Neurovascular Coupling Response Research Articles

Pendulum Study: Active Visual Tracking Elicits Non‐Selective Elevations in Cerebral Blood Flow

Neurovascular coupling (NVC) describes the effective matching of cerebral blood flow (CBF) to regions of neuro‐metabolic demand. There is increasing interest to assess human NVC for both basic research and its potential role in vascular‐cognitive impairment. The clinical utility of NVC relies on a standardized protocol for which the driving metabolic demands are highly‐selective. Various research groups deploy divergent strategies to elicit visual NVC responses, including inactive processes (visual grating), passive visual tracking (target with predictable motion) and active visual tracking (target with unpredictable motion). These strategies differ in degree of cognitive and metabolic demand and may elicit different NVC responses, thus precluding study comparison.The present NVC assessment evaluated temporal and regional responsiveness of blood flow (transcranial Doppler) to the visual cortex [via the posterior cerebral artery (PCA)] and blood pressure (Finapres NOVA) during visual stimulation in 19 healthy subjects while also measuring middle cerebral artery (MCA) blood flow. Visual stimulation included 10 cycles of 30‐seconds with eyes‐closed, followed by 30‐seconds with eyes‐open tracking a moving computerized target. Each subject completed three trials of passive tracking and three trials of active tracking (114 NVC protocols, 1140 individual hyperemias). A custom eye‐scanning apparatus followed eye motion to quantify visual target‐tracking vigilance. Additional custom software was used to quantify NVC.The data demonstrated that active tracking elicited greater NVC responses compared to passive tracking. Specifically, there was 26% greater change in the mean elevation of PCA blood velocity (p=<0.000) and 13% greater peak NVC response (p<0.01). The MCA response was also greater during active tracking (mean response 111% greater, peak response 41% greater; both p<0.001). Visual target‐tracking vigilance was linearly correlated to the degree of hyperemia in the MCA and PCA, as well blood pressure during NVC.It was observed that active and passive visual tracking elicit different NVC responses and cannot be reliably compared. That PCA and MCA responses were greater with active tracking suggests an elevated global CBF (i.e. not selective to regions perfused by the PCA) that may result from recruitment of brain centres responsible for sustained attention and executive function. In other words, active tracking leads to non‐selective elevations in global CBF and greater target‐tracking vigilance impacts the NVC response. These findings are a critical step to better understand and standardize the evaluation of NVC in humans and for potential clinical deployment of NVC assessments.Support or Funding InformationNatural Sciences and Engineering Research Council; Alberta Innovates Research Studentship; NSERC; CIHR; Libin Cardiovascular Institute; Hotchkiss Brain Institute; Compute CanadaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Network analysis identifies consensus physiological measures of neurovascular coupling in humans

Intimate communication between neural and vascular structures is required to match neuronal metabolism to blood flow, a process termed neurovascular coupling. The number of laboratories assessing neurovascular coupling in humans is increasing due to clinical interest in disease states, and basic science interest in a non-anesthetized, non-craniotomized, unrestrained, in vivo model. However, there is a lack of knowledge regarding how best to characterize the neurovascular response. To address this knowledge gap, we have amassed a highly powered human neurovascular coupling dataset, and deployed a network-based approach to reveal the most powerful and consistent metrics for quantifying neurovascular coupling. Using dimensionality reduction, community-based clustering, and majority-voting of traditional metrics (e.g. peak response, time to peak) and non-traditional metrics (e.g. varying time windows, pulsatility), we have identified which of the existing metrics predominantly characterize the neurovascular coupling response, are stable within and across participants, and explain the vast majority of the variance within our dataset of over 300 trials. We then harnessed our empirical approach to generate powerful novel metrics of neurovascular coupling, termed iAmplitude, iRate, and iPulsatility, which increase sensitivity when capturing population differences. These metrics may be useful to optimally understand neurovascular coupling in health and disease.

Neurovascular Coupling Remains Intact During Incremental Ascent to High Altitude (4240 m) in Acclimatized Healthy Volunteers.

