Ex-vivo MRI Research Articles

Abstract 4136863: Diffuse Functional and Structural Abnormalities in Fibrosis: Potential Structural Basis for Sustaining Atrial Fibrillation

Background: Structural remodeling is associated with atrial fibrillation (AF), but detailed structural and functional characteristics is not well defined. Goal: Using a novel transgenic goat model with cardiac-specific overexpression of TGF-β1 leading to increased cardiac fibrosis, we evaluated detailed structural and functional differences between fibrotic and healthy regions of the atria. Methods: Ex-vivo MRI and histology were used to evaluate fibrosis, fiber disarray, and structural anisotropy. Ex-vivo MRI intensity values were scaled to standard deviations around the mean. The functional analysis examined conduction speeds and direction heterogeneity. Conduction anisotropy was measured along the fiber direction obtained with diffusion tensor imaging. Results: The transgenic goats (n=12) had, on average, 21% of the left atria labeled as fibrotic determined from ex-vivo MRI. The histology samples taken from the labeled fibrotic regions had an increase in fibrosis percentage compared to labeled healthy regions (7.78±3.76% vs 2.80±1.86%, p<0.01). The structural anisotropy was lower in fibrotic regions (0.196±0.002 vs 0.244±0.002, p<0.01). Fiber disarray was greater in the fibrotic regions (20.3±0.2° vs 19.2±0.1°, p<0.01). The fibrotic regions had slower conduction speeds (0.78±0.02 m/s vs 1.12±0.02 m/s, p<0.01) and more aligned conduction directions (30.5±0.2° vs 31.6±0.1°, p<0.01), potentially developing unidirectional conduction block. Conduction anisotropy, measured on the fiber directions, was found to be lower in the fibrotic regions (1.86±0.05 vs 2.10±0.02, p=0.04). As scaled MRI intensity increased, the conduction speed, heterogeneity, and anisotropy all decreased. Conclusions: Functional and structural differences exist between fibrotic and healthy regions of the atria. Though statistically significant, the changes are not discrete. The correlation showed gradual functional abnormalities with MRI intensities. Fibrotic regions tended to have increased fiber disarray, slower conduction, and more unidirectional propagation with lower conduction and structural anisotropy. Diffuse functional and structural abnormalities may allow fibrotic regions to serve as a substrate to sustain AF.

Small animal brain surgery with neither a brain atlas nor a stereotaxic frame

BackgroundStereotaxic surgery is a cornerstone in brain research for the precise positioning of electrodes and probes, but its application is limited to species with available brain atlases and tailored stereotaxic frames. Addressing this limitation, we introduce an alternative technique for small animal brain surgery that requires neither an aligned brain atlas nor a stereotaxic frame. New methodThe new method requires an ex-vivo high-contrast MRI brain scan of one specimen and access to a micro-CT scanner. The process involves attaching miniature markers to the skull, followed by CT scanning of the head. Subsequently, MRI and CT images are co-registered using standard image processing software and the targets for brain recordings are marked in the MRI image. During surgery, the animal's head is stabilized in any convenient orientation, and the probe’s 3D position and angle are tracked using a multi-camera system. We have developed a software that utilizes the on-skull markers as fiducial points to align the CT/MRI 3D model with the surgical positioning system, and in turn instructs the surgeon how to move the probe to reach the targets within the brain. ResultsOur technique allows the execution of insertion tracks connecting two points in the brain. We successfully applied this method for neuropixels probe positioning in owls, quails, and mice, demonstrating its versatility. Comparison with existing methodsWe present an alternative to traditional stereotaxic brain surgeries that does not require established stereotaxic tools. Thus, this method is especially of advantage for research in non-standard and novel animal models.

