In vivo measurements of lamination patterns in the human cortex.

The laminar composition of the cerebral cortex is tightly connected to the development and connectivity of the brain, as well as to function and pathology. Although most of the research on the cortical layers is done with the aid of ex vivo histology, there have been recent attempts to use magnetic resonance imaging (MRI) with potential in vivo applications. However, the high-resolution MRI technology and protocols required for such studies are neither common nor practical. In this article, we present a clinically feasible method for assessing the laminar properties of the human cortex using standard pulse sequence available on any common MRI scanner. Using a series of low-resolution inversion recovery (IR) MRI scans allows us to calculate multiple T1 relaxation time constants for each voxel. Based on the whole-brain T1 -distribution, we identify six different gray matter T1 populations and their variation across the cortex. Based on this, we show age-related differences in these population and demonstrate that this method is able to capture the difference in laminar composition across varying brain areas. We also provide comparison to ex vivo high-resolution MRI scans. We show that this method is feasible for the estimation of layer variability across large population cohorts, which can lead to research into the links between the cortical layers and function, behavior and pathologies that was heretofore unexplorable.

Brain volumetric changes in the general population following the COVID-19 outbreak and lockdown.

The coronavirus disease 2019 (COVID-19) outbreak introduced unprecedented health-risks, as well as pressure on the economy, society, and psychological well-being due to the response to the outbreak. In a preregistered study, we hypothesized that the intense experience of the outbreak potentially induced stress-related brain modifications in the healthy population, not infected with the virus. We examined volumetric changes in 50 participants who underwent MRI scans before and after the COVID-19 outbreak and lockdown in Israel. Their scans were compared with those of 50 control participants who were scanned twice prior to the pandemic. Following COVID-19 outbreak and lockdown, the test group participants uniquely showed volumetric increases in bilateral amygdalae, putamen, and the anterior temporal cortices. Changes in the amygdalae diminished as time elapsed from lockdown relief, suggesting that the intense experience associated with the pandemic induced transient volumetric changes in brain regions commonly associated with stress and anxiety. The current work utilizes a rare opportunity for real-life natural experiment, showing evidence for brain plasticity following the COVID-19 global pandemic. These findings have broad implications, relevant both for the scientific community as well as the general public.

The effect of civil and military flights on coagulation, fibrinolysis and blood flow: insight from a rat model.

BACKGROUND: Air travel thrombosis continues to be a controversial topic. Exposure to hypoxia and hypobaric conditions during air travel is assumed a risk factor. The aim of this study is to explore changes in parameters of coagulation, fibrinolysis and blood flow in a rat model of exposure to hypobaric conditions that imitate commercial and combat flights. METHODS: Sixty Sprague-Dawley male rats, aged 10 weeks, were divided into 5 groups according to the type and duration of exposure to hypobaric conditions. The exposure conditions were 609 m and 7620 m for 2 and 12 h duration. Blood count, thrombin- antithrombin complex, D-dimer, interleukin-1 and interleukin-6 were analyzed. All rats went through flight angiography MRI at day 13-post exposure. RESULTS: No effect of the various exposure conditions was observed on coagulation, fibrinolytic system, IL-1 or IL-6. MRI angiography showed blood flow reduction in lower limb to less than 30% in 50% of the rats. The reduction in blood flow was more pronounced in the left vessel than in the right vessel (p = 0.006, Wilcoxon signed rank test). The extent of occlusion differed across exposure groups in the right, but not the left vessel (p = 0.002, p = 0.150, respectively, Kruskal-Wallis test). However, these differences did not correlate with the exposure conditions. CONCLUSION: In the present rat model, no clear correlation between various hypobaric conditions and activation of coagulation was observed. The reduction in blood flow in the lower limb also occurred in the control group and was not related to the type of exposure.

Analysis of magnetization transfer (MT) influence on quantitative mapping of T2 relaxation time.

PURPOSE: Multi-echo spin-echo (MESE) protocol is the most effective tool for mapping T2 relaxation in vivo. Still, MESE extensive use of radiofrequency pulses causes magnetization transfer (MT)-related bias of the water signal, instigated by the presence of macromolecules (MMP). Here, we analyze the effects of MT on MESE signal, alongside their impact on quantitative T2 measurements. METHODS: Study used 3 models: in vitro urea phantom, ex vivo horse brain, and in vivo human brain. MT ratio (MTR) was measured between single-SE and MESE protocols under different scan settings including varying echo train lengths, number of slices, and inter-slice gap. MTR and T2 values were extracted for each model and protocol. RESULTS: MT interactions biased MESE signals, and in certain settings, the corresponding T2 values. T2 underestimation of up to 4.3% was found versus single-SE values in vitro and up to 13.8% ex vivo, correlating with the MMP content. T2 bias originated from intra-slice saturation of the MMP, rather than from indirect saturation in multi-slice acquisitions. MT-related signal attenuation was caused by slice crosstalk and/or partial T1 recovery, whereas smaller contribution was caused by MMP interactions. Inter-slice gap had a similar effect on in vivo MTR (21.2%), in comparison to increasing the number of slices (18.9%). CONCLUSIONS: MT influences MESE protocols either by uniformly attenuating the entire echo train or by cumulatively attenuating the signal along the train. Although both processes depend on scan settings and MMP content, only the latter will cause underestimation of T2 .

