A century after “the war to end all wars,” we continue to find our human community divided by conflict and our military service members at the leading edge. The ghostly scars of shell shock, later ...termed post-traumatic stress disorder (PTSD), have haunted generations of soldiers, as well as civilian survivors of many types of trauma, since long before the Great War. Despite current societal acceptance of PTSD as a disorder worthy of compassion, diagnostic recognition, and multidisciplinary research, these scars have remained, like ghosts, largely and frustratingly invisible in the sense that little is understood of their cellular basis in . . .
Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative ...conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.
High-resolution MRI and histopathological study of the brains of patients who had died from Covid-19 showed punctate hyperintensities and punctate or linear hypointensities, which represented various ...forms of pauci-inflammatory microvasculopathy. No evidence of active viral infection was found.
The engineering of a 3T human MRI scanner equipped with 300mT/m gradients – the strongest gradients ever built for an in vivo human MRI scanner – was a major component of the NIH Blueprint Human ...Connectome Project (HCP). This effort was motivated by the HCP's goal of mapping, as completely as possible, the macroscopic structural connections of the in vivo healthy, adult human brain using diffusion tractography. Yet, the 300mT/m gradient system is well suited to many additional types of diffusion measurements. Here, we present three initial applications of the 300mT/m gradients that fall outside the immediate scope of the HCP. These include: 1) diffusion tractography to study the anatomy of consciousness and the mechanisms of brain recovery following traumatic coma; 2) q-space measurements of axon diameter distributions in the in vivo human brain and 3) postmortem diffusion tractography as an adjunct to standard histopathological analysis. We show that the improved sensitivity and diffusion-resolution provided by the gradients are rapidly enabling human applications of techniques that were previously possible only for in vitro and animal models on small-bore scanners, thereby creating novel opportunities to map the microstructure of the human brain in health and disease.
•Diffusion spectrum imaging to study traumatic coma recovery•In vivo human axon diameter measurements using 300mT/m gradients•High-resolution (0.6mm isotropic) diffusion imaging in whole, fixed human brain
Diffusion tensor MRI is sensitive to the coherent structure of brain tissue and is commonly used to study large-scale white matter structure. Diffusion in gray matter is more isotropic, however, ...several groups have observed coherent patterns of diffusion anisotropy within the cerebral cortical gray matter. We extend the study of cortical diffusion anisotropy by relating it to the local coordinate system of the folded cerebral cortex. We use 1mm and sub-millimeter isotropic resolution diffusion imaging to perform a laminar analysis of the principal diffusion orientation, fractional anisotropy, mean diffusivity and partial volume effects. Data from 6 in vivo human subjects, a fixed human brain specimen and an anesthetized macaque were examined. Large regions of cortex show a radial diffusion orientation. In vivo human and macaque data displayed a sharp transition from radial to tangential diffusion orientation at the border between primary motor and somatosensory cortex, and some evidence of tangential diffusion in secondary somatosensory cortex and primary auditory cortex. Ex vivo diffusion imaging in a human tissue sample showed some tangential diffusion orientation in S1 but mostly radial diffusion orientations in both M1 and S1.
► Measurement of diffusion anisotropy in the in vivo human cerebral cortex. ► Dominant diffusion orientation compared to the local cortical orientation. ► Analysis of cortical depth-dependent diffusion features and partial volume effects. ► Diffusion in the cortex is predominantly orthogonal to the cortical surface. ► Evidence of tangential diffusion in S1 and to a lesser extent S2 and A1.
Abstract
The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to ...characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms.
In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry.
All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed.
All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.
Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.
ABSTRACTThe ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. ...Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
Cerebral axonal connections begin to develop before birth during radial migration in each brain area. A number of theories are still actively debated regarding the link between neuronal migration, ...developing connectivity, and gyrification. Here, we used high angular resolution diffusion tractography on postmortem fetal human brains (postconception week (W) 17-40) to document the regression of radial and tangential organization likely to represent migration pathways and the emergence of corticocortical organization and gyrification. The dominant radial organization at W17 gradually diminished first in dorsal parieto-occipital and later in ventral frontotemporal regions with regional variation: radial organization persisted longer in the crests of gyri than at the depths of sulci. The dominant tangential organization of the ganglionic eminence at W17 also gradually disappeared by term, together with the disappearance of the ganglionic eminence. A few immature long-range association pathways were visible at W17, gradually became evident by term. Short-range corticocortical tracts emerged prior to gyrification in regions where sulci later developed. Our results suggest that the regional regression of radial organization and regional emergence of fetal brain connectivity proceeds in general from posterodorsal to anteroventral with local variations.
The engineering of a 3 T human MRI scanner equipped with 300 mT/m gradients - the strongest gradients ever built for an in vivo human MRI scanner - was a major component of the NIH Blueprint Human ...Connectome Project (HCP). This effort was motivated by the HCP's goal of mapping, as completely as possible, the macroscopic structural connections of the in vivo healthy, adult human brain using diffusion tractography. Yet, the 300 mT/m gradient system is well suited to many additional types of diffusion measurements. Here, we present three initial applications of the 300 mT/m gradients that fall outside the immediate scope of the HCP. These include: 1) diffusion tractography to study the anatomy of consciousness and the mechanisms of brain recovery following traumatic coma; 2) q-space measurements of axon diameter distributions in the in vivo human brain and 3) postmortem diffusion tractography as an adjunct to standard histopathological analysis. We show that the improved sensitivity and diffusion-resolution provided by the gradients are rapidly enabling human applications of techniques that were previously possible only for in vitro and animal models on small-bore scanners, thereby creating novel opportunities to map the microstructure of the human brain in health and disease.
We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of ...non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.
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