Early intensive rehabilitation reverses locomotor disruption, decrease brain inflammation and induces neuroplasticity following experimental Cerebral Palsy

BackgroundCerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Early intensive sensorimotor rehabilitation has been shown to change brain structure and reduce CP symptoms severity. We combined environmental enrichment (EE) and treadmill training (TT) to observe the effects of a one-week program of sensorimotor stimulation (EETT) in animals exposed to a CP model and explored possible mechanisms involved in the functional recovery. MethodsPregnant Wistar rats were injected with Lipopolysaccharide (LPS − 200 µg/kg) intraperitoneally at embryonic days 18 and 19. At P0, pups of both sexes were exposed to 20′ anoxia at 37 °C. From P2 to P21, hindlimbs were restricted for 16 h/day during the dark cycle. EETT lasted from P21 to P27. TT − 15 min/day at 7 cm/s. EE − 7 days in enriched cages with sensorimotor stimulus. Functional 3D kinematic gait analysis and locomotion were analyzed. At P28, brains were collected for ex-vivo MRI and histological assessment. Neurotrophins and key proteins involved in CNS function were assessed by western blotting. ResultsCP model caused gross and skilled locomotor disruption and altered CNS neurochemistry. EETT reversed locomotor dysfunction with minor effects over gait kinematics. EETT also decreased brain inflammation and glial activation, preserved myelination, upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in the brain and spinal cord. ConclusionsUsing this translational approach based on intensive sensorimotor rehabilitation, we highlight pathways engaged in the early developmental processes improving neurological recovery observed in CP.

Comparative utility of MRI and EEG for early detection of cortical dysmaturation after postnatal systemic inflammation in the neonatal rat

BackgroundExposure to postnatal systemic inflammation is associated with increased risk of brain injury in preterm infants, leading to impaired maturation of the cerebral cortex and adverse neurodevelopmental outcomes. However, the optimal method for identifying cortical dysmaturation is unclear. Herein, we compared the utility of electroencephalography (EEG), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) at different recovery times after systemic inflammation in newborn rats. MethodsSprague Dawley rat pups of both sexes received single-daily lipopolysaccharide (LPS; 0.3 mg/kg i.p.; n = 51) or saline (n = 55) injections on postnatal days (P)1, 2, and 3. A subset of these animals were implanted with EEG electrodes. Cortical EEG was recorded for 30 min from unanesthetized, unrestrained pups at P7, P14, and P21, and in separate groups, brain tissues were collected at these ages for ex-vivo MRI analysis (9.4 T) and Golgi–Cox staining (to assess neuronal morphology) in the motor cortex. ResultsPostnatal inflammation was associated with reduced cortical pyramidal neuron arborization from P7, P14, and P21. These changes were associated with dysmature EEG features (e.g., persistence of delta waveforms, higher EEG amplitude, reduced spectral edge frequency) at P7 and P14, and higher EEG power in the theta and alpha ranges at P21. By contrast, there were no changes in cortical DTI or NODDI in LPS rats at P7 or P14, while there was an increase in cortical fractional anisotropy (FA) and decrease in orientation dispersion index (ODI) at P21. ConclusionsEEG may be useful for identifying the early evolution of impaired cortical development after early life postnatal systemic inflammation, while DTI and NODDI seem to be more suited to assessing established cortical changes.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the “LATE-NC network”. Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Ex-vivo 1.5T MR Imaging versus CT in Estimating the Size of the Pathologically Invasive Component of Lung Adenocarcinoma Spectrum Lesions.

The purpose of this study was to investigate whether ex-vivo MRI enables accurate estimation of the invasive component of lung adenocarcinoma. We retrospectively reviewed 32 patients with lung adenocarcinoma who underwent lung lobectomy. The specimens underwent MRI at 1.5T. The boundary between the lesion and the normal lung was evaluated on a 5-point scale in each three MRI sequences, and a one-way analysis of variance and post-hoc tests were performed. The invasive component size was measured histopathologically. The maximum diameter of each solid component measured on CT and MR T1-weighted (T1W) images and the maximum size obtained from histopathologic images were compared using the Wilcoxon signed-rank test. Inter-reader agreement was evaluated using intraclass correlation coefficients (ICC). T1W images were determined to be optimal for the delineation of the lesions (P < 0.001). The histopathologic invasive area corresponded to the area where the T1W ex-vivo MR image showed a high signal intensity that was almost equal to the intravascular blood signal. The maximum diameter of the solid component on CT was overestimated compared with the maximum invasive size on histopathology (mean, 153%; P < 0.05), while that on MRI was evaluated mostly accurately without overestimation (mean, 108%; P = 0.48). The interobserver reliability of the measurements using CT and MRI was good (ICC = 0.71 on CT, 0.74 on MRI). Ex-vivo MRI was more accurate than conventional CT in delineating the invasive component of lung adenocarcinoma.

