Axon Density Research Articles

White Matter Degeneration Pathways Associated With Tau Deposition in Alzheimer Disease.

The dynamics of white matter (WM) changes are understudied in Alzheimer disease (AD). Our goal was to study the association between flortaucipir PET and WM health using neurite orientation dispersion and density imaging (NODDI) and evaluate its association with cognitive performance. Specifically, we focused on NODDI's Neurite Density Index (NDI), which aids in capturing axonal degeneration in WM and has greater specificity than single-shell diffusion MRI methods. We estimated regional flortaucipir PET standard uptake value ratios (SUVRs) from 3 regions corresponding to Braak stage I, III/IV, and V/VI to capture the spatial distribution pattern of the 3R/4R tau in AD. Then, we evaluated the associations between these measurements and NDIs in 29 candidate WM tracts using Pearson correlation and multiple regression models. Based on 223 participants who were amyloid positive (mean age of 78 years and 57.0% male, 119 cognitively unimpaired, 56 mild cognitive impairment, and 48 dementia), the results showed that WM tracts NDI decreased with increasing regional Braak tau SUVRs. Of all the significant WM tracts, the uncinate fasciculus (r = -0.274 for Braak I, -0.311 for Braak III/IV, and -0.292 for Braak V/VI, p < 0.05) and cingulum adjoining hippocampus (r = -0.274, -0.288, -0.233, p < 0.05), both tracts anatomically connected to areas of early tau deposition, were consistently found to be within the top 5 distinguishing WM tracts associated with flortaucipir SUVRs. The increase in tau deposition measurable outside the medial temporal lobes in Braak III-VI was associated with a decrease in NDI in the middle and inferior temporal WM tracts. For cognitive performance, WM NDI had similar coefficients of determination (r 2 = 31%) as regional Braak flortaucipir SUVRs (29%), and together WM NDI and regional Braak flortaucipir SUVRs explained 46% of the variance in cognitive performance. We found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages, suggesting a spatial pattern in WM damage. NDI, a specific marker of axonal density, provides complementary information about disease staging and progression in addition to tau deposition. Measurements of WM changes are important for the mechanistic understanding of multifactorial pathways through which AD causes cognitive dysfunction.

Topography of associations between cardiovascular risk factors and myelin loss in the ageing human brain

Our knowledge of the mechanisms underlying the vulnerability of the brain’s white matter microstructure to cardiovascular risk factors (CVRFs) is still limited. We used a quantitative magnetic resonance imaging (MRI) protocol in a single centre setting to investigate the cross-sectional association between CVRFs and brain tissue properties of white matter tracts in a large community-dwelling cohort (n = 1104, age range 46–87 years). Arterial hypertension was associated with lower myelin and axonal density MRI indices, paralleled by higher extracellular water content. Obesity showed similar associations, though with myelin difference only in male participants. Associations between CVRFs and white matter microstructure were observed predominantly in limbic and prefrontal tracts. Additional genetic, lifestyle and psychiatric factors did not modulate these results, but moderate-to-vigorous physical activity was linked to higher myelin content independently of CVRFs. Our findings complement previously described CVRF-related changes in brain water diffusion properties pointing towards myelin loss and neuroinflammation rather than neurodegeneration.

Topographical mapping of catecholaminergic axon innervation in the flat-mounts of the mouse atria: a quantitative analysis

The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4–5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent cells were also strongly TH-IR. Our work provides a comprehensive topographical map of the catecholaminergic efferent axon morphology, innervation, and distribution in the whole atria at single cell/axon/varicosity scale that may be used in future studies to create a cardiac sympathetic-brain atlas.

