Neurovascular Function in a Novel Model of Experimental Atherosclerosis

AbstractObjectiveAtherosclerosis is a major risk factor for dementia. The aims of this study were to determine if experimental atherosclerosis leads to altered neurovascular function and causes neurovascular damage.Approach and ResultsWe analysed cerebral blood volume in male C57BL6/J mice injected with an adeno-associated virus (AAV) vector for mutated proprotein convertase subtilisin/kexin type 9 (PCSK9D377Y) fed a Western diet for 35 weeks to induce atherosclerosis (ATH) and 9-12m male wild-type (WT) C57BL/6J. We imaged blood volume responses to sensory stimulation and vascular reactivity gas challenges in the cortex of the brain through a thinned cranial window using 2D-optical imaging spectroscopy (2D-OIS). Neural activity was also recorded with multi-channel electrodes. Stimulation-evoked cortical haemodynamics, in terms of cerebral blood volume, were significantly reduced in ATH mice compared to WT and evoked neural activity was also significantly lower. However, vascular reactivity as assessed by 10% hypercapnia, remained intact in ATH mice. Immunohistochemistry in ATH mice revealed a reduced number of cortical neurons and pericytes in the cortex, but increased astrogliosis. qRT-PCR revealed significantly enhanced TNFα & IL1β in ATH mice compared to WT as well as significant upregulation of eNOS.ConclusionSystemic atherosclerosis causes significant neurovascular decline by 9m in atherosclerotic mice characterised by reduced neural activity, associated with loss of neurons and subsequent reduced cortical haemodynamics in response to physiological stimulations. The altered neurovascular function in ATH mice is chiefly mediated by TNFα.HighlightsSystemic atherosclerosis leads to significantly reduced stimulus-evoked hemodynamic responses in the cortex by 9m of age in the rAAV8-mPCSK9-D377Y mouse model of atherosclerosis compared to wild-type controls.Reduced cerebral haemodynamics are related to reduced neural activity in the cortex that could be due to a loss of cortical neurons potentially caused by significant TNFa-mediated neuroinflammation.

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Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer’s Disease

10.1101/848713 ◽

2019 ◽

Author(s):

Osman Shabir ◽

Paul Sharp ◽

Monica A Rebollar ◽

Luke Boorman ◽

Clare Howarth ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Blood Volume ◽

Neural Activity ◽

Cerebral Blood Volume ◽

Neurovascular Coupling ◽

Cranial Window ◽

Model Of Alzheimer’S Disease ◽

The Brain

AbstractEarly impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6-9 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy by driving an increased baseline blood flow to the brain, thereby potentially enhancing the clearance of beta-amyloid.

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Contralateral dissociation between neural activity and cerebral blood volume during recurrent acute focal neocortical seizures

Epilepsia ◽

10.1111/epi.12726 ◽

2014 ◽

Vol 55 (9) ◽

pp. 1423-1430 ◽

Cited By ~ 17

Author(s):

Sam Harris ◽

Luke Boorman ◽

Michael Bruyns‐Haylett ◽

Aneurin Kennerley ◽

Hongtao Ma ◽

...

Keyword(s):

Blood Volume ◽

Neural Activity ◽

Cerebral Blood Volume ◽

Neocortical Seizures

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Validating layer-specific VASO across species

10.1101/2020.07.24.219378 ◽

2020 ◽

Author(s):

Laurentius Renzo Huber ◽

Benedikt A Poser ◽

Amanda L Kaas ◽

Elizabeth J Fear ◽

Sebastian Desbach ◽

...

Keyword(s):

Optical Imaging ◽

Neural Activity ◽

Cerebral Blood Volume ◽

Fold Increase ◽

Cortical Layer ◽

Physiological Parameter ◽

Reliable Estimate ◽

List Type ◽

Somatosensory Stimulation ◽

Bold Fmri

AbstractCerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (>=7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated and thus interpretation of such data is confounded. Here we cross-validate layer-dependent VASO fMRI contrast in a preclinical rat model using well established (but invasive) imaging methods in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Through direct comparison of response magnitude, across time, negligible changes in hematocrit ratio during activation (neuronal or vascular) are inferred. Quantified cortical layer profiling is demonstrated and in agreement between both VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical excitatory and inhibitory processing independent of confounding large draining veins which hamper BOLD fMRI studies. While we find increased VASO based CBV reactivity (3.1 ± 1.2 fold increase) in humans compared to rats it is demonstrated that this reflects differences in stimulus design rather than confounds of the VASO signal source. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent fMRI results and should supersede BOLD fMRI as the method of choice in neuroscience application studies.HighlightsOur goal is to validate layer-specific VASO fMRI with gold standard methodsLayer-specific VASO sequences are implemented for 7T imaging in humans and ratsComparisons of VASO, optical imaging, and MION confirm the expected contrast originSomatosensory stimulation in humans and rats reveal the same layer-fMRI signaturesWe confirm that VASO is a valid measure to estimate layer-specific neural activityGraphical abstract

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Detection of local microvascular proliferation in IDH wild-type Glioblastoma using relative Cerebral Blood Volume

10.1101/2021.04.19.21255589 ◽

2021 ◽

Author(s):

María del Mar Álvarez-Torres ◽

Elies Fuster-García ◽

Javier Juan-Albarracín ◽

Gaspar Reynés ◽

Fernando Aparici-Robles ◽

...