Beyond Macrostructure: Is There a Role for Radiomics Analysis in Neuroimaging ?

The most commonly used neuroimaging biomarkers of brain structure, particularly in neurodegenerative diseases, have traditionally been summary measurements from ROIs derived from structural MRI, such as volume and thickness. Advances in MR acquisition techniques, including high-field imaging, and emergence of learning-based methods have opened up opportunities to interrogate brain structure in finer detail, allowing investigators to move beyond macrostructural measurements. On the one hand, superior signal contrast has the potential to make appearance-based metrics that directly analyze intensity patterns, such as texture analysis and radiomics features, more reliable. Quantitative MRI, particularly at high-field, can also provide a richer set of measures with greater interpretability. On the other hand, use of neural networks-based techniques has the potential to exploit subtle patterns in images that can now be mined with advanced imaging. Finally, there are opportunities for integration of multimodal data at different spatial scales that is enabled by developments in many of the above techniques-for example, by combining digital histopathology with high-resolution ex-vivo and in-vivo MRI. Some of these approaches are at early stages of development and present their own set of challenges. Nonetheless, they hold promise to drive the next generation of validation and biomarker studies. This article will survey recent developments in this area, with a particular focus on Alzheimer's disease and related disorders. However, most of the discussion is equally relevant to imaging of other neurological disorders, and even to other organ systems of interest. It is not meant to be an exhaustive review of the available literature, but rather presented as a summary of recent trends through the discussion of a collection of representative studies with an eye towards what the future may hold.

Autonomic neuro-cardiac profile of electrical, structural and neuronal remodeling in myocardial infarction-induced heart failure.

Heart failure is a clinical syndrome typified by abnormal autonomic tone, impaired ventricular function, and increased arrhythmic vulnerability. This study aims to examine electrophysiological, structural and neuronal remodeling following myocardial infarction in a rabbit heart failure model to establish its neuro-cardiac profile. Weight-matched adult male New Zealand White rabbits (3.2±0.1kg, n=25) were randomized to have coronary ligation surgeries (HF group, n=13) or sham procedures (SHM group, n=12). Transthoracic echocardiography was performed six weeks post-operatively. On week 8, dual-innervated Langendorff-perfused heart preparations were set up for terminal experiments. Seventeen hearts (HF group, n=10) underwent ex-vivo cardiac MRI. Twenty-two hearts (HF group, n=7) were examined histologically. Electrical remodeling and abnormal autonomic profile were evident in HF rabbits with exaggerated sympathetic and attenuated vagal effect on ventricular fibrillation threshold, ventricular refractoriness and restitution curves, in addition to increased spatial restitution dispersion. Histologically, there was significant neuronal enlargement at the heart hila and conus arteriosus in HF. Structural remodeling was characterized by quantifiable myocardial scarring, enlarged left ventricles, altered ventricular geometry and impaired contractility. In an infarct-induced rabbit heart failure model, extensive structural, neuronal and electrophysiological remodeling in conjunction with abnormal autonomic profile provide substrates for ventricular arrhythmias.

An anatomical and connectivity atlas of the marmoset cerebellum

The cerebellum is essential for motor control and cognitive functioning, engaging in bidirectional communication with the cerebral cortex. The common marmoset, a small non-human primate, offers unique advantages for studying cerebello-cerebral circuits. However, the marmoset cerebellum is not well described in published resources. In this study, we present a comprehensive atlas of the marmoset cerebellum comprising (1) fine-detailed anatomical atlases and surface-analysis tools of the cerebellar cortex based on ultra-high-resolution exvivo MRI, (2) functional connectivity and gradient patterns of the cerebellar cortex revealed by awake resting-state fMRI, and (3) structural-connectivity mapping of cerebellar nuclei using high-resolution diffusion MRI tractography. The atlas elucidates the anatomical details of the marmoset cerebellum, reveals distinct gradient patterns of intra-cerebellar and cerebello-cerebral functional connectivity, and maps the topological relationship of cerebellar nuclei in cerebello-cerebral circuits. As version 5 of the Marmoset Brain Mapping project, this atlas is publicly available at https://marmosetbrainmapping.org/MBMv5.html.