Resolution considerations in imaging of the cortical layers.

The cortical layers are a finger print of brain development, function, connectivity and pathology. Obviously, the formation of the layers and their composition is essential to cognition and behavior. The layers were traditionally measured by histological means but recent studies utilizing MRI suggested that T1 relaxation imaging consist of enough contrast to separate the layers. Indeed extreme resolution, post mortem, studies demonstrated this phenomenon. Yet, one of the limiting factors of using T1 MRI to visualize the layers in neuroimaging research is partial volume effect. This happen when the image resolution is not high enough and two or more layers resides within the same voxel. In this paper we demonstrate that due to the physical small thickness of the layers it is highly unlikely that high resolution imaging could resolve the layers. By contrast, we suggest that low resolution multi T1 mapping conjugate with composition analysis could provide practical means for measuring the T1 layers. We suggest an acquisition platform that is clinically feasible and could quantify measures of the layers. The key feature of the suggested platform is that separation of the layers is better achieved in the T1 relaxation domain rather than in the spatial image domain.

Resolving relaxometry and diffusion properties within the same voxel in the presence of crossing fibres by combining inversion recovery and diffusion-weighted acquisitions.

PURPOSE: A comprehensive image-based characterization of white matter should include the ability to quantify myelin and axonal attributes irrespective of the complexity of fibre organization within the voxel. While progress has been made with diffusion MRI-based approaches to measure axonal morphology, to date available myelin metrics simply assign a single scalar value to the voxel, reflecting some form of average of its constituent fibres. Here, a new experimental framework that combines diffusion MRI and relaxometry is introduced. It provides, for the first time, the ability to assign to each unique fibre system within a voxel, a unique value of the longitudinal relaxation time, T1, which is largely influenced by the myelin content. METHODS: We demonstrate the method through simulations, in a crossing fibres phantom, in fixed brains and in vivo. RESULTS: The method is capable of recovering unique values of T1 for each fibre population. CONCLUSION: The ability to extract fibre-specific relaxometry properties will provide enhanced specificity and, therefore, sensitivity to differences in white matter architecture, which will be invaluable in many neuroimaging studies. Further the enhanced specificity should ultimately lead to earlier diagnosis and access to treatment in a range of white matter diseases where axons are affected.

ß-Alanine supplementation improves fractional anisotropy scores in the hippocampus and amygdala in 60-80-year-old men and women.

Recently, ß-alanine (BA) supplementation was shown to improve cognitive function in older adults with decreased cognitive function. Mechanisms supporting these improvements have not been well defined. This study examined the effects of 10-weeks of BA supplementation on changes in circulating brain inflammatory markers, brain derived neurotrophic factor (BDNF), and brain morphology. Twenty participants were initially randomized into BA (2.4 g·d-1) or placebo (PL) groups. At each testing session, participants provided a resting blood sample and completed the Montreal cognitive assessment (MoCA) test and magnetic resonance imaging, which included diffusion tensor imaging to assess brain tissue integrity. Only participants that scored at or below normal for the MoCA assessment were analyzed (6 BA and 4 PL). The Mann-Whitney U test was used to examine Δ (POST-PRE) differences between the groups. No differences in Δ scores were noted in any blood marker (BDNF, CRP, TNF-α and GFAP). Changes in fractional anisotropy scores were significantly greater for BA than PL in the right hippocampus (p = 0.033) and the left amygdala (p = 0.05). No other differences were noted. The results provide a potential mechanism of how BA supplementation may improve cognitive function as reflected by improved tissue integrity within the hippocampus and amygdala.

Parent-child couples display shared neural fingerprints while listening to stories.

Neural fingerprinting is a method to identify individuals from a group of people. Here, we established a new connectome-based identification model and used diffusion maps to show that biological parent-child couples share functional connectivity patterns while listening to stories. These shared fingerprints enabled the identification of children and their biological parents from a group of parents and children. Functional patterns were evident in both cognitive and sensory brain networks. Defining "typical" shared biological parent-child brain patterns may enable predicting or even preventing impaired parent-child connections that develop due to genetic or environmental causes. Finally, we argue that the proposed framework opens new opportunities to link similarities in connectivity patterns to behavioral, psychological, and medical phenomena among other populations. To our knowledge, this is the first study to reveal the neural fingerprint that represents distinct biological parent-child couples.

