuroimaging literature. Some of the challenges pertinent to the mapping of SAF include their variable anatomical course and proximity to the cortical mantle, leading to partial volume effects and potentially affecting streamline trajectory estimation. This work considers the impact of seeding and filtering strategies and choice of scanner, acquisition, data resampling to propose a whole-brain, surface-based short (≤30-40 mm) SAF tractography approach. The framework is shown to produce longer streamlines with a predilection for connecting gyri as well as high cortical coverage. We further demonstrate that certain areas of subcortical white matter become disproportionally underrepresented in diffusion-weighted MRI data with lower angular and spatial resolution and weaker diffusion weighting; however, collecting data with stronger gradients than are usually available clinically has minimal impact, making our framework translatable to data collected on commonly available hardware. Finally, the tractograms are examined using voxel- and surface-based measures of consistency, demonstrating moderate reliability, low repeatability and high between-subject variability, urging caution when streamline count-based analyses of SAF are performed.

Disentangling the variability of the superficial white matter organization using regional-tractogram-based population stratification.

Each variation of the cortical folding pattern implies a particular rearrangement of the geometry of the fibers of the underlying white matter. While this rearrangement only impacts the ends of the long pathways, it may affect most of the trajectory of the short bundles. Therefore, mapping the short fibers of the human brain using diffusion-based tractography requires a dedicated strategy to overcome the variability of the folding patterns. In this paper, we propose a fiber-based stratification strategy splitting the population into homogeneous groups for disentangling the superficial white matter bundle organization. This strategy introduces a new refined fiber distance which includes angular considerations for inferring fine-grained atlases of the short bundles surrounding a specific sulcus and a subtractogram distance that quantifies the similitude between fiber sets of two different subjects. The stratification splits the population into groups with similar regional fiber organization using manifold learning. We first successfully test the hypothesis that the main source of variability of the regional fiber organization is the variability of the regional folding pattern. Then, in each group, we proceed with the automatic identification of the most stable bundles, at a higher granularity level than what can be achieved with the non-stratified whole population, enabling the disentanglement of the very variable configuration of the short fibers. Finally, the method searches for bundle correspondence across groups to build a population level atlas. As a proof of concept, the atlas refinement achieved by this strategy is illustrated for the fibers that surround the central sulcus and the superior temporal sulcus using the HCP dataset.

Pyramid-Shape Crossings and Intercrossing Fibers Are Key Elements for Construction of the Neural Network in the Superficial White Matter of the Human Cerebrum.

Structural analysis of the superficial white matter is prerequisite for the understanding of highly integrated functions of the human cerebral cortex. However, the principal components, U-fibers, have been regarded as simple wires to connect adjacent gyri (inter-gyral U-fibers) but have never been thought as indispensable elements of anatomical structures to construct the cortical network. Here, we reported such novel structures made of U-fibers. Seven human cerebral hemispheres were treated with Klingler's method and subjected to fiber dissection (FD). Additionally, tractography using diffusion spectrum imaging (DSI) was performed. Our FD and DSI tractography succeeded disclosing a new type of U-fibers that was hidden in and ran along the white matter ridge of a gyral convolution (intra-gyral U-fibers). They were distinct from inter-gyral U-fibers which paved sulcal floors. Both intra- and inter-gyral U-fibers converged from various directions into junctional areas of white matter ridges, organizing novel anatomical structures, "pyramid-shape crossings". U-fibers to form pyramid-shape crossings also render routes for communication between crossings. There were 97 (mean, range 73-148) pyramid-shape crossings per lateral cortical surface. They are key structures to construct the neural network for intricate communications throughout the entire cerebrum. They can be new anatomical landmarks, too, for the segmentation of the cerebral cortex.

Mapping Short Association Fibers in the Early Cortical Visual Processing Stream Using In Vivo Diffusion Tractography.

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome.

Superficial white matter: A review on the dMRI analysis methods and applications.