Quantifying changes in local basal ganglia structural connectivity in the 6-hydroxydopamine model of Parkinson's Disease using correlational tractography.

In recent years, tractography based on diffusion magnetic resonance imaging (dMRI) has become a popular tool for studying microstructural changes resulting from brain diseases like Parkinson's Disease (PD). Quantitative anisotropy (QA) is a parameter that is used in deterministic fiber tracking as a measure of connection between brain regions. It remains unclear, however, if microstructural changes caused by lesioning the median forebrain bundle (MFB) to create a Parkinsonian rat model can be resolved using tractography based on ex-vivo diffusion MRI. This study aims to fill this gap and enable future mechanistic research on structural changes of the whole brain network rodent models of PD. Specifically, it evaluated the ability of correlational tractography to detect structural changes in the MFB of 6-hydroxydopamine (6-OHDA) lesioned rats. The findings reveal that correlational tractography can detect structural changes in lesioned MFB and differentiate between the 6-OHDA and control groups. Imaging results are supported by behavioral and histological evidence demonstrating that 6-OHDA lesioned rats were indeed Parkinsonian. The results suggest that QA and correlational tractography is appropriate to examine local structural changes in rodent models of neurodegenerative disease. More broadly, we expect that similar techniques may provide insight on how disease alters structure throughout the brain, and as a tool to optimize therapeutic interventions.

Ventricular anatomical complexity and sex differences impact predictions from electrophysiological computational models.

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O'Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocardium is smooth may produce inaccurate predictions towards the location of reentry channels in in-silico tachycardia inducibility studies.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with lower R2 relaxation rate: an ex-vivo MRI and pathology investigation

Limbic predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is common in persons older than 80 years of age and is associated with cognitive decline and increased likelihood of dementia. The MRI signature of LATE-NC has not been fully determined. In this study, the association of LATE-NC with the transverse relaxation rate, R2, was investigated in a large number of community-based older adults. Cerebral hemispheres from 738 participants of the Rush Memory and Aging Project, Religious Orders Study, and Minority Aging Research Study, were imaged ex-vivo with multi-echo spin-echo MRI and underwent detailed neuropathologic examination. Voxel-wise analysis revealed a novel spatial pattern of lower R2 for higher LATE-NC stage, controlling for other neuropathologies and demographics. This pattern was consistent with the distribution of LATE-NC in gray matter, and also involved white matter providing temporo-temporal, fronto-temporal, and temporo-basal ganglia connectivity. Furthermore, analysis at different LATE-NC stages showed that R2 imaging may capture the general progression of LATE-NC, but only when TDP-43 inclusions extend beyond the amygdala.

Association of small vessel disease with tau pathology

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with β-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.

A semi-automatic registration protocol to match ex-vivo high-field 7T MR images and histological slices in surgical samples from patients with drug-resistant epilepsy

BackgroundMRI is a fundamental tool to detect brain structural anomalies and improvement in this technique has the potential to visualize subtle abnormalities currently undetected. Correlation between pre-operative MRI and histopathology is required to validate the neurobiological basis of MRI abnormalities. However, precise MRI-histology matching is very challenging with the surgical samples. We previously developed a coregistration protocol to match the in-vivo MRI with ex-vivo MRI obtained from surgical specimens. Now, we complete the process to successfully align ex-vivo MRI data with the proper digitalized histological sections in an automatic way. New methodThe implemented pipeline is composed by the following steps: a) image pre-processing made of MRI and histology volumes conversion and masking; b) gross rigid body alignment between MRI volume and histology virtual slides; c) rigid alignment between each MRI section and histology slice and estimate of the correlation coefficient for each step to select the MRI slice that best matches histology; d) final linear registration of the selected slices. ResultsThis method is fully automatic, except for the first masking step, fast and reliable in comparison to the manual one, as assessed using a Bland-Altman plot. Comparison with existing methodsThe visual assessment usually employed for choosing the best fitting ex-vivo MRI slice for each stained section takes hours and requires practice. Goubran et al. (2015) proposed an iterative registration protocol but its aim and methods were different from ours. No others similar methods are reported in the literature. ConclusionsThis protocol completes our previous pipeline. The ultimate goal will be to apply the entire process to finely investigate the relationship between clinical MRI data and histopathological features in patients with drug-resistant epilepsy.

