A time-invariant visco-elastic windkessel model relating blood flow and blood volume

The difference between the rate of change of cerebral blood volume (CBV) and cerebral blood flow (CBF) following stimulation is thought to be due to circumferential stress relaxation in veins (Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679-689). In this paper we explore the visco-elastic properties of blood vessels, and present a dynamic model relating changes in CBF to changes in CBV. We refer to this model as the visco-elastic windkessel (VW) model. A novel feature of this model is that the parameter characterising the pressure-volume relationship of blood vessels is treated as a state variable dependent oil the rate of change of CBV, producing hysteresis in the pressure-volume space during vessel dilation and contraction. The VW model is nonlinear time-invariant, and is able to predict the observed differences between the time series of CBV and that of CBF measurements following changes in neural activity. Like the windkessel model derived by Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679-689, the VW model is primarily a model of haemodynamic changes in the venous compartment. The VW model is demonstrated to have the following characteristics typical of visco-elastic materials: (1) hysteresis, (2) creep, and (3) stress relaxation, hence it provides a unified model of the visco-elastic properties of the vasculature. The model will not only contribute to the interpretation of the Blood Oxygen Level Dependent (BOLD) signals from functional Magnetic Resonance Imaging (fMRI) experiments, but also find applications in the study and modelling of the brain vasculature and the haemodynamics of circulatory and cardiovascular systems. (C) 2009 Elsevier Inc. All rights reserved

A dynamic model of neurovascular coupling: implications for blood vessel dilation and constriction

Neurovascular coupling in response to stimulation of the rat barrel cortex was investigated using concurrent multichannel electrophysiology and laser Doppler flowmetry. The data were used to build a linear dynamic model relating neural activity to blood flow. Local field potential time series were subject to current source density analysis, and the time series of a layer IV sink of the barrel cortex was used as the input to the model. The model output was the time series of the changes in regional cerebral blood flow (CBF). We show that this model can provide excellent fit of the CBF responses for stimulus durations of up to 16 s. The structure of the model consisted of two coupled components representing vascular dilation and constriction. The complex temporal characteristics of the CBF time series were reproduced by the relatively simple balance of these two components. We show that the impulse response obtained under the 16-s duration stimulation condition generalised to provide a good prediction to the data from the shorter duration stimulation conditions. Furthermore, by optimising three out of the total of nine model parameters, the variability in the data can be well accounted for over a wide range of stimulus conditions. By establishing linearity, classic system analysis methods can be used to generate and explore a range of equivalent model structures (e.g., feed-forward or feedback) to guide the experimental investigation of the control of vascular dilation and constriction following stimulation. (C) 2010 Elsevier Inc. All rights reserved

Contributions and complexities from the use of in-vivo animal models to improve understanding of human neuroimaging signals.

Many of the major advances in our understanding of how functional brain imaging signals relate to neuronal activity over the previous two decades have arisen from physiological research studies involving experimental animal models. This approach has been successful partly because it provides opportunities to measure both the hemodynamic changes that underpin many human functional brain imaging techniques and the neuronal activity about which we wish to make inferences. Although research into the coupling of neuronal and hemodynamic responses using animal models has provided a general validation of the correspondence of neuroimaging signals to specific types of neuronal activity, it is also highlighting the key complexities and uncertainties in estimating neural signals from hemodynamic markers. This review will detail how research in animal models is contributing to our rapidly evolving understanding of what human neuroimaging techniques tell us about neuronal activity. It will highlight emerging issues in the interpretation of neuroimaging data that arise from in-vivo research studies, for example spatial and temporal constraints to neuroimaging signal interpretation, or the effects of disease and modulatory neurotransmitters upon neurovascular coupling. We will also give critical consideration to the limitations and possible complexities of translating data acquired in the typical animals models used in this area to the arena of human fMRI. These include the commonplace use of anaesthesia in animal research studies and the fact that many neuropsychological questions that are being actively explored in humans have limited homologues within current animal models for neuroimaging research. Finally we will highlighting approaches, both in experimental animals models (e.g. imaging in conscious, behaving animals) and human studies (e.g. combined fMRI-EEG), that mitigate against these challenges

Extensive and Persistent Disruption of Neurovascular Coupling by a Single Cerebral Microinfarct