Neurovascular coupling (NVC) is the temporal link between neuronal metabolic activity and regional cerebral blood flow (CBF), supporting adequate delivery of nutrients. Exposure to high altitude (HA) imposes several stressors, including hypoxia and hypocapnia, which modulate cerebrovascular tone in an antagonistic fashion. Whether these contrasting stressors and subsequent adaptations affect NVC during incremental ascent to HA is unclear. The aim of this study was to assess whether incremental ascent to HA influences the NVC response. Given that CBF is sensitive to changes in arterial blood gasses, in particular PaCO2, we hypothesized that the vasoconstrictive effect of hypocapnia during ascent would decrease the NVC response. 10 healthy study participants (21.7 ± 1.3 years, 23.57 ± 2.00 kg/m2, mean ± SD) were recruited as part of a research expedition to HA in the Nepal Himalaya. Resting posterior cerebral artery velocity (PCAv), arterial blood gasses (PaO2, SaO2, PaCO2, [HCO3-], base excess and arterial blood pH) and NVC response of the PCA were measured at four pre-determined locations: Calgary/Kathmandu (1045/1400 m, control), Namche (3440 m), Deboche (3820 m) and Pheriche (4240 m). PCAv was measured using transcranial Doppler ultrasound. Arterial blood draws were taken from the radial artery and analyzed using a portable blood gas/electrolyte analyzer. NVC was determined in response to visual stimulation (VS; Strobe light; 6 Hz; 30 s on/off × 3 trials). The NVC response was averaged across three VS trials at each location. PaO2, SaO2, and PaCO2 were each significantly decreased at 3440, 3820, and 4240 m. No significant differences were found for pH at HA (P > 0.05) due to significant reductions in [HCO3-] (P < 0.043). As expected, incremental ascent to HA induced a state of hypoxic hypocapnia, whereas normal arterial pH was maintained due to renal compensation. NVC was quantified as the delta (Δ) PCAv from baseline for mean PCAv, peak PCAv and total area under the curve (ΔPCAv tAUC) during VS. No significant differences were found for Δmean, Δpeak or ΔPCAv tAUC between locations (P > 0.05). NVC remains remarkably intact during incremental ascent to HA in healthy acclimatized individuals. Despite the array of superimposed stressors associated with ascent to HA, CBF and NVC regulation may be preserved coincident with arterial pH maintenance during acclimatization.

Neurovascular coupling response to cognitive examination in healthy controls: a multivariate analysis.

Cognitive testing with transcranial Doppler ultrasonography (TCD) has been used to assess neurovascular coupling (NVC), but few studies address its multiple contributions. Subcomponent analysis considers the relative myogenic (resistance area product, RAP) and metabolic (critical closing pressure (CrCP)) contributors. The aim of this study was to investigate the changes in subcomponents that occur with cognitive stimulation with the Addenbrooke's Cognitive Examination (ACE‐III) in healthy controls. Healthy volunteers underwent continuous recording of bilateral TCD, heart rate (HR, three‐lead ECG), end‐tidal CO 2 (ETCO 2, capnography), and mean arterial pressure (MAP, Finometer). The study comprised a 5‐min baseline recording, followed by all 20 paradigms from the ACE‐III. The cerebral blood flow velocity (CBFv) response was decomposed into the relative contributions (subcomponents); V BP (MAP), V CrCP (CrCP), and V RAP (RAP). Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC). Forty bilateral datasets were obtained (27 female, 37 right hand dominant). V BP increased at task initiation in all paradigms but differed between tasks (range (SD): 4.06 (8.92)–16.04 (12.23) %, P < 0.05). HR, but not ETCO 2, also differed significantly (P < 0.05). Changes in V RAP reflected changes in MAP, but in some paradigms atypical responses were seen. V CrCP AUC varied significantly within paradigm sections (range [SD]: 18.4 [24.17] to 244.21 [243.21] %*s, P < 0.05). All paradigms demonstrated changes in subcomponents with cognitive stimulation, and can be ranked based on their relative presumed metabolic demand. The integrity of NVC requires further investigation in patient populations.