Neuropathologic and clinical correlates of cerebral microbleeds in community‐based older adults

Cerebral microbleeds (CMBs) are common in older adults and have been linked to hypertension, cognitive decline, and CAA. However, it remains unclear what the neuropathologic correlates of CMBs are in community-based older adults. The aim of this study was to determine the neuropathologic and clinical correlates of CMBs in community-based older adults when controlling for demographic factors, and also to investigate the relationship between neuropathologies and the location of CMBs in the brain. A total of 289 participants from two longitudinal cohort studies of aging, the Rush Memory and Aging Project and Religious Orders Study, were included in this work. Participants received annual clinical evaluation and cognitive assessment, ex-vivo MRI, and neuropathologic examination by a board-certified neuropathologist (blinded to clinical and imaging findings) on one brain hemisphere (Fig. 1). A total of 8 pathologies were assessed (Fig. 2). Manual identification of CMBs on ex-vivo T2*-weighted gradient echo images was done by an experienced rater blinded to all clinical and pathological information. The total number of CMBs as well as the number of CMBs per lobe were recorded for each participant. Poisson regression was used to investigate the associations of the total and regional number of CMBs with neuropathologies and clinical factors, controlling for demographics and postmortem interval. A significance threshold of p<0.01 was used after applying Bonferroni correction. The total number of CMBs in the whole brain was associated with CAA (beta=0.0517, p<0.0001), diabetes (beta=0.0997, p<0.0001), and arteriosclerosis (beta=0.0535, p=0.0007). The number of CMBs in the frontal lobe was also associated with CAA (beta=0.0796, p<0.0001), diabetes (beta=0.1531, p<0.0001), and arteriosclerosis (beta=0.0792, p<0.0001). The number of CMBs in the occipital and temporal lobes were correlated with diabetes (beta=0.2208, p=0.0006). In the basal ganglia, there was a slight association between number of microbleeds and microinfarcts (beta=0.1774, p=0.0075). The present study on the neuropathologic and clinical correlates of cerebral microbleeds combined detailed neuropathologic examination and ex-vivo MRI in a large number of community-based older adults. CMBs were shown to be associated with CAA, arteriosclerosis, and diabetes in the whole brain and in the frontal lobe.

Neuropathologic correlates of shape of subcortical brain structures

Age-related neuropathologies have devastating effects on subcortical brain structures. MRI can be used to explore patterns of atrophy associated with various diseases, however, definitive diagnosis of age-related neuropathologies is only possible at autopsy. The purpose of this work was to combine ex-vivo MRI and detailed neuropathology in a large community cohort of older adults to conduct the most comprehensive investigation to-date on the association of age-related neuropathologies with the shape of subcortical brain structures. Cerebral hemispheres were obtained from 814 participants of the Rush Memory and Aging Project and Religious Orders Study, two longitudinal cohort studies of aging (Fig. 1). A single brain hemisphere from each participant was imaged ex-vivo on a clinical 3T MRI scanner, while immersed in 4% formaldehyde solution. Following ex-vivo MRI, all hemispheres underwent detailed neuropathologic examination by a board-certified neuropathologist blinded to clinical and imaging findings (Fig. 2). T2-weighted images from all hemispheres were used to segment nucleus accumbens, amygdala, caudate, hippocampus, putamen, and thalamus. Subcortical shape measures were computed using the ENIGMA-Shape protocol. Vertex-wise linear regression was performed for each subcortical structure, modeling the logarithm of the Jacobian determinant at each vertex as a function of a comprehensive list of age-related neuropathologies controlling for demographics and scanners. The analysis first considered data from all hemispheres (left hemispheres were mirrored to appear like right hemispheres and the opposite), and then was repeated considering left and right hemispheres separately. When considering all hemispheres (Fig. 3), Alzheimer's pathology, atherosclerosis, and TDP-43 pathology were all associated with unique patterns of inward deformation of the hippocampus and amygdala. When considering left and right hemispheres separately (Fig. 4), the results were relatively similar to the combined analysis. Also, when considering the right hemispheres alone, arteriolosclerosis was associated with inward deformation of the putamen and thalamus. Lewy bodies, infarcts and cerebral amyloid angiopathy did not show any links to the shape of subcortical brain structures. Among the different age-related neuropathologies, Alzheimer's pathology, TDP-43 pathology, atherosclerosis and arteriolosclerosis are the ones that have independent contributions on shape abnormalities of subcortical brain structures that could potentially contribute towards in-vivo prediction of these neuropathologies.