The CONNECT project: Combining macro- and micro-structure.

In recent years, diffusion MRI has become an extremely important tool for studying the morphology of living brain tissue, as it provides unique insights into both its macrostructure and microstructure. Recent applications of diffusion MRI aimed to characterize the structural connectome using tractography to infer connectivity between brain regions. In parallel to the development of tractography, additional diffusion MRI based frameworks (CHARMED, AxCaliber, ActiveAx) were developed enabling the extraction of a multitude of micro-structural parameters (axon diameter distribution, mean axonal diameter and axonal density). This unique insight into both tissue microstructure and connectivity has enormous potential value in understanding the structure and organization of the brain as well as providing unique insights to abnormalities that underpin disease states. The CONNECT (Consortium Of Neuroimagers for the Non-invasive Exploration of brain Connectivity and Tracts) project aimed to combine tractography and micro-structural measures of the living human brain in order to obtain a better estimate of the connectome, while also striving to extend validation of these measurements. This paper summarizes the project and describes the perspective of using micro-structural measures to study the connectome.

Visualization of cortical lamination patterns with magnetic resonance imaging.

The ability to image the cortex laminar arrangements in vivo is one of the holy grails of neuroscience. Recent studies have visualized the cortical layers ex vivo and in vivo (on a small region of interest) using high-resolution T(1)/T(2) magnetic resonance imaging (MRI). In this study, we used inversion-recovery (IR) MRI to increase the sensitivity of MRI toward cortical architecture and achieving whole-brain characterization of the layers, in vivo, in 3D on humans and rats. Using the IR measurements, we computed 3D signal intensity plots along the cortex termed corticograms to characterize cortical substructures. We found that cluster analyses of the multi-IR images along the cortex divides it into at least 6 laminar compartments. To validate our observations, we compared the IR-MRI analysis with histology and revealed a correspondence, although these 2 measures do not represent similar quantities. The abilities of the method to segment the cortex into layers were demonstrated on the striate cortex (visualizing the stripe of Gennari) and on the frontal cortex. We conclude that the presented methodology can serve as means to study and characterize individual cortical architecture and organization.

A Method for In-Vivo Mapping of Axonal Diameter Distributions in the Human Brain Using Diffusion-Based Axonal Spectrum Imaging (AxSI).

In this paper we demonstrate a generalized and simplified pipeline called axonal spectrum imaging (AxSI) for in-vivo estimation of axonal characteristics in the human brain. Whole-brain estimation of the axon diameter, in-vivo and non-invasively, across all fiber systems will allow exploring uncharted aspects of brain structure and function relations with emphasis on connectivity and connectome analysis. While axon diameter mapping is important in and of itself, its correlation with conduction velocity will allow, for the first time, the explorations of information transfer mechanisms within the brain. We demonstrate various well-known aspects of axonal morphometry (e.g., the corpus callosum axon diameter variation) as well as other aspects that are less explored (e.g., axon diameter-based separation of the superior longitudinal fasciculus into segments). Moreover, we have created an MNI based mean axon diameter map over the entire brain for a large cohort of subjects providing the reference basis for future studies exploring relation between axon properties, its connectome representation, and other functional and behavioral aspects of the brain.

Mapping apparent eccentricity and residual ensemble anisotropy in the gray matter using angular double-pulsed-field-gradient MRI.

Conventional diffusion MRI methods are mostly capable of portraying microarchitectural elements such as fiber orientation in white matter from detection of diffusion anisotropy, which arises from the coherent organization of anisotropic compartments. Double-pulsed-field-gradient MR methods provide a means for obtaining microstructural information such as compartment shape and microscopic anisotropies even in scenarios where macroscopic organization is absent. Here, we apply angular double-pulsed-gradient-spin-echo MRI in the rat brain both ex vivo and in vivo for the first time. Robust angular dependencies are detected in the brain at long mixing time (t(m) ). In many pixels, the oscillations seem to originate from residual directors in randomly oriented media, i.e., from residual ensemble anisotropy, as corroborated by quantitative simulations. We then developed an analysis scheme that enables one to map of structural indices such as apparent eccentricity (aE) and residual phase (φ) that enables characterization of the rat brain in general, and especially the rat gray matter. We conclude that double-pulsed-gradient-spin-echo MRI may in principle become important in characterizing gray matter morphological features and pathologies in both basic and applied neurosciences.

3D virtual reconstruction and quantitative assessment of the human intervertebral disc's annulus fibrosus: a DTI tractography study.