The Neurovascular Coupling Response Remains Intact During Incremental Ascent to High Altitude (4370m) in Acclimatized Healthy Volunteers

Neurovascular coupling (NVC) is the link between neuronal metabolic activity and regional cerebral blood flow. NVC is responsible for ensuring adequate delivery of nutrients (O2 and glucose) during periods of increased neuronal metabolic demand. Exposure to high‐altitude (HA) elicits ventilatory and acid‐base adjustments for maintaining blood pH. Acute exposure to HA causes hypoxic vasodilation. Hypoxia also drives a ventilatory response, inducing hypocapnia, a potent vasoconstrictor. Whether these dynamic and conflicting responses affect NVC during incremental ascent to HA is unclear.The aim of this project was to assess whether changes in arterial blood gases (ABGs) associated with ascent to HA influences the NVC response. Given that CBF is particularly sensitive to changes in PaCO2, we hypothesized that hypocapnic vasoconstriction during ascent would decrease the NVC response with ascent.10 healthy study participants (21.7±1.3 yrs, 70.46±13.65kg, mean±SD) were recruited as part of a research expedition to Everest base camp, Nepal. Resting posterior cerebral artery velocity (PCAv), ABGs (PaO2, PaCO2), SaO2, arterial blood pH and bicarbonate [HCO3−] were measured at four locations: Calgary (1045m; baseline; BL), Namche (3440m), Deboche (3820m) and Pheriche (4370m). Resting PCAv was measured using transcranial Doppler ultrasound. Arterial blood draws were taken from the radial artery and analysed using a portable blood gas/electrolyte analyser used to monitor changes in ABGs (PaCO2, PaO2, SaO2), pH and [HCO3−] during ascent. NVC was tested via visual stimulation (VS; Strobe light; 6Hz; 30sec on/off ×3). The NVC response was averaged across three VS trials at each location. NVC was quantified as the change (delta) in mean and peak PCAv from baseline, during VS.A one‐factor‐repeated measures analysis of variance (ANOVA) was used to assess for differences in baseline PCAv, NVC, ABGs, blood pH and [HCO3−] between locations. PaO2, PaCO2 and SaO2 were significantly decreased from BL at each altitude (P&lt;0.001, P&lt;0.016 and P&lt;0.013, respectively). No significant differences were found for pH at any location compared to BL (P&gt;0.05) due to reductions in arterial [HCO3−] (P&lt;0.043). No significant differences were found in baseline PCAv between locations (P&gt;0.05) or for mean or peak NVC responses (P&gt;0.085 and P&gt;0.08 respectively).As expected, incremental ascent to HA induced a state of hypoxic hypocapnia, as demonstrated by significant reductions in PaO2, SaO2 and PaCO2, whereas arterial pH was maintained via reductions in [HCO3−]. Our data suggests that NVC remains remarkably intact during incremental ascent to HA in healthy acclimatized individuals. Despite the array of superimposed stressors associated with ascent to HA, CBF and NVC regulation may be a unique function of arterial pH maintenance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Bayesian population receptive field modelling

We introduce a probabilistic (Bayesian) framework and associated software toolbox for mapping population receptive fields (pRFs) based on fMRI data. This generic approach is intended to work with stimuli of any dimension and is demonstrated and validated in the context of 2D retinotopic mapping. The framework enables the experimenter to specify generative (encoding) models of fMRI timeseries, in which experimental stimuli enter a pRF model of neural activity, which in turns drives a nonlinear model of neurovascular coupling and Blood Oxygenation Level Dependent (BOLD) response. The neuronal and haemodynamic parameters are estimated together on a voxel-by-voxel or region-of-interest basis using a Bayesian estimation algorithm (variational Laplace). This offers several novel contributions to receptive field modelling. The variance/covariance of parameters are estimated, enabling receptive fields to be plotted while properly representing uncertainty about pRF size and location. Variability in the haemodynamic response across the brain is accounted for. Furthermore, the framework introduces formal hypothesis testing to pRF analysis, enabling competing models to be evaluated based on their log model evidence (approximated by the variational free energy), which represents the optimal tradeoff between accuracy and complexity. Using simulations and empirical data, we found that parameters typically used to represent pRF size and neuronal scaling are strongly correlated, which is taken into account by the Bayesian methods we describe when making inferences. We used the framework to compare the evidence for six variants of pRF model using 7 T functional MRI data and we found a circular Difference of Gaussians (DoG) model to be the best explanation for our data overall. We hope this framework will prove useful for mapping stimulus spaces with any number of dimensions onto the anatomy of the brain.

Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response.