Associations of automatically segmented, enlarged perivascular spaces with neuropathology and cognition in community‐based older adults

Previous studies on the associations between enlarged perivascular spaces (EPVS) and pathology have used manual assessment of EPVS burden, with limitations on cohorts and access to pathology. In this work, we first developed a deep learning model to automatically segment EPVS on MRI. We then combined total and regional EPVS measurements with detailed neuropathology and longitudinal cognitive assessment on 817 community-based older adults to investigate EPVS links to neuropathology and cognition (Fig. 1). Data: This work included 817 participants from three longitudinal cohort studies of aging. All participants underwent annual cognitive assessment, ex-vivo T2 -weighted imaging (0.6x0.6x1.5 mm) using clinical 3T MRI, and detailed neuropathologic examination by a board-certified neuropathologist blinded to all data (Fig. 2). Pathologies assessed: gross and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), amyloid plaques, neurofibrillary tangles, Lewy bodies, and TDP-43. Segmentation: Data from 10 participants and manually segmented EPVS were used to train convolutional neural networks (Fig. 3) to automatically segment EPVS. The trained networks were used to segment and quantify total and regional EPVS clusters in the ex-vivo MRI data of all participants. Model performance validation: Using 100 randomly generated ROIs, EPVS were 1) identified by an expert neuroradiologist, and 2) manually segmented by an experienced observer. Neuroradiologist and observer were blind to each other. Model segmentation accuracy and sensitivity were evaluated. Associations with neuropathologies, controlling for demographics, were investigated using elastic-net regularized linear regression. Linear mixed-effects models were used to investigate independent association of EPVS with cognitive decline independent of neuropathologies and demographics. Model validation showed 68% average sensitivity, DSC=0.66 segmentation accuracy, and high correlation (Pearson, ρ=0.91) in segmentation volume per ROI (Fig. 4). EPVS number was associated with gross infarcts, microscopic infarcts, and diabetes in multiple brain regions, and with CAA in occipital and temporal lobes (Fig. 5). Total and frontal lobe EPVS were associated with faster decline in visuospatial ability, (-0.0079, p=0.036) and (-0.0071, p=0.018) respectively, independent of neuropathologies, diabetes and demographics. This is the largest investigation on neuropathologic and cognitive correlates of EPVS conducted to date, generating robust evidence on EPVS associations with infarcts, CAA and diabetes, and independent contributions on cognitive decline.

Spatial and temporal profile of high-frequency oscillations in posttraumatic epileptogenesis