273 Dystonia is associated with macro and microstructural abnormalities of the cerebellum: A nested case-control study

OBJECTIVES/GOALS: Dystonia is a brain disorder which causes excessive muscle activation, manifesting as abnormal movements. Neuroimaging studies of dystonia have revealed changes in a network involving the cerebellum. We sought out to determine whether subjects with dystonia in the UK Biobank exhibit MRI-based cerebellar pathology. METHODS/STUDY POPULATION: This nested case-control study drew from the UK Biobank, a cohort of &gt;500,000 subjects in the United Kingdom, aged 40-69, enrolled 2006-2010. Eligible subjects must have undergone diffusion-weighted brain MRI. Dystonia cases were ascertained using ICD10 codes. We selected controls without neurologic diagnoses, matched (1:3) on age, sex, imaging site, and medical comorbidities. Mean diffusivity, fractional anisotropy, intracellular and isotropic volume fractions, and orientation dispersion were extracted from four white-matter tracts (inferior, middle, superior cerebellar peduncles; superior thalamic radiations) along with cerebellum, basal ganglia, and whole-brain grey and white-matter volumes. Means were compared using two-tailed t-tests and the Benjamini-Hochberg procedure (FDR = 0.05). RESULTS/ANTICIPATED RESULTS: 23 cases of dystonia and 69 control subjects were selected and ascertained. After correcting for multiple-comparisons (40 volumetric and 35 diffusion-related), intracellular-volume-fraction (ICVF) of the middle- and superior-cerebellar peduncles was significantly lower in subjects with dystonia, suggesting reduced axon density. Volumetric analysis showed significantly reduced volumes of the motor cerebellum (lobules VI and VIII). There were no differences in basal ganglia, cortical, or whole-brain volumes. DISCUSSION/SIGNIFICANCE: These findings support the hypothesis that abnormalities of cerebellar networks contribute to dystonia. In future we will use similar techniques to assess these tracts in subjects with dystonia who are undergoing Deep Brain Stimulation, with the goal of guiding stimulation targeting, and predicting therapeutic outcomes.

White matter microstructure is associated with the precision of visual working memory

Visual working memory is critical for goal-directed behavior as it maintains continuity between previous and current visual input. Functional neuroimaging studies have shown that visual working memory relies on communication between distributed brain regions, which implies an important role for long-range white matter connections in visual working memory performance. Here, we characterized the relationship between the microstructure of white matter association tracts and the precision of visual working memory representations. To that purpose, we devised a delayed estimation task which required participants to reproduce visual features along a continuous scale. A sample of 80 healthy adults performed the task and underwent diffusion-weighted MRI. We applied mixture distribution modelling to quantify the precision of working memory representations, swap errors, and guess rates, all of which contribute to observed responses. Latent components of microstructural properties in sets of anatomical tracts were identified by principal component analysis. We found an interdependency between fibre coherence in the bilateral superior longitudinal fasciculus (SLF) I, SLF II, and SLF III, on one hand, and the bilateral inferior fronto-occipital fasciculus (IFOF), on the other, in mediating the precision of visual working memory in a functionally specific manner. We also found that individual differences in axonal density in a network comprising the bilateral inferior longitudinal fasciculus (ILF) and SLF III and right SLF II, in combination with a supporting network located elsewhere in the brain, form a common system for visual working memory to modulate response precision, swap errors, and random guess rates.

Association of adverse childhood experience-related increase in neurite density with sensory over-responsivity in autism spectrum disorder: A neurite orientation dispersion and density imaging study

Sensory over-responsivity (SOR) causes social and daily distress in individuals with autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, ASD individuals are at higher risk of adverse childhood experiences (ACEs), which induce abnormal neuronal development. However, whether or how ACEs are associated with abnormal neural development and SOR in ASD remains to be determined. Forty-five individuals with ASD and 43 TD individuals underwent T1-weighted and neurite orientation dispersion and density imaging; the axonal and dendritic densities were defined as the neurite density index (NDI). Voxel-based analyses were performed to explore the brain regions associated with SOR. The relationships between severity of ACEs and SOR, and NDI in the brain regions were examined. ASD individuals showed a significantly positive association between SOR severity and NDI in the right superior temporal gyrus (STG), which was not found in TD individuals. Severity of ACEs correlated significantly with that of SOR and NDI in the right STG in ASD; ASD individuals having severe SOR showed significantly higher NDI in the right STG than those with mild SOR and TD individuals. In individuals with ASD, NDI in the right STG, but not ACEs, could predict the severity of SOR, which was not shown in TD subjects. Our findings suggest that severe ACEs are involved in excessive neurite density in the right STG in ASD. ACE-associated excessive neurite density in the right STG is critical for SOR in ASD, which may be a therapeutic target in the future.

Commissural dentate granule cell projections and their rapid formation in the adult brain.

Dentate granule cells (GCs) have been characterized as unilaterally projecting neurons within each hippocampus. Here, we describe a unique class, the commissural GCs, which atypically project to the contralateral hippocampus in mice. Although commissural GCs are rare in the healthy brain, their number and contralateral axon density rapidly increase in a rodent model of temporal lobe epilepsies. In this model, commissural GC axon growth appears together with the well-studied hippocampal mossy fiber sprouting and may be important for the pathomechanisms of epilepsy. Our results augment the current view on hippocampal GC diversity and demonstrate powerful activation of a commissural wiring program in the adult brain.