Models designed to study neurovascular coupling (NVC) describe a possible cerebral hemisphere dominance dependent on task completed and preference in handedness. We investigated whether passive arm manoeuvre performed with dominant (Dom-Arm) or non-dominant arm (ND-Arm) stimulated haemodynamic differences in either contralateral (Cont-H) or ipsilateral (Ipsil-H) cerebral hemisphere. Healthy individuals lying in supine position, had measurements of beat-to-beat blood pressure (BP, mmHg), electrocardiogram (HR, bpm), end-tidal CO2 (etCO2, mmHg), and bilateral insonation of the middle cerebral arteries (MCA, cms-1). Arm movement was performed for 60s with passive flexion and extension of the elbow (1Hz), before manoeuvre was repeated on other arm. Data were normalised and effect of treatment was analysed for differences between manoeuvres and within each time period. Seventeen (eight males) healthy volunteers, aged 56±7years, were studied. Dom-Arm and ND-Arm manoeuvres stimulated a comparable temporal response in peripheral and cerebral haemodynamic parameters between Cont-H and Ipsil-H. Both manoeuvres can be used to evoke similar bilateral MCA responses in assessing NVC. This finding should lead to more efficient protocols when using passive arm movement for NVC studies in healthy subjects.

A Prospective Transcranial Doppler Ultrasound-Based Evaluation of the Acute and Cumulative Effects of Sport-Related Concussion on Neurovascular Coupling Response Dynamics.

Sport-related concussion has been shown to alter cerebral blood flow (CBF) both acutely and chronically, and may exert cumulative effects across multiple injuries. Such dysfunction may be mediated by trauma-induced deficits to CBF control mechanisms, though our understanding of these effects is limited, including dynamics of neurovascular coupling (NVC) responses (i.e., CBF responses to neurologic demand). A total of 179 junior-level contact sport athletes completed preseason testing; 42 reported never having experienced a concussion (Hx-) while 31 had endured three or more (Hx3+). A total of 18 athletes suffered concussions during the study period and were re-tested 3 days, 2 weeks, and 1 month post-injury. NVC dynamics were indexed via CBF velocity in the posterior (PCAv) and middle (MCAv) cerebral arteries during cycles of 20 sec eyes closed and 40 sec eyes open to a visual stimulus (reading). Acutely following concussion, peak rate of PCAv increase during the activation phase was delayed by over 50% and PCAv response magnitude was elevated by over 30%, compared with preseason. Response magnitude remained elevated at 2 weeks despite symptom resolution. Independent medical clearance for full return-to-play was inversely related to the magnitude of increase in the NVC response at 3 days post-injury. No post-injury changes were observed in MCAv, blood pressure, or end-tidal carbon dioxide levels during visual stimulation. No NVC metric differences were observed between the Hx- and Hx3+ groups at preseason. Via multiple potential mechanisms, acute sport-related concussion may induce compensatory alterations in NVC response dynamics that may be related to clinical recovery. Such effects do not appear to be persistent across multiple injuries.

Cerebral haemodynamic response to somatosensory stimulation in neonatal lambs.

Cerebral haemodynamic response to neural stimulation has been extensively studied in adults, but little is known about cerebral haemodynamic response in the fetal and neonatal brain. The present study describes the cerebral haemodynamic response measured by near infrared spectroscopy to somatosensory stimulation in newborn lambs, in comparison to recent findings in fetal sheep. The cerebral haemodynamic responses in the newborn lamb brain can involve an increase in oxyhaemoglobin (oxyHb), or a decrease of oxyHb suggestive of reduced perfusion and oxygenation. Positive correlations between changes in oxyHb and mean arterial blood pressure were found in newborn but not fetal sheep, which suggests the result is unlikely to be due to immature autoregulation alone. In contrast to adult studies, hypercapnia increased the changes in cerebral blood flow and oxyHb in most of the lambs in response to somatosensory stimulation. The neurovascular coupling response has been defined for the adult brain, but in the neonate non-invasive measurement of local cerebral perfusion using near infrared spectroscopy or blood oxygen level-dependent functional magnetic resonance imaging have yielded variable and inconsistent results, including negative responses suggesting decreased perfusion and localized tissue tissue hypoxia. Also, the impact of permissive hypercapnia (P aC O2>50mmHg) in the management of neonates on cerebrovascular responses to somatosensory input is unknown. Using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) in eight anaesthetized newborn lambs, we studied the cerebral haemodynamic functional response to left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8s. Stimulation always produced a somatosensory evoked response, and superficial cortical perfusion measured by laser Doppler flowmetry predominantly increased following median nerve stimulation. However, with 1.8s stimulation, oxyHb responses in the contralateral hemisphere were either positive (i.e. increased oxyHb), negative, or absent; and with 4.8 and 7.8s stimulations, both positive and negative responses were observed. Hypercapnia increased baseline oxyHb and total Hb consistent with cerebral vasodilatation, and six of seven lambs tested showed increased Δtotal Hb responses after the 7.8s stimulation, among which four lambs also showed increased ΔoxyHb responses. In two of three lambs, the negative ΔoxyHb response became a positive pattern during hypercapnia. These results show that instead of functional hyperaemia, somatosensory stimulation can evoke negative (decreased oxyHb, total Hb) functional responses in the neonatal brain suggestive of decreased local perfusion and vasoconstriction, and that hypercapnia produces both baseline hyperperfusion and increased functional hyperaemia.