The intervertebral disc's (IVD) annulus fibrosus (AF) retains the hydrostatic pressure of the nucleus pulposus (NP), controls the range of motion, and maintains the integrity of the motion segment. The microstructure of the AF is not yet fully understood and quantitative characterization is lacking, leaving a caveat in modern medicine's ability to prevent and treat disc failure (e.g., disc herniation). In this study, we show a reconstruction of the 3D microstructure of the fibers that constitute the AF via MRI diffusion tensor imaging (DTI) followed by fiber tracking. A quantitative analysis presents an anisotropic structure with significant architectural differences among the annuli along the width of the fibrous belt. These findings indicate that the outer annuli's construction reinforces the IVD while providing a sufficient degree of motion. Our findings also suggest an increased role of the outer annuli in IVD nourishment.

In vivo measurement of axon diameter distribution in the corpus callosum of rat brain.

Here, we present the first in vivo non-invasive measurement of the axon diameter distribution in the rat corpus callosum. Previously, this measurement was only possible using invasive histological methods. The axon diameter, along with other physical properties, such as the intra-axonal resistance, membrane resistance and capacitance etc. helps determine many important functional properties of nerves, such as their conduction velocity. In this work, we provide a novel magnetic resonance imaging method called AxCaliber, which can resolve the distinct signatures of trapped water molecules diffusing within axons as well as water molecules diffusing freely within the extra-axonal space. Using a series of diffusion weighted magnetic resonance imaging brain scans, we can reliably infer both the distribution of axon diameters and the volume fraction of these axons within each white matter voxel. We were able to verify the known microstructural variation along the corpus callosum of the rat from the anterior (genu) to posterior (splenium) regions. AxCaliber yields a narrow distribution centered approximately 1 microm in the genu and splenium and much broader distributions centered approximately 3 microm in the body of the corpus callosum. The axon diameter distribution found by AxCaliber is generally broader than those usually obtained by histology. One factor contributing to this difference is the significant tissue shrinkage that results from histological preparation. To that end, AxCaliber might provide a better estimate of the in vivo morphology of white matter. Being a magnetic resonance imaging based methodology, AxCaliber has the potential to be used in human scanners for morphological studies of white matter in normal and abnormal development, and white matter related diseases.

Selective atrophy of the connected deepest cortical layers following small subcortical infarct.

OBJECTIVE: To explore whether in patients with chronic small subcortical infarct the cortical layers of the connected cortex are differentially affected and whether these differences correlate with clinical symptomatology. METHODS: Twenty patients with a history of chronic small subcortical infarct affecting the corticospinal tracts and 15 healthy controls were included. Connected primary motor cortex was identified with tractography starting from infarct. T1-component probability maps were calculated from T1 relaxation 3T MRI, dividing the cortex into 5 laminar gaussian classes. RESULTS: Focal cortical thinning was observed in the connected cortex and specifically only in its deepest laminar class compared to the nonaffected mirrored cortex (p < 0.001). There was loss of microstructural integrity of the affected corticospinal tract with increased mean diffusivity and decreased fractional anisotropy compared to the contralateral nonaffected tract (p ≤ 0.002). Clinical scores were correlated with microstructural damage of the corticospinal tracts and with thinning of the cortex and specifically only its deepest laminar class (p < 0.001). No differences were found in the laminar thickness pattern of the bilateral primary motor cortices or in the microstructural integrity of the bilateral corticospinal tracts in the healthy controls. CONCLUSION: Our results support the concept of secondary neurodegeneration of connected primary motor cortex after a small subcortical infarct affecting the corticospinal tract, with observations that the main cortical thinning occurs in the deepest cortex and that the clinical symptomatology is correlated with this cortical atrophy pattern. Our findings may contribute to a better understanding of structural reorganization and functional outcomes after stroke.

In vivo correlation between axon diameter and conduction velocity in the human brain.

The understanding of the relationship between structure and function has always characterized biology in general and neurobiology in particular. One such fundamental relationship is that between axon diameter and the axon's conduction velocity (ACV). Measurement of these neuronal properties, however, requires invasive procedures that preclude direct elucidation of this relationship in vivo. Here we demonstrate that diffusion-based MRI is sensitive to the fine microstructural elements of brain wiring and can be used to quantify axon diameter in vivo. Moreover, we demonstrate the in vivo correlation between the diameter of an axon and its conduction velocity in the human brain. Using AxCaliber, a novel magnetic resonance imaging technique that enables us to estimate in vivo axon diameter distribution (ADD) and by measuring the interhemispheric transfer time (IHTT) by electroencephalography, we found significant linear correlation, across a cohort of subjects, between brain microstructure morphology (ADD) and its physiology (ACV) in the tactile and visual sensory domains. The ability to make a quantitative assessment of a fundamental physiological property in the human brain from in vivo measurements of ADD may shed new light on neurological processes occurring in neuroplasticity as well as in neurological disorders and neurodegenerative diseases.