We studied the role of temporal and spatial changes in high-frequency oscillation (HFO, 80–500 Hz) generation in epileptogenesis following traumatic brain injury (TBI).Experiments were conducted on adult male Sprague Dawley rats. For the TBI group, fluid percussion injury (FPI) on the left sensorimotor area was performed to induce posttraumatic epileptogenesis. For the sham control group, only the craniotomy was performed. After TBI, 8 bipolar micro-electrodes were implanted bilaterally in the prefrontal cortex, perilesional area and homotopic contralateral site, striatum, and hippocampus. Long-term video/local field potential (LFP) recordings were performed for up to 21 weeks to identify and characterize seizures and capture HFOs. The electrode tip locations and the volume of post TBI brain lesions were further estimated by ex-vivo MRI scans. HFOs were detected during slow-wave sleep and categorized as ripple (80–200 Hz) and fast ripple (FR, 250–500 Hz) events. HFO rates and the HFO peak frequencies were compared in the 8 recording locations and across 8-weeks following TBI.Data from 48 rats (8 sham controls and 40 TBI rats) were analyzed. Within the TBI group, 22 rats (55%) developed recurrent spontaneous seizures (E+ group), at an average of 62.2 (+17.1) days, while 18 rats (45%) did not (E- group). We observed that the HFOs in the E+ group had a higher mean peak frequency than the E- group and the sham group (P < 0.05). Furthermore, the FR rate of the E+ group showed a significant increase compared to the E-group (P < 0.01) and sham control group (P < 0.01), specifically in the perilesional area, homotopic contralateral site, bilateral hippocampus, and to a lesser degree bilateral striatum. When compared across time, the increased FR rate in the E+ group occurred immediately after the insult and remained stable across the duration of the experiment. In addition, lesion size was not statistically different in the E+ and E- group and was not correlated with HFO rates.Our results suggest that TBI results in the formation of a widespread epileptogenic network. FR rates serve as a biomarker of network formation and predict the future development of epilepsy, however FR are not a temporally specific biomarker of TBI sequelae responsible for epileptogenesis. These results suggest that in patients, future risk of post-TBI epilepsy can be predicted early using FR.

The effect of beta-amyloid and tau protein aggregations on magnetic susceptibility of anterior hippocampal laminae in Alzheimer's diseases

Previous studies have reported the changes of magnetic susceptibility induced by iron deposition in hippocampus of Alzheimer's disease (AD) brains. It is well-known that hippocampus is divided into well-defined laminar architecture, which, however, is difficult to be resolved with in-vivo MRI due to the limited imaging resolution. The present study aims to investigate layer-specific magnetic susceptibility in the hippocampus of AD patients using high-resolution ex-vivo MRI, and elucidate its relationship with beta amyloid (Aβ) and tau protein histology. We performed quantitative susceptibility mapping (QSM) and T2* mapping on postmortem anterior hippocampus samples from four AD, four Primary Age-Related Tauopathy (PART), and three control brains. We manually segmented each sample into seven layers, including four layers in the cornu ammonis1 (CA1) and three layers in the dentate gyrus (DG), and then evaluated AD-related alterations of susceptibility and T2* values and their correlations with Aβ and tau in each hippocampal layer. Specifically, we found (1) layer-specific variations of susceptibility and T2* measurements in all samples; (2) the heterogeneity of susceptibility were higher in all layers of AD patients compared with the age- and gender-matched PART cases while the heterogeneity of T2* values were lower in four layers of CA1; and (3) voxel-wise MRI-histological correlation revealed both susceptibility and T2* values in the stratum molecular (SM) and stratum lacunosum (SL) layers were correlated with the Aβ content in AD, while the T2* values in the stratum radiatum (SR) layer were correlated with the tau content in the PART but not AD. These findings suggest a selective effect of the Aβ- and tau-pathology on the susceptibility and T2* values in the different layers of anterior hippocampus. Particularly, the alterations of magnetic susceptibility in the SM and SL layers may be associated with Aβ aggregation, while those in the SR layermay reflect the age-related tau protein aggregation.

Modelling Cortical Laminar Connectivity in the Macaque Brain.

In 1991, Felleman and Van Essen published their seminal study regarding hierarchical processing in the primate cerebral cortex. Their work encompassed a widescale analysis of connections reported through tracing between 35 regions in the macaque visual cortex, extending from cortical regions to the laminar level. In this work, we revisit laminar-level connectivity in the macaque brain using a whole-brain MRI-based approach. We use multimodal ex-vivo MRI imaging of the macaque brain in both white and grey matter, which are then integrated via a simple model of laminar connectivity. This model uses a granularity-based approach to define a set of rules that expands cortical connections to the laminar level. Different fiber tracking routines are then examined in order to explore the ability of our model to infer laminar connectivity. The network of macaque cortical laminar connectivity resulting from the chosen routine is then validated in the visual cortex by comparison to findings from Felleman and Van Essen with an 83% accuracy level. By using a more comprehensive definition of the cortex that addresses its heterogenous laminar composition, we can explore a new avenue of structural connectivity on the laminar level.