Neurovascular coupling response is maintained despite exposure to repetitive sub-concussive head trauma over the course of one contact-sport season

ObjectiveTo examine how head-impact exposures affect the elevation in cerebral blood velocity (CBV) in the posterior cerebral artery (PCA) during visual tasks.DesignProspective Cohort.SettingLaboratory.ParticipantsTo date: 40 male contact-sport athletes (19.4±1.2 years) and 3 cross-country athletes (20.0±1.0 years) have completed testing (non-contact controls).InterventionTranscranial Doppler ultrasound indexed PCA CBV during visual tasks. Participants closed their eyes (20-seconds), and when prompted, opened them and completed a visual task (40-seconds). Testing occurred prior-to and upon-completion-of the competitive athletic season. Raw traces from each trial were averaged to enhance the signal-to-noise ratio of outcome measurements. Independent variable tested was time (2).OutcomeEyes-closed CBV (cm/s), peak elevation in CBV (cm/s), relative change in CBV (%) and total activation during the first 30 seconds of the task (indexed via area under the curve-AUC). Head-impact exposure was characterised in a subset of contact-sport athletes (n=29) using the xPatch (X2 Biosystems).Main resultsRM-ANOVA indicated the contact-sport season had no effects on any outcome metrics: Eyes-closed CBV (p=0.181), peak CBV (p=0.117),% CBV elevation (p=0.252) and AUC (p=0.366), despite experiencing cumulative peak linear accelerations of 8147.2±6215.5g, and cumulative peak rotational accelerations of 34.5×106± 59.0×106rad/?s2.ConclusionsThe results from this study suggest neurovascular coupling metrics are maintained throughout a contact-sport season. This indicates nutrient delivery is maintained for neurocognitive challenges despite possible impairments in cerebrovasculature’s ability to buffer blood pressure challenges associated elevations in rotational accelerations experienced during a contact-sport season.Competing interestsNone.

A history of multiple concussions does not alter the transcranial doppler-based assessment of the neurovascular coupling response

ObjectiveTo determine how a history of 3+ concussions alters elevations in cerebral blood velocity (CBV) in the posterior cerebral artery (PCA) during visual tasks.DesignRetrospective Cohort.SettingLaboratory.Participants136 male contact-sport athletes (19.1±1.4 years, 66 football, 70 hockey) were recruited; 39 presented with 0 previous concussions, 16 with 3+ previous concussions; exclusion criteria included history of concussion within 6 months.InterventionTranscranial Doppler ultrasound indexed PCA-CBV during a series of visual tasks. Participants closed their eyes (20-seconds) and, when prompted, opened their eyes to complete a visual task (40-seconds). Testing occurred prior to the start of their athletic season. The visual trial raw traces were averaged together to enhance the signal-to-noise ratio of outcome measurements. The independent variable tested was concussion history.OutcomesEyes-closed CBV (cm/s), peak elevation in CBV after eyes-open (cm/s), relative change in CBV (%), and total activation during the first 30 seconds of the task (indexed via area under the curve-AUC)Main resultsIndependent samples T-Tests indicated there were no effects of concussion history on any outcome: Eyes-closed CBV (p=0.950), peak CBV (p=0.903), % CBV elevation (p=0.593), and AUC (p=0.718).ConclusionsA history of multiple concussions does not alter the cerebrovasculature’s ability to maintain nutrient delivery required for visual challenges in cortical areas supplied by the PCA. This is an important finding; despite the long-term neurocognitive deficits associated with a history of concussions, the transcranial Doppler assessment of neurovascular coupling appears intact for this population of younger adult contact-sport athletes.Competing interestsNone.

Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as "neurovascular coupling" (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity.SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses.

Demographic and Systemic Hemodynamic Influences in Mechanisms of Cerebrovascular Regulation in Healthy Adults

A competent cerebrovascular regulation maintains an adequate cerebral blood flow by 3 major mechanisms: cerebral autoregulation (CA), vasomotor reactivity (VMR), namely to CO2, and neurovascular coupling (NVC). However, most studies generalize their results based on a response to a single parameter. Using a full battery of neurovascular stress tests, our study aims to evaluate the relationships among grades of CA, VMR, and NVC, and how their interplay is influenced by demographic and systemic hemodynamic factors. Fifty-eight healthy adults were recruited to fit each decade age stratum from 20 to 80 years old with similar sex ratio. Arterial blood pressure (Finometer), cerebral blood flow velocity in the middle cerebral arteries (transcranial Doppler), electrocardiogram, and end-tidal CO2 were monitored. We assessed CA by transfer function analysis, VMR at hypocapnia and hypercapnia (carbogen 5%), and NVC response during the N-Back Task. The Montreal Cognitive Assessment scores were recorded. Neurovascular stress tests were not affected by age or gender, and no correlation was found between their outputs (P > .05). Systemic hemodynamic parameters during tasks as well as cognitive scores had no correlation with cerebrovascular measurements (P > .05). Age and gender do not have major influence on the 3 major cerebrovascular regulation mechanisms. Our results also pinpoint the fact that neurovascular stress tests measure different aspects of cerebrovascular control, and that their outputs are uncorrelated and cannot be used interchangeability. Being independent of age and cognitive status, neurovascular stress tests seem adequate for studying several cerebrovascular conditions affecting the aging brain.

A model of neurovascular coupling and the BOLD response PART II

A mathematical model is developed which describes a signalling mechanism of neurovascular coupling with a model of a pyramidal neuron and its corresponding fMRI BOLD response. In the first part of two papers (Part I) we described the integration of the neurovascular coupling unit extended to include a complex neuron model, which includes the important Na/K ATPase pump, with a model that provides a BOLD signal taking its input from the cerebral blood flow and the metabolic rate of oxygen consumption. We showed that this produced a viable signal in terms of initial dip, positive and negative BOLD signals. In this paper (PART II) our model predicts the variations of the BOLD response due to variations in neuronal activity and indicates that the BOLD signal could be used as an initial biomarker for neuronal dysfunction or variations in the perfusion of blood to the cerebral tissue. We have compared the simulated hypoxic BOLD response to experimental BOLD signals observed in the hippocampus during hypoxia showing good agreement. This approach of combined quantitative modelling of neurovascular coupling response and its BOLD response will enable more specific assessment of a brain region.

Where’s Waldo? The utility of a complicated visual search paradigm for transcranial Doppler-based assessments of neurovascular coupling

BackgroundThe concept of neurovascular coupling has been postulated since the late 1800s and has been demonstrated most commonly in humans using visual stimuli (e.g. reading, checkerboards). These traditional paradigms evoke only a moderate cerebral blood flow response due to the relative simplicity of the visual stimuli. New methodForty subjects completed three visual paradigms each challenging the visual processing areas to a different extent: reading text, complicated visual searching (new method: Where’s Waldo) and viewing coloured dots. Posterior and middle cerebral artery (PCA, MCA) velocities were recorded using transcranial Doppler ultrasound during each visual paradigm. ResultsPrior to the presentation of the visual stimuli there were no differences in mean arterial pressure, or PCA or MCA velocities for the three paradigms. All three paradigms led to an elevation in PCA and MCA velocities after a delay (∼1.1s). Whereas velocity elevation was consistent across the three paradigms in the MCA, it was markedly larger during the Where’s Waldo task in the PCA. Thus, although the onset of the neurovascular coupling response was similar across the three visual paradigms, its overall magnitude was stimulus-dependent. Comparison with existing methodsGiven that PCA velocity can be affected by blood pressure or carbon dioxide alterations, traditional neurovascular coupling paradigms (e.g. reading, checkerboards) appear to have a lower signal-to-noise ratio than that observed in complicated visual search tasks such as Where’s Waldo. ConclusionsWe recommend complicated visual search paradigms such as Where’s Waldo be considered for future transcranial Doppler-based neurovascular coupling studies.