The mapping of human brain connections is still an on going task. Unlike deep white matter (DWM), which has been extensively studied and well documented, superficial white matter (SWM) has been often left aside. Improving our understanding of the SWM is an important goal for a better understanding of the brain network and its relation to several pathologies. The shape and localization of these short bundles present a high variability across subjects. Furthermore, the small diameter of most superficial bundles and partial volume effects induced by their proximity to the cortex leads to complex tratography issues. Therefore, the mapping of SWM bundles and the use of the resulting atlases for clinical studies requiere dedicated methodologies that are reviewed in this paper.

The neuroimaging findings of monocarboxylate transporter 1 deficiency.

Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections. Patients with homozygous mutations are known to have a more severe phenotype with mild to moderate developmental delay and an increased prevalence of epilepsy. There is only one recent report of the neuroimaging findings of this disorder as reported by Al-Khawaga et al. (Front Pediatr. 7:299, 2019). We report the neuroimaging abnormalities in two siblings with similar clinical presentation of recurrent ketoacidosis, seizures, and developmental delay. Whole exome sequencing in the younger sibling confirmed a known pathogenic homozygous mutation in MCT1, also known as SLC16A1 gene. Brain MRI showed a similar very distinctive pattern of signal abnormality at the gray-white matter junction, basal ganglia, and thalami in both patients. Both siblings had agenesis of the corpus callosum. Knowledge of this pattern of brain involvement might contribute to an earlier diagnosis and timely management of this rare and under recognized disorder.

The cingulum and cingulate U-fibers in children and adolescents with autism spectrum disorders.

The cingulum is the major fiber system connecting the cingulate and surrounding medial cortex and medial temporal lobe internally and with other brain areas. It is important for social and emotional functions related to core symptomatology in autism spectrum disorders (ASDs). While the cingulum has been examined in autism, the extensive system of cingulate U-fibers has not been studied. Using probabilistic tractography, we investigated white matter fibers of the cingulate cortex by distinguishing its deep intra-cingulate bundle (cingulum proper) and short rostral anterior, caudal anterior, posterior, and isthmus cingulate U-fibers in 61 ASD and 54 typically developing children and adolescents. Increased mean and radial diffusivity of the left cingulum proper was observed in the ASD group, replicating previous findings on the cingulum. For cingulate U-fibers, an atypical age-related decline in right posterior cingulate U-fiber volume was found in the ASD group, which appeared to be driven by an abnormally large volume in younger children. History of repetitive and restrictive behavior was negatively associated with right caudal anterior cingulate U-fiber volume, linking cingulate motor areas with neighboring gyri. Aberrant development in U-fiber volume of the right posterior cingulate gyrus may underlie functional abnormalities found in this region, such as in the default mode network.

Assessment of ferritin content in multiple sclerosis brains using temperature-induced R*2 changes.

PURPOSE: Current MRI techniques cannot reliably assess iron content in white matter due to the confounding diamagnetic effect of myelin. The purpose of this study was to validate with histology a novel iron mapping technique that uses the temperature dependency of the paramagnetic susceptibility in multiple sclerosis (MS) brains, where white matter has been reported to show significant variations in iron content. METHODS: We investigated post mortem brain tissue from three MS patients and one control subject. Temperature-dependent R2* relaxometry was performed between 4°C and 37°C. The resulting temperature coefficient ( TcR2*) maps were compared with immunohistochemical stains for ferritin light chain. RESULTS: Good agreement between TcR2* maps and ferritin staining was found by way of visual comparison and quantitative analysis. The highest iron concentrations were detected at the edge of MS lesions and in the basal ganglia. For all regions, except the subcortical U-fibers, there was a significant negative correlation between the TcR2* values and the ferritin count. CONCLUSION: This study provides further evidence that TcR2* may be a reliable measure of white matter iron content due to the elimination of myelin-induced susceptibility changes and is well suited for further research into neurological diseases with distortions of the iron homeostasis. Magn Reson Med 79:1609-1615, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The superficial white matter in Alzheimer's disease.

White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P < 0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini-Mental State Examination scores (P < 0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease.

Direct Inside-Out Observation of Superficial White Matter Fasciculi in the Human Brain.