AxoNet 2.0: A Deep Learning-Based Tool for Morphometric Analysis of Retinal Ganglion Cell Axons.

Assessment of glaucomatous damage in animal models is facilitated by rapid and accurate quantification of retinal ganglion cell (RGC) axonal loss and morphologic change. However, manual assessment is extremely time- and labor-intensive. Here, we developed AxoNet 2.0, an automated deep learning (DL) tool that (i) counts normal-appearing RGC axons and (ii) quantifies their morphometry from light micrographs. A DL algorithm was trained to segment the axoplasm and myelin sheath of normal-appearing axons using manually-annotated rat optic nerve (ON) cross-sectional micrographs. Performance was quantified by various metrics (e.g., soft-Dice coefficient between predicted and ground-truth segmentations). We also quantified axon counts, axon density, and axon size distributions between hypertensive and control eyes and compared to literature reports. AxoNet 2.0 performed very well when compared to manual annotations of rat ON (R2 = 0.92 for automated vs. manual counts, soft-Dice coefficient = 0.81 ± 0.02, mean absolute percentage error in axonal morphometric outcomes < 15%). AxoNet 2.0 also showed promise for generalization, performing well on other animal models (R2 = 0.97 between automated versus manual counts for mice and 0.98 for non-human primates). As expected, the algorithm detected decreased in axon density in hypertensive rat eyes (P ≪ 0.001) with preferential loss of large axons (P < 0.001). AxoNet 2.0 provides a fast and nonsubjective tool to quantify both RGC axon counts and morphological features, thus assisting with assessing axonal damage in animal models of glaucomatous optic neuropathy. This deep learning approach will increase rigor of basic science studies designed to investigate RGC axon protection and regeneration.

Morphometric Analysis of Retinal Ganglion Cell Axons in Normal and Glaucomatous Brown Norway Rats Optic Nerves.

A reference atlas of optic nerve (ON) retinal ganglion cell (RGC) axons could facilitate studies of neuro-ophthalmic diseases by detecting subtle RGC axonal changes. Here we construct an RGC axonal atlas for normotensive eyes in Brown Norway rats, widely used in glaucoma research, and also develop/evaluate several novel metrics of axonal damage in hypertensive eyes. Light micrographs of entire ON cross-sections from hypertensive and normotensive eyes were processed through a deep learning-based algorithm, AxoNet2.0, to determine axonal morphological properties and were semiquantitatively scored using the Morrison grading scale (MGS) to provide a damage score independent of AxoNet2.0 outcomes. To construct atlases, ONs were conformally mapped onto an ON "template," and axonal morphometric data was computed for each region. We also developed damage metrics based on myelin morphometry. In normotensive eyes, average axon density was ∼0.3 axons/µm2 (i.e., ∼80,000 axons in an ON). We measured axoplasm diameter, eccentricity, cross-sectional area, and myelin g-ratio and thickness. Most morphological parameters exhibited a wide range of coefficients of variation (CoV); however, myelin thickness CoV was only ∼2% in normotensive eyes. In hypertensive eyes, increased myelin thickness correlated strongly with MGS (P < 0.0001). We present the first comprehensive normative RGC axon morphometric atlas for Brown Norway rat eyes. We suggest objective, repeatable damage metrics based on RGC axon myelin thickness for hypertensive eyes. These tools can evaluate regional changes in RGCs and overall levels of damage in glaucoma studies using Brown Norway rats.

Enhancing Functional Recovery after Segmental Nerve Defect Using Nerve Allograft Treated with Plasma-Derived Exosome.