Neurovascular Coupling Response Dysfunction after Ischemic Stroke: The Possible Mechanism in Cognition Impairment

One of the cardinal aspects of post-ischemic stroke disabilities is cognitive decline correlated with higher long-term mortality rate. There are various hypotheses about cognition impairment after ischemic stroke, but lately, neurovascular coupling (NVC) response impairment and neurovascular unit (NVU) disruption have been proposed as causes for cognitive decline. The NVC mechanism, a feature of the brain’s intrinsic micro circulation, regulates local cerebral blood flow (CBF) in accordance with the underlying neuronal activity. It seems that, cerebral ischemia triggers several molecular and cellular cascades including excitotoxicity, neuroinflammation, oxidative stress and blood brain barrier (BBB) disruption which eventually leads to NVU malfunction and NVC response impairment which results in cognitive dysfunction in many stroke patients. This review tries to focus on the factors involved in NVC response that might affect cognition after ischemic stroke.

Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage.

Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K(+)) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca(2+) events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca(2+) signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca(2+) signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca(2+) signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca(2+) stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca(2+) and elevation of extracellular K(+)). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca(2+) release events leading to inversion of NVC. Significance statement: Aneurysmal subarachnoid hemorrhage (SAH)--strokes involving cerebral aneurysm rupture and release of blood onto the brain surface--are associated with high rates of morbidity and mortality. A common complication observed after SAH is the development of delayed cerebral ischemia at sites often remote from the site of rupture. Here, we provide evidence that SAH-induced changes in astrocyte Ca(2+) signaling lead to a switch in the polarity of the neurovascular coupling response from vasodilation to vasoconstriction. Thus, after SAH, signaling events that normally lead to vasodilation and enhanced delivery of blood to active brain regions cause vasoconstriction that would limit cerebral blood flow. These findings identify astrocytes as a key player in SAH-induced decreased cortical blood flow.

Optogenetic neuronal stimulation promotes functional recovery after stroke.

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.

Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity.

PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end‐tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive‐moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P <0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P <0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics.

Pyramidal Cells and Cytochrome P450 Epoxygenase Products in the Neurovascular Coupling Response to Basal Forebrain Cholinergic Input

Activation of the basal forebrain (BF), the primary source of acetylcholine (ACh) in the cortex, broadly increases cortical cerebral blood flow (CBF), a response downstream to ACh release. Although endothelial nitric oxide and cholinoceptive GABA (γ-aminobutyric acid) interneurons have been implicated, little is known about the role of pyramidal cells in this response and their possible interaction with astrocytes. Using c-Fos immunohistochemistry as a marker of neuronal activation and laser-Doppler flowmetry, we measured changes in CBF evoked by BF stimulation following pharmacological blockade of c-Fos-identified excitatory pathways, astroglial metabolism, or vasoactive mediators. Pyramidal cells including those that express cyclooxygenase-2 (COX-2) displayed c-Fos upregulation. Glutamate acting via NMDA, AMPA, and mGlu receptors was involved in the evoked CBF response, NMDA receptors having the highest contribution (~33%). In contrast, nonselective and selective COX-2 inhibition did not affect the evoked CBF response (+0.4% to 6.9%, ns). The metabolic gliotoxins fluorocitrate and fluoroacetate, the cytochrome P450 epoxygenase inhibitor MS-PPOH and the selective epoxyeicosatrienoic acids (EETs) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) all blocked the evoked CBF response by ~50%. Together, the data demonstrate that the hyperemic response to BF stimulation is largely mediated by glutamate released from activated pyramidal cells and by vasoactive EETs, likely originating from activated astrocytes.