Background: Recent methodological advances in the study of the cerebral white matter have left short association fibers relatively underexplored due to their compact and juxtacortical nature, which represent significant challenges for both post-mortem post-cortex removal dissection and magnetic resonance-based diffusion imaging. Objective: To introduce a novel inside-out post-mortem fiber dissection technique to assess short association fiber anatomy. Methods: Six cerebral specimens were obtained from a body donation program and underwent fixation in formalin. Following two freezing and thawing cycles, a standardized protocol involving peeling fibers from deep structures towards the cortex was developed. Results: The inside-out technique effectively exposed the superficial white matter. The procedure revealed distinguishable intergyral fibers, demonstrating their dissectability and enabling the identification of their orientation. The assessment of layer thickness was possible through direct observation and ex vivo morphological magnetic resonance imaging. Conclusion: The inside-out fiber technique effectively demonstrates intergyral association fibers in the post-mortem human brain. It adds to the neuroscience armamentarium, overcoming methodological obstacles and offering an anatomical substrate essential for neural circuit modeling and the evaluation of neuroimaging congruence. Impact statement The inside-out fiber dissection technique enables a totally new perception of cerebral connectivity as the observer navigates inside the parenchyma and looks toward the cerebral surface with the subcortical white matter and the cortical mantle in place. This approach has proven very effective for exposing intergyral association fibers, which have shown to be much more distinguishable from an inner perspective. It gave rise to unprecedented images of the human superficial white matter and allowed, for the first time, direct observation of this vast mantle of fascicles on entire cerebral hemisphere aspects.

Neuropeptide FF (NPFF)-positive nerve cells of the human cerebral cortex and white matter in controls, selected neurodegenerative diseases, and schizophrenia.

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.

Short superficial white matter and aging: a longitudinal multi-site study of 1293 subjects and 2711 sessions.

It is estimated that short association fibers running immediately beneath the cortex may make up as much as 60% of the total white matter volume. However, these have been understudied relative to the long-range association, projection, and commissural fibers of the brain. This is largely because of limitations of diffusion MRI fiber tractography, which is the primary methodology used to non-invasively study the white matter connections. Inspired by recent anatomical considerations and methodological improvements in superficial white matter (SWM) tractography, we aim to characterize changes in these fiber systems in cognitively normal aging, which provide insight into the biological foundation of age-related cognitive changes, and a better understanding of how age-related pathology differs from healthy aging. To do this, we used three large, longitudinal and cross-sectional datasets (N = 1293 subjects, 2711 sessions) to quantify microstructural features and length/volume features of several SWM systems. We find that axial, radial, and mean diffusivities show positive associations with age, while fractional anisotropy has negative associations with age in SWM throughout the entire brain. These associations were most pronounced in the frontal, temporal, and temporoparietal regions. Moreover, measures of SWM volume and length decrease with age in a heterogenous manner across the brain, with different rates of change in inter-gyri and intra-gyri SWM, and at slower rates than well-studied long-range white matter pathways. These features, and their variations with age, provide the background for characterizing normal aging, and, in combination with larger association pathways and gray matter microstructural features, may provide insight into fundamental mechanisms associated with aging and cognition.

Superficial white matter across development, young adulthood, and aging: volume, thickness, and relationship with cortical features.

Superficial white matter (SWM) represents a significantly understudied part of the human brain, despite comprising a large portion of brain volume and making up a majority of cortico-cortical white matter connections. Using multiple, high-quality datasets with large sample sizes (N = 2421, age range 5-100) in combination with methodological advances in tractography, we quantified features of SWM volume and thickness across the brain and across development, young adulthood, and aging. We had four primary aims: (1) characterize SWM thickness across brain regions (2) describe associations between SWM volume and age (3) describe associations between SWM thickness and age, and (4) quantify relationships between SWM thickness and cortical features. Our main findings are that (1) SWM thickness varies across the brain, with patterns robust across individuals and across the population at the region-level and vertex-level; (2) SWM volume shows unique volumetric trajectories with age that are distinct from gray matter and other white matter trajectories; (3) SWM thickness shows nonlinear cross-sectional changes across the lifespan that vary across regions; and (4) SWM thickness is associated with features of cortical thickness and curvature. For the first time, we show that SWM volume follows a similar trend as overall white matter volume, peaking at a similar time in adolescence, leveling off throughout adulthood, and decreasing with age thereafter. Notably, the relative fraction of total brain volume of SWM continuously increases with age, and consequently takes up a larger proportion of total white matter volume, unlike the other tissue types that decrease with respect to total brain volume. This study represents the first characterization of SWM features across the large portion of the lifespan and provides the background for characterizing normal aging and insight into the mechanisms associated with SWM development and decline.