Cerebral microinfarcts (CMI), microscopic brain lesions caused by blockade of small blood vessels, have recently emerged as a potential determinant of cognitive decline. Though small in size, our recent work demonstrated that a single, strategically placed CMI was sufficient to disrupt sensory input in a behavioral task. However, the means by which such small lesions disrupt brain function remain poorly understood. We imaged vascular function in awake, head-fixed mice using two-photon microscopy to examine the impact of CMI on neurovascular coupling. CMI were generated in cortex by photothrombotic occlusion of single penetrating vessels through a thinned-skull cranial window. Vibrissa-evoked dilation of individual arteries and arterioles within the primary vibrissa cortex were tracked over four time periods: pre-occlusion, acute (2-3 days post-occlusion), subacute (7-9 days) and chronic (14-21 days). In the acute phase, dilatory responses were markedly attenuated compared to pre-occlusion (2.2 ± 0.5% mean dilation over baseline vs. 11.2 ± 0.8%, p \u3c 0.001). Dilatory responses during the subacute (7.8 ± 1.1%) and chronic (6.5 ± 1.1%) phases partially recovered but remained significantly attenuated in magnitude and time to dilation compared to pre-occlusion (p \u3c 0.01). Critically, vascular dysfunction was observed well beyond the borders of the CMI, as infarcts with an average radius of 0.19 ± 0.05 mm generated deficits in dilation at distances exceeding 1 mm away from the vessel targeted for occlusion. Analysis of dilations in a separate cohort of mice during the hyperacute time period (0-3 hours post-occlusion), revealed that the dilatory deficit is first expressed in the immediate vicinity of the stroke and then propagates outward from the occlusion site. While unresponsive to sensory stimulation, vasodilation could be evoked by isoflurane inhalation, albeit attenuated in the subacute phase (156.7 ± 5.3% of pre-stroke levels vs. 134.6 ± 4.3% subacute, p = 0.02). Expression of c-Fos following an extended period of vibrissa stimulation was reduced in the peri-infarct tissue in the acute time period, with gradual recovery initiating distal to the stroke apparent in subacute and chronic mice. This indicated that loss of sensory-evoked vasodilation is attributed to a combination of altered vascular mechanical properties and a deficit in neural connectivity and/or activity. Thus, CMI disrupt brain function well beyond the regions of overt tissue infarction and this effect, combined with their widespread distribution in the aged brain, may contribute to the pathogenesis of CMI in vascular dementia

Linear superposition of sensory-evoked and ongoing cortical hemodynamics.

Modern non-invasive brain imaging techniques utilize changes in cerebral blood flow, volume and oxygenation that accompany brain activation. However, stimulus-evoked hemodynamic responses display considerable inter-trial variability even when identical stimuli are presented and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. To investigate this issue, 2-dimensional optical imaging spectroscopy was used to measure cortical hemodynamics in response to sensory stimuli in anesthetized rodents. Pre-stimulus cortical hemodynamics displayed spontaneous periodic fluctuations and as such, data from individual stimulus presentation trials were assigned to one of four groups depending on the phase angle of pre-stimulus hemodynamic fluctuations and averaged. This analysis revealed that sensory evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase angle of ongoing fluctuations at stimulus onset. To investigate the origin of this phenomenon, "null-trials" were collected without stimulus presentation. Subtraction of phase averaged "null trials" from their phase averaged stimulus-evoked counterparts resulted in four similar time series that resembled the mean stimulus-evoked response. These analyses suggest that linear superposition of evoked and ongoing cortical hemodynamic changes may be a property of the structure of inter-trial variability

Investigation of events in the EEG signal correlated with changes in both oxygen and glucose in the brain

Since the brain has no constant energy reserves, a continuous supply of energy substrates is central to all processes that maintain the functionality of the neuronal cells. EEG has been found to be tightly related to variations in the concentration of the energy substrates such as oxygen and glucose. Prediction of neural activation is particularly useful as it could contribute significantly in the prevention, stabilization, or treatment of diseases such as Alzheimer's disease, migraine headache, and ischemic stroke, in which signaling between neurons and brain vessels is threatened because of dysfunctions that affect the neuronal, astroglial, and/or vascular components of the neurovascular unit. This work deals with investigation of events in the EEG signal correlated with changes in both oxygen and glucose signals in the brain. The topic is to implement a model that through measures of oxygen and glucose in the brain of rats allow to achieve a good estimation of the neural signals, which reflecting the simultaneous metabolic changes, during spontaneous oscillation and electrical stimulation

Investigation of events in the EEG signal correlated with changes in both oxygen and glucose in the brain

Since the brain has no constant energy reserves, a continuous supply of energy substrates is central to all processes that maintain the functionality of the neuronal cells. EEG has been found to be tightly related to variations in the concentration of the energy substrates such as oxygen and glucose. Prediction of neural activation is particularly useful as it could contribute significantly in the prevention, stabilization, or treatment of diseases such as Alzheimer's disease, migraine headache, and ischemic stroke, in which signaling between neurons and brain vessels is threatened because of dysfunctions that affect the neuronal, astroglial, and/or vascular components of the neurovascular unit. This work deals with investigation of events in the EEG signal correlated with changes in both oxygen and glucose signals in the brain. The topic is to implement a model that through measures of oxygen and glucose in the brain of rats allow to achieve a good estimation of the neural signals, which reflecting the simultaneous metabolic changes, during spontaneous oscillation and electrical stimulation