Nerve injuries can result in detrimental functional outcomes. Currently, autologous nerve graft offers the best outcome for segmental peripheral nerve injury. Allografts are alternatives, but do not have comparable results. This study evaluated whether plasma-derived exosome can improve nerve regeneration and functional recovery when combined with decellularized nerve allografts. The effect of exosomes on Schwann cell proliferation and migration were evaluated. A rat model of sciatic nerve repair was used to evaluate the effect on nerve regeneration and functional recovery. A fibrin sealant was used as the scaffold for exosome. Eighty-four Lewis rats were divided into autograft, allograft, and allograft with exosome groups. Gene expression of nerve regeneration factors was analyzed on postoperative day 7. At 12 and 16 weeks, rats were subjected to maximum isometric tetanic force and compound muscle action potential. Nerve specimens were then analyzed by means of histology and immunohistochemistry. Exosomes were readily taken up by Schwann cells that resulted in improved Schwann cell viability and migration. The treated allograft group had functional recovery (compound muscle action potential, isometric tetanic force) comparable to that of the autograft group. Similar results were observed in gene expression analysis of nerve regenerating factors. Histologic analysis showed no statistically significant differences between treated allograft and autograft groups in terms of axonal density, fascicular area, and myelin sheath thickness. Plasma-derived exosome treatment of decellularized nerve allograft may provide comparable clinical outcomes to that of an autograft. This can be a promising strategy in the future as an alternative for segmental peripheral nerve repair. Off-the-shelf exosomes may improve recovery in nerve allografts.

Artificial PGA/Collagen-based Bilayer Conduit in Short Gap Interposition Setting Provides Comparable Regenerative Potential to Direct Suture.

Sixty-six female Lewis rats were randomly divided into the sham group (n = 13); no reconstruction (no-recon) group (n = 13; rat model with 10 mm sciatic nerve defect); direct group (n = 20; rat sciatic nerve injury directly connected by 10-0 Nylon); and SGI group (n = 20; sciatic nerve injury repaired using 5-mm Nerbridge). Motor function and histological recovery were evaluated. The sciatic nerve and gastrocnemius muscle were harvested for quantification of the degree of nerve regeneration and muscle atrophy. The SGI and direct groups achieved equal recovery in both functional and histological outcomes. At weeks 3 and 8 postsurgery, there was a significant improvement in the sciatic functional index of the SGI group when compared with that of the no-recon group (P < 0.05). Furthermore, the direct and SGI groups had less muscle atrophy at 4 and 8 weeks postsurgery compared with the no-recon group (P < 0.05). The axon density and diameter at the distal site in the SGI group were significantly higher than that in the no-recon group and comparable to that in the direct and sham groups. An artificial nerve conduit has equal potential as direct suture in motor nerve reconstruction when used in the SGI setting.

Full-scale scaffold model of the human hippocampus CA1 area

The increasing availability of quantitative data on the human brain is opening new avenues to study neural function and dysfunction, thus bringing us closer and closer to the implementation of digital twin applications for personalized medicine. Here we provide a resource to the neuroscience community: a computational method to generate full-scale scaffold model of human brain regions starting from microscopy images. We have benchmarked the method to reconstruct the CA1 region of a right human hippocampus, which accounts for about half of the entire right hippocampal formation. Together with 3D soma positioning we provide a connectivity matrix generated using a morpho-anatomical connection strategy based on axonal and dendritic probability density functions accounting for morphological properties of hippocampal neurons. The data and algorithms are supplied in a ready-to-use format, suited to implement computational models at different scales and detail.

Silk-in-Silk Nerve Guidance Conduits Enhance Regeneration in a Rat Sciatic Nerve Injury Model.

Advanced nerve guidance conduits can provide an off-the-shelf alternative to autografts for the rehabilitation of segmental peripheral nerve injuries. In this study, the excellent processing ability of silk fibroin and the outstanding cell adhesion quality of spider dragline silk are combined to generate a silk-in-silk conduit for nerve repair. Fibroin-based silk conduits (SC) are characterized, and Schwann cells are seeded on the conduits and spider silk. Rat sciatic nerve (10mm) defects are treated with an autograft (A), an empty SC, or a SC filled with longitudinally aligned spider silk fibers (SSC) for 14weeks. Functional recovery, axonal re-growth, and re-myelination are assessed. The material characterizations determine a porous nature of the conduit. Schwann cells accept the conduit and spider silk as growth substrate. The in vivo results show a significantly faster functional regeneration of the A and SSC group compared to the SC group. In line with the functional results, the histomorphometrical analysis determines a comparable axon density of the A and SSC groups, which is significantly higher than the SC group. These findings demonstrate that the here introduced silk-in-silk nerve conduit achieves a similar regenerative performance as autografts largely due to the favorable guiding properties of spider dragline silk.

MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.

White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aβ42 , Aβ40 , pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß=-0.13; P =0.049). Further, higher levels of NfL (ß=-0.22; P =0.009) and GFAP (ß=-0.29; P =0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.

