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In this review, we have amalgamated the literature, taking a multimodal neuroimaging approach to quantify the relationship between neuronal firing and haemodynamics during a task paradigm (i.e., neurovascular coupling response), while considering confounding physiological influences. Original research articles that used concurrent neuronal and haemodynamic quantification in humans (n ≥ 10) during a task paradigm were included from PubMed, Scopus, Web of Science, EMBASE and PsychINFO. Articles published before 31 July 2023 were considered for eligibility. Rapid screening was completed by the first author. Two authors completed the title/abstract and full‐text screening. Article quality was assessed using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross‐Sectional Studies. A total of 364 articles were included following title/abstract and full‐text screening. The most common combination was EEG/functional MRI (68.7%), with cognitive (48.1%) and visual (27.5%) tasks being the most common. The majority of studies displayed an absence/minimal control of blood pressure, arterial gas concentrations and/or heart rate (92.9%), and only 1.3% monitored these factors. A minority of studies restricted or collected data pertaining to caffeine (7.4%), exercise (0.8%), food (0.5%), nicotine (2.7%), the menstrual cycle (0.3%) or cardiorespiratory fitness levels (0.5%). The cerebrovasculature is sensitive to numerous factors; thus, to understand the neurovascular coupling response fully, better control for confounding physiological influences of blood pressure and respiratory metrics is imperative during study‐design formulation. Moreover, further work should continue to examine sex‐based differences, the influence of sex steroid hormone concentrations and cardiorespiratory fitness. What is the topic of this review?This review examines literature using simultaneous multimodal neuroimaging to measure the relationship between neuronal firing and haemodynamics during task paradigms (i.e., neurovascular coupling). This review focuses on the control of physiological, psychological and lifestyle factors of the included articles.What advances does it highlight?The review underscores the critical need for improved control of physiological and lifestyle confounders, such as blood pressure, carbon dioxide levels, caffeine intake, exercise, menstrual cycle phase and sex comparisons, in study designs to ensure more accurate and reliable findings in neurovascular coupling research. [ABSTRACT FROM AUTHOR]

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer's disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A dense network of blood vessels distributes blood to different regions of the brain. To meet the temporarily and spatially varying energy demand resulting from changes in neuronal activity, the vasculature is able to locally up-regulate the blood supply. However, to which extent diameter changes of different vessel types contribute to the up-regulation, as well as the spatial and temporal characteristics of their changes, are currently unknown. Here, we present a new simulation method, which solves an inverse problem to calculate diameter changes of individual blood vessels needed to achieve predefined blood flow distributions in microvascular networks. This allows us to systematically compare the impact of different vessel types in various regulation scenarios. Moreover, the method offers the advantage that it handles the stochastic nature of blood flow originating from tracking the movement of individual red blood cells. Since the inverse problem is formulated for time-averaged pressures and flow rates, a deterministic approach for calculating the diameter changes is used, which allows us to apply the method for large realistic microvascular networks with high-dimensional parameter spaces. Our results obtained in both artificial and realistic microvascular networks reveal that diameter changes at the level of capillaries enable a very localized regulation of blood flow. In scenarios where only larger vessels, i.e., arterioles, are allowed to adapt, the flow increase cannot be confined to a specific activated region and flow changes spread into neighboring regions. Furthermore, relatively small dilations and constrictions of all vessel types can lead to substantial changes of capillary blood flow distributions. This suggests that small scale regulation is necessary to obtain a localized increase in blood flow.

A dense network of blood vessels distributes blood to different regions of the brain. To meet the temporarily and spatially varying energy demand resulting from changes in neuronal activity, the vasculature is able to locally up-regulate the blood supply. However, to which extent diameter changes of different vessel types contribute to the up-regulation, as well as the spatial and temporal characteristics of their changes, are currently unknown. Here, we present a new simulation method, which solves an inverse problem to calculate diameter changes of individual blood vessels needed to achieve predefined blood flow distributions in microvascular networks. This allows us to systematically compare the impact of different vessel types in various regulation scenarios. Moreover, the method offers the advantage that it handles the stochastic nature of blood flow originating from tracking the movement of individual red blood cells. Since the inverse problem is formulated for time-averaged pressures and flow rates, a deterministic approach for calculating the diameter changes is used, which allows us to apply the method for large realistic microvascular networks with high-dimensional parameter spaces. Our results obtained in both artificial and realistic microvascular networks reveal that diameter changes at the level of capillaries enable a very localized regulation of blood flow. In scenarios where only larger vessels, i.e., arterioles, are allowed to adapt, the flow increase cannot be confined to a specific activated region and flow changes spread into neighboring regions. Furthermore, relatively small dilations and constrictions of all vessel types can lead to substantial changes of capillary blood flow distributions. This suggests that small scale regulation is necessary to obtain a localized increase in blood flow. [ABSTRACT FROM AUTHOR]