Reduced asymmetry of the hand knob area and decreased sensorimotor u-fiber connectivity in middle-aged adults with autism.

Individuals with autism spectrum disorder (ASD) frequently present with impairments in motor skills (e.g., limb coordination, handwriting and balance), which are observed across the lifespan but remain largely untreated. Many adults with ASD may thus experience adverse motor outcomes in aging, when physical decline naturally occurs. The 'hand knob' of the sensorimotor cortex is an area that is critical for motor control of the fingers and hands. However, this region has received little attention in ASD research, especially in adults after midlife. The hand knob area of the precentral (PrChand) and postcentral (PoChand) gyri was semi-manually delineated in 49 right-handed adults (25 ASD, 24 typical comparison [TC] participants, aged 41-70 years). Using multimodal (T1-weighted, diffusion-weighted, and resting-state functional) MRI, we examined the morphology, ipsilateral connectivity and laterality of these regions. We also explored correlations between hand knob measures with motor skills and autism symptoms, and between structural and functional connectivity measures. Bayesian analyses indicated moderate evidence of group effects with greater right PrChand volume and reduced leftward laterality of PrChand and PoChand volume in the ASD relative to TC group. Furthermore, the right PoC-PrChand u-fibers showed increased mean diffusivity in the ASD group. In the ASD group, right u-fiber volume positively correlated with corresponding functional connectivity but did not survive multiple comparisons correction. Correlations of hand knob measures and behavior were observed in the ASD group but did not survive multiple comparisons correction. Our findings suggest that morphological laterality and u-fiber connectivity of the sensorimotor network, putatively involved in hand motor/premotor function, may be diminished in middle-aged adults with ASD, perhaps rendering them more vulnerable to motor decline in old age. The altered morphology may relate to atypical functional motor asymmetries found in ASD earlier in life, possibly reflecting altered functional asymmetries over time.

Machine learning to investigate superficial white matter integrity in early multiple sclerosis.

BACKGROUND AND PURPOSE: This study aims todetermine the sensitivity of superficial white matter (SWM) integrity as a metric to distinguish early multiple sclerosis (MS) patients from healthy controls (HC). METHODS: Fractional anisotropy and mean diffusivity (MD) values from SWM bundles across the cortex and major deep white matter (DWM) tracts were extracted from 29 early MS patients and 31 age- and sex-matched HC. Thickness of 68 cortical regions and resting-state functional-connectivity (RSFC) among them were calculated. The distribution of structural and functional metrics between groups were compared using Wilcoxon rank-sum test. Utilizing a machine learning method (adaptive boosting), 6 models were built based on: 1-SWM, 2-DWM, 3-SWM and DWM, 4-cortical thickness, or 5-RSFC measures. In model 6, all features from previous models were incorporated. The models were trained with nested 5-folds cross-validation. Area under the receiver operating characteristic curve (AUCroc ) values were calculated to evaluate classification performance of each model. Permutation tests were used to compare the AUCroc values. RESULTS: Patients had higher MD in SWM bundles including insula, inferior frontal, orbitofrontal, superior and medial temporal, and pre- and post-central cortices (p < .05). No group differences were found for any other MRI metric. The model incorporating SWM and DWM features provided the best classification (AUCroc = 0.75). The SWM model provided higher AUCroc (0.74), compared to DWM (0.63), cortical thickness (0.67), RSFC (0.63), and all-features (0.68) models (p < .001 for all). CONCLUSION: Our results reveal a non-random pattern of SWM abnormalities at early stages of MS even before pronounced structural and functional alterations emerge.

Homozygous UNC13A Variant in an Infant With Congenital Encephalopathy and Severe Neuromuscular Phenotype: A Case Report With Detailed Central Nervous System Neuropathologic Findings.