In Vitro Myelination of Peripheral Axons in a Coculture of Rat Dorsal Root Ganglion Explants and Schwann Cells.

The process of myelination is essential to enable rapid and sufficient signal transduction in the nervous system. In the peripheral nervous system, neurons and Schwann cells engage in a complex interaction to control the myelination of axons. Disturbances of this interaction and breakdown of the myelin sheath are hallmarks of inflammatory neuropathies and occur secondarily in neurodegenerative disorders. Here, we present a coculture model of dorsal root ganglion explants and Schwann cells, which develops a robust myelination of peripheral axons to investigate the process of myelination in the peripheral nervous system, study axon-Schwann cell interactions, and evaluate the potential effects of therapeutic agents on each cell type separately. Methodologically, dorsal root ganglions of embryonic rats (E13.5) were harvested, dissociated from their surrounding tissue, and cultured as whole explants for 3 days. Schwann cells were isolated from 3-week-old adult rats, and sciatic nerves were enzymatically digested. The resulting Schwann cells were purified by magnetic-activated cell sorting and cultured under neuregulin and forskolin-enriched conditions. After 3 days of dorsal root ganglion explant culture, 30,000 Schwann cells were added to one dorsal root ganglion explant in a medium containing ascorbic acid. The first signs of myelination were detected on day 10 of coculture, through scattered signals for myelin basic protein in immunocytochemical staining. From day 14 onward, myelin sheaths were formed and propagated along the axons. Myelination can be quantified by myelin basic protein staining as a ratio of the myelination area and axon area, to account for the differences in axonal density. This model provides experimental opportunities to study various aspects of peripheral myelination in vitro, which is crucial for understanding the pathology of and possible treatment opportunities for demyelination and neurodegeneration in inflammatory and neurodegenerative diseases of the peripheral nervous system.

Safety and efficacy of intravesical instillation of resiniferatoxin in healthy cats: A preliminary study.

To evaluate the safety of intravesical application of resiniferatoxin (RTX) in healthy cats and its effects on calcitonin gene-related peptide (CGRP) and substance P (SP) produced by C-fibers. Seven adult female cats received either 25 mL of saline (control; n = 1), or intravesical RTX at 5, 25, or 50 μg in 25 mL of saline to a final concentration of 0.2 μg/mL (318 nM), 1 μg/mL (1,591 nM), and 2 μg/mL (3,181 nM) (n = 2 per group). The treatment was instilled into the urinary bladder for 20 min. Plasma concentrations of RTX were measured at 0, 0.5, 1, and 4 h. Physical exam, complete blood count, and serum biochemical analysis were performed on day 0, 7, and 14. After 14 days, the sacral dorsal root ganglia (DRG) and the urinary bladder were harvested for histological and immunofluorescence analysis. Intravesical RTX was well tolerated and plasma concentrations were below the quantifiable limits except for one cat receiving 1 μg/mL. Mild to moderate histopathological changes, including epithelial changes, edema, and blood vessel proliferation, were observed at lower doses (0.2 and 1 μg/mL), and were more severe at the higher dose (2 μg/mL). C-fiber ablation was observed in the urinary bladder tissue at all doses, as shown by an apparent reduction of both CGRP and SP immunoreactive axons. A dose of 25 μg (1 μg/mL) of RTX instilled in the urinary bladder of healthy cats appeared to decrease the density of SP and CGRP nerve axons innervating bladder and induced moderate changes in the bladder tissue.

Novel insights into axon diameter and myelin content in late childhood and adolescence.

White matter microstructural development in late childhood and adolescence is driven predominantly by increasing axon density and myelin thickness. Ex vivo studies suggest that the increase in axon diameter drives developmental increases in axon density observed with pubertal onset. In this cross-sectional study, 50 typically developing participants aged 8-18years were scanned using an ultra-strong gradient magnetic resonance imaging scanner. Microstructural properties, including apparent axon diameter $({d}_a)$, myelin content, and g-ratio, were estimated in regions of the corpus callosum. We observed age-related differences in ${d}_a$, myelin content, and g-ratio. In early puberty, males had larger ${d}_a$ in the splenium and lower myelin content in the genu and body of the corpus callosum, compared with females. Overall, this work provides novel insights into developmental, pubertal, and cognitive correlates of individual differences in apparent axon diameter and myelin content in the developing human brain.