Keyword(s):

Blood Volume ◽

Cerebral Blood Volume ◽

Statistical Tests ◽

Dynamic Susceptibility ◽

Wild Type ◽

Dynamic Susceptibility Contrast ◽

Relative Cerebral Blood Volume ◽

Microvascular Proliferation ◽

Susceptibility Contrast ◽

Definition Of

ABSTRACTBackgroundThe microvascular proliferation (MVP) and the microvessel area (MVA) are known as diagnostic and prognostic biomarkers for glioblastoma; nevertheless, its measurement is costly, labor-intense, and invasive. MRI perfusion biomarkers such as such as relative cerebral blood volume (rCBV) may be a feasible alternative to predict MVP and estimate MVA.PurposeThis study aims to evaluate the detection capacity of MRI markers such as rCBV to detect local microvascular proliferation in IDH wild-type glioblastoma. In addition, we aim to analyze the association between rCBV values and the microvessel area in different regions of the tumor.Study typeRetrospective study.Population and subjectsData from 71 tissue blocks belonging to 17 IDH wild-type glioblastoma patients were compiled from the Ivy GAP database.Field Strength/Sequence1.5T or 3.0T. Pregadolinium and postgadolinium-based contrast agent-enhanced T1-weighted MRI, T2- and FLAIR T2-weighted, and dynamic susceptibility contrast (DSC) T2* perfusion.AssessmentWe analyzed preoperative MRIs to establish the association between the maximum and mean relative cerebral blood volume (rCBVmax and rCBVmean) with the presence/absence of microvascular proliferation and with the microvessel area for each tumor block.Statistical testsSpearman’s correlation and Mann-Whitney test.ResultsSignificant positive correlations were found between rCBV and MVA in the analyzed tumor blocks (p<0.001). Additionally, significant differences in rCBV were found between blocks with MVP and blocks without MVP (p<0.0001).Data conclusionThe rCBV is shown as significantly different in those tissue blocks with microvascular proliferation from those blocks without it, and it is significantly correlated with microvessels area. This method allows a local detection and definition of MVP and MVA in different regions of the glioblastoma since the first diagnostic stage and in a non-invasive way.

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A Rat Model of Somatosensory-Evoked Reflex Seizures Induced by Peripheral Stimulation

10.1101/506352 ◽

2018 ◽

Author(s):

Aleksandra Bortel ◽

Ze Shan Yao ◽

Amir Shmuel

Keyword(s):

Animal Model ◽

Blood Volume ◽

Cerebral Blood Volume ◽

List Type ◽

Evoked Responses ◽

Peripheral Stimulation ◽

Reflex Seizures ◽

Linear Probe ◽

The Brain ◽

Stimulation Of

ABSTRACTObjectiveWe introduce a novel animal model of somatosensory stimulation-induced reflex seizures which generates focal seizures without causing damage to the brain.MethodsSpecifically, we electrically stimulated digits or forepaws of adult rats sedated with dexmedetomidine while imaging cerebral blood volume and recording neurophysiological activity in cortical area S1FL. For the recordings, we either inserted a linear probe into the D3 digit representation or we performed surface electrocorticography (ECoG) recordings.ResultsPeripheral stimulation of a digit or the forepaw elicited seizures that were followed by a refractory period with decreased neuronal activity, or another seizure or a normal response. LFP amplitudes in response to electrical pulses during the seizures (0.28 ± 0.03 mV) were higher than during normal evoked responses (0.25 ± 0.05 mV) and refractory periods (0.2 ± 0.08 mV). Seizures generated during the stimulation period showed prolonged after-discharges that were sustained for 20.9±1.9 s following the cessation of the stimulus. High-frequency oscillations were observed prior to and during the seizures, with amplitudes higher than those associated with normal evoked responses. The seizures were initially focal. Optical imaging of the cerebral blood volume response showed that they propagated from the onset zone to adjacent cortical areas, beyond the S1FL representation of the stimulated digit or forepaw. The spatial extent during seizures was on average 1.74 times larger during the stimulation and 4.1 times following its cessation relative to normal evoked responses. Seizures were recorded not only by probes inserted into cortex but also with ECoG arrays (24.1±5.8 seizures per rat) placed over the dura matter, indicating that the seizures were not induced by damage caused by inserting the probes to cortex. Stimulation of the forepaw elicited more seizures (18.8±8.5 seizures per rat) than stimulation of a digit (1.7±0.7). Unlike rats sedated with dexmedetomidine, rats anesthetized with urethane showed no seizures, indicating that the seizures may depend on the use of the mild sedative dexmedetomidine.SignificanceOur proposed animal model generates seizures induced by electrical sensory stimulation free of artifacts and brain damage. It can be used for studying the mechanisms underlying the generation and propagation of reflex seizures and for evaluating antiepileptic drugs.HIGHLIGHTSPeripheral stimulation of the rat forepaw or digits induces seizuresSeizures are evoked with no direct application of convulsants, electro-stimulation or damage to the brainSeizures are focal at onset, then spread beyond the spatial representation of the digit or forepawSeizures persist following the cessation of the stimulusProposed animal model may support the study of reflex seizures and improving therapeutic interventions

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