Uncoordinated 13 (UNC13A) affects movement in Caenorhabditis elegans (C. elegans). It is responsible for docking, priming, and stabilizing synaptic vesicle fusion complexes in the neuronal synapse and neuromuscular junction (NMJ). It also plays an important role in central nervous system development. We report the detailed clinical history and central nervous system neuropathologic findings in an infantile case with homozygous UNC13A loss of function variant, in order to advance the understanding of this critically important synaptic vesicle protein. This is the first detailed central nervous system neuropathologic report of this rare case of homozygous UNC13A loss.

Adult onset acute disseminated encephalomyelitis: A case report.

Acute disseminated encephalomyelitis is an immune mediated demyelinating disorder of the central nervous system, it predominantly affects children in the age group between of 5-8 years. Is most widely thought to be a post-viral, post-vaccination autoimmune phenomenon. We present a case of 40 years old Pakistani male arrived to ER agitated with decrease level of consciousness and delirium, develop tonic-clonic convulsion and it was relieved by DIAZEPAM. This is the first attack to the patient with no past medical history of similar presentation. MRI showed supra and infratentorial white matter high T2/FLAIR signal abnormalities, involving supratentorial cortical and subcortical parito-occipital region, also to less extent at deep white matter predominantly right tempro-occipital region in asymmetric pattern. Involvement of juxta cortical and U fibers. MRI raised the possibility of adult onset Acute disseminated encephalomyelitis, after exclusion of other causes of juxta cortical and U fibers involvement (based on imaging analysis with consideration of clinical presentation and available lab results).

The origin and development of subcortical U-fibers in gyrencephalic ferrets.

In the white matter of the human cerebrum, the majority of cortico-cortical fibers are of short range, connecting neighboring cortical areas. U-fibers represent connections between neighboring areas and are located in the white matter immediately deep to the cerebral cortex. Using gyrencephalic carnivore ferrets, here we investigated the neurochemical, anatomical and developmental features of U-fibers. We demonstrate that U-fibers were derived from neighboring cortical areas in ferrets. U-fiber regions in ferrets were intensely stained with Gallyas myelin staining and Turnbull blue iron staining. We further found that U-fibers were derived from neurons in both upper and lower layers in neighboring areas of the cerebral cortex and that U-fibers were formed later than axons in the deep white matter during development. Our findings shed light on the fundamental features of U-fibers in the gyrencephalic cerebral cortex. Because genetic manipulation techniques for ferrets are now available, ferrets should be an important option for investigating the development, functions and pathophysiological changes of U-fibers.

Proteoglycan (Keratan Sulfate) Barrier in Developing Human Forebrain Isolates Cortical Epileptic Networks From Deep Heterotopia, Insulates Axonal Fascicles, and Explains Why Axosomatic Synapses Are Inhibitory.

Axons from deep heterotopia do not extend through U-fibers, except transmantle dysplasias. Keratan sulfate (KS) in fetal spinal cord/brainstem median septum selectively repels glutamatergic axons while enabling GABAergic commissural axons. Immunocytochemical demonstration of KS in neocortical resections and forebrain at autopsy was studied in 12 fetuses and neonates 9-41 weeks gestational age (GA), 9 infants, children, and adolescents and 5 patients with focal cortical dysplasias (FCD1a). From 9 to 15 weeks GA, no KS is seen in the cortical plate; 19-week GA reactivity is detected in the molecular zone. By 28 weeks GA, patchy granulofilamentous reactivity appears in extracellular matrix and adheres to neuronal somata with increasing intensity in deep cortex and U-fibers at term. Perifascicular KS surrounds axonal bundles of both limbs of the internal capsule and within basal ganglia from 9 weeks GA. Thalamus and globus pallidus exhibit intense astrocytic reactivity from 9 weeks GA. In FCD1a, U-fiber reactivity is normal, discontinuous or radial. Ultrastructural correlates were not demonstrated; KS is not electron-dense. Proteoglycan barrier of the U-fiber layer impedes participation of deep heterotopia in cortical epileptic networks. Perifascicular KS prevents aberrant axonal exit from or entry into long and short tracts. KS adhesion to neuronal somatic membranes may explain inhibitory axosomatic synapses.