Sigma-1 Receptor Activation Improves Oligodendrogenesis and Promotes White-Matter Integrity after Stroke in Mice with Diabetic Mellitus

Diabetes mellitus (DM) is a major risk factor for stroke and exacerbates white-matter damage in focal cerebral ischemia. Our previous study showed that the sigma-1 receptor agonist PRE084 ameliorates bilateral common-carotid-artery occlusion-induced brain damage in mice. However, whether this protective effect can extend to white matter remains unclear. In this study, C57BL/6 mice were treated with high-fat diets (HFDs) combined with streptozotocin (STZ) injection to mimic type 2 diabetes mellitus (T2DM). Focal cerebral ischemia in T2DM mice was established via injection of the vasoconstrictor peptide endothelin-1 (ET-1) into the hippocampus. Three different treatment plans were used in this study. In one plan, 1 mg/kg of PRE084 (intraperitoneally) was administered for 7 d before ET-1 injection; the mice were sacrificed 24 h after ET-1 injection. In another plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 7 d. In the third plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 21 d. The Y-maze, novel object recognition, and passive avoidance tests were used to assess neurobehavioral outcomes. We found no cognitive dysfunction or white-matter damage 24 h after ET-1 injection. However, 7 and 21 d after ET-1 injection, the mice showed significant cognitive impairment and white-matter damage. Only PRE084 treatment for 21 d could improve this white-matter injury; increase axon and myelin density; decrease demyelination; and increase the expressions of myelin regulator 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNpase) and myelin oligodendrocyte protein (MOG) (which was expressed by mature oligodendrocytes), the number of nerve/glial-antigen 2 (NG2)-positive cells, and the expression of platelet-derived growth factor receptor-alpha (PDGFRα), all of which were expressed by oligodendrocyte progenitor cells in mice with diabetes and focal cerebral ischemia. These results indicate that maybe there was more severe white-matter damage in the focal cerebral ischemia of the diabetic mice than in the mice with normal blood glucose levels. Long-term sigma-1 receptor activation may promote oligodendrogenesis and white-matter functional recovery in patients with stroke and with diabetes.

Hypoxic pre-conditioned adipose-derived stem/progenitor cells embedded in fibrin conduits promote peripheral nerve regeneration in a sciatic nerve graft model.

Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells (ADSPCs) in peripheral nerve recovery. Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs. This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned (2% oxygen for 72 hours) autologous ADSPCs (n = 9). This treatment mode was compared with three others: fibrin conduit seeded with ADSPCs cultivated under normoxic conditions (n = 9); non-cell-carrying conduit (n = 9); and nerve autograft only (n = 9). A 16-week follow-up included functional testing (sciatic functional index and static sciatic index) as well as postmortem muscle mass analyses and morphometric nerve evaluations (histology, g-ratio, axon density, and diameter). At 8 weeks, the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups, indicating faster functional regeneration. Furthermore, histologic evaluation showed significantly increased axon outgrowth/branching, axon density, remyelination, and a reduced relative connective tissue area. Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts. Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.

Cortical Contributions to Imagined Power Grip Task: An EEG-Triggered TMS Study.

Previous studies have demonstrated that motor imagery leads to desynchronization in the alpha rhythm within the contralateral primary motor cortex. However, the underlying electrophysiological mechanisms responsible for this desynchronization during motor imagery remain unclear. To examine this question, we conducted an investigation using EEG in combination with noninvasive transcranial magnetic stimulation (TMS) during index finger abduction (ABD) and power grip imaginations. The TMS was administered employing diverse coil orientations to selectively stimulate corticospinal axons, aiming to target both early and late synaptic inputs to corticospinal neurons. TMS was triggered based on the alpha power levels, categorized in 20th percentile bins, derived from the individual alpha power distribution during the imagined tasks of ABD and power grip. Our analysis revealed negative correlations between alpha power and motor evoked potential (MEP) amplitude, as well as positive correlations with MEP latency across all coil orientations for each imagined task. Furthermore, we conducted functional network analysis in the alpha band to explore network connectivity during imagined index finger abduction and power grip tasks. Our findings indicate that network connections were denser in the fronto-parietal area during imagined ABD compared to power grip conditions. Moreover, the functional network properties demonstrated potential for effectively classifying between these two imagined tasks. These results provide functional evidence supporting the hypothesis that alpha oscillations may play a role in suppressing MEP amplitude and latency during imagined power grip. We propose that imagined ABD and power grip tasks may activate different populations and densities of axons at the cortical level.