Development of an Awake Behaving model for Laser Doppler Flowmetry in Mice

Bien que le cerveau ne constitue que 2% de la masse du corps chez les humains, il présente l’activité métabolique la plus élevée dans le corps, et en conséquence, constitue un organe hautement vascularisé. En fait, l’approvisionnement en sang dans le cerveau est strictement modulé au niveau régional par un mécanisme fondamental nommé couplage neurovasculaire (CNV), qui associe les besoins métaboliques locaux au flux sanguin cérébral [1, 2]. Notre compréhension du CNV sous des conditions physiologiques et pathologiques a été améliorée par un large éventail d’études menées chez les rongeurs. Néanmoins, ces études ont été réalisées soit sous anesthésie, soit chez la souris éveillée et immobilisée, afin d’éviter le mouvement de la tête pendant l'acquisition de l'image. Les anesthésiques, ainsi que le stress induit par la contention, peuvent altérer l'hémodynamique cérébrale, ce qui pourrait entraver les résultats obtenus. Par conséquent, il est essentiel de contrôler ces facteurs lors de recherches futures menées au sujet de la réponse neurovasculaire. Au cours de l’étude présente, nous avons développé un nouveau dispositif pour l'imagerie optique éveillée, où la tête de la souris est immobilisée, mais son corps est libre de marcher, courir ou se reposer sur une roue inclinée. En outre, nous avons testé plusieurs protocoles d'habituation, selon lesquels la souris a été progressivement entraînée pour tolérer l’immobilisation de tête, afin de minimiser le stress ressenti lors des sessions d'imagerie. Enfin, nous avons, pour la première fois, cherché à valider l'efficacité de ces protocoles d'habituation dans la réduction du stress, en mesurant l'évolution des taux plasmatiques de corticostérone tout au long de notre étude. Nous avons noté que les souris s'étaient rapidement adaptées à la course sur la roue et que les signes visibles de stress (luttes, vocalisations et urination) étaient nettement réduits suite à deux sessions d'habituation. Néanmoins, les taux de corticostérone n'ont pas été significativement réduits chez les souris habituées, par rapport aux souris naïves qui ont été retenues sur la roue sans entraînement préalable (p> 0,05). Ce projet met en évidence la nécessité d'une mesure quantitative du stress, car une réduction des comportements observables tels que l'agitation ou la lutte peut être indicative non pas d'un niveau de stress plus faible, mais plutôt d'un désespoir comportemental. Des recherches supplémentaires sont nécessaires pour déterminer si la fixation de la tête lors de l'imagerie optique chez la souris peut être obtenue avec des niveaux de stress plus faibles, et si le stress induit par la contrainte effectuée avec notre dispositif est associé à des changements de la réponse hémodynamique.Whilst the brain only constitutes 2% of total body weight in humans, it exhibits the highest metabolic activity in the body, and as such is a highly vascularized organ. In fact, regional blood supply within the brain is strictly modulated through a fundamental process termed neurovascular coupling (NVC), which couples local metabolic needs with cerebral blood flow [1, 2]. A wide array of optical imaging studies in rodents has enhanced our understanding of NVC under physiological and pathological conditions. Nevertheless, these studies have been performed either under anesthesia, or in the awake mouse using restraint to prevent head-motion during image acquisition. Both anesthetics and restraint-induced stress have been clearly shown to alter cerebral hemodynamics, thereby potentially interfering with the obtained results [3, 4]. Hence, it is essential to control for these factors during future research which investigates the neurovascular response. In the present study, we have developed a new apparatus for awake optical imaging, where the mouse is head-restraint whilst allowed to walk, run or rest on an inclined wheel. In addition, we have tested several habituation protocols, according to which the mouse was gradually trained to tolerate head-restraint, in order to minimize the stress experienced during imaging sessions. Lastly, we have, for the first time, sought to validate the efficiency of these habituation protocols in reducing stress, by measuring the evolution of plasma corticosterone levels throughout the study. We noted that the mice had quickly adapted to running on the wheel, and that the overt signs of stress (struggling, vocalizations and urination) were clearly reduced within two habituation sessions. Nevertheless, corticosterone levels were not significantly reduced in habituated mice, relative to naïve mice that were restrained on the wheel without prior training (p > 0.05). This project highlights the necessity for a quantitative measure of stress, as a reduction in observable behaviors such as agitation or struggling may be indicative not of lower stress, but rather, of behavioral despair. Further research is needed to determine whether head-fixation during optical imaging in mice can be achieved with lower stress levels, and if restraint-induced stress using our apparatus is associated with changes in the hemodynamic response