Highlights • Cellular and molecular mechanisms underlying increases in regional blood flow in response to neuronal activity are not fully understood. • We have compared the effects of 79 in vivo and 36 in vitro experimental attempts to inhibit the neurovascular response. • Blockade of neuronal NO synthase (nNOS) has the largest effect of any individual target, reducing the neurovascular response by 64%. • This points to the existence of an unknown key signalling mechanism which accounts for approximately one third of the neurovascular response. Abstract The mechanisms of neurovascular coupling contribute to ensuring brain energy supply is sufficient to meet demand. Despite significant research interest, the mechanisms underlying increases in regional blood flow that follow heightened neuronal activity are not completely understood. This article presents a systematic review and analysis of published data reporting the effects of pharmacological or genetic blockade of all hypothesised signalling pathways of neurovascular coupling. Our primary outcome measure was the percent reduction of the neurovascular response assessed using in vivo animal models. Selection criteria were met by 50 primary sources reporting the effects of 79 treatments. Experimental conditions were grouped into categories targeting mechanisms mediated by nitric oxide (NO), prostanoids, purines, potassium, amongst others. Blockade of neuronal NO synthase was found to have the largest effect of inhibiting any individual target, reducing the neurovascular response by 64% (average of 11 studies). Inhibition of multiple targets in combination with nNOS blockade had no further effect. This analysis points to the existence of an unknown signalling mechanism accounting for approximately one third of the neurovascular response. [ABSTRACT FROM AUTHOR]

Background The 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 method Forty 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. Results Prior 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 (∼1.1 s). 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 methods Given 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. Conclusions We recommend complicated visual search paradigms such as Where ’ s Waldo be considered for future transcranial Doppler-based neurovascular coupling studies. [ABSTRACT FROM AUTHOR]

Loss- or gain-of-function mutations in ATP-sensitive potassium channel (K-ATP)-encoding genes, KCNJ8 and ABCC9 , cause human central nervous system disorders with unknown pathogenesis. Here, using mice, zebrafish, and cell culture models, we investigated cellular and molecular causes of brain dysfunctions derived from altered K-ATP channel function. We show that genetic/chemical inhibition or activation of KCNJ8/ABCC9-containing K-ATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar vascular smooth muscle cell (VSMC) differentiation, respectively. We further show that brain VSMCs develop from KCNJ8/ABCC9-containing K-ATP channel-expressing mural cell progenitor and that K-ATP channel cell autonomously regulates VSMC differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Consistent with defective VSMC development, Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and neuronal-evoked vasodilation leading to local hyperemia. Our results demonstrate a role for KCNJ8/ABCC9-containing K-ATP channels in the differentiation of brain VSMC, which in turn is necessary for fine-tuning of cerebral blood flow. [Display omitted] • Pericyte-enriched K-ATP channel cell autonomously promotes arterial VSMC development • K-ATP channel controls VSMC differentiation by modulating Ca2+ oscillation via VDCC • K-ATP channel dysfunction leads to defective VSMC differentiation • VSMC defects evoked by K-ATP channel dysfunction leads to neurovascular uncoupling Ando et al. show that an ATP-sensitive potassium (K-ATP) channel composed of Kir6.1 (KCNJ8) and Sur2B (ABCC9) is essential for brain functional hyperemic responses and that this reflects a critical and brain-specific role of K-ATP channels during vascular smooth muscle cell (VSMC) differentiation from mural cell progenitors. [ABSTRACT FROM AUTHOR]

1. Obesity/metabolic syndrome is associated with augmented a-adrenoceptor sensitivity and impaired hyperaemic responses to exercise. Thus, it is possible that this elevated a-adrenoceptor constriction contributes to the blunted hyperaemic response. 2. Male lean and obese Zucker rats were instrumented for acute measurements of blood pressure (BP) and iliac blood flow (BF). Changes in BP and BF were determined in anaesthetized animals in response to intravenous administration of increasing doses of the a1-adrenoceptor agonist phenylephrine (PE). Once BF and BP returned to normal, a single bolus of the a-adrenoceptor antagonist phentolamine (0.5 mg) was administered. In separate animals, the spinotrapezius muscle was exteriorized for direct in situ observation of the microcirculation in response to phentolamine and muscle contraction. 3. Administration of PE demonstrated that iliac BF is highly autoregulated in the face of increasing perfusion pressure. Iliac conductance following phentolamine was significantly greater in obese rats. Following phentolamine administration, iliac vascular conductance was significantly greater in obese rats compared with lean animals. However, a-adrenoceptor blockade did not significantly alter arteriolar diameter in the spinotrapezius muscle during muscle contraction in either lean or obese animals. 4. These results suggest a greater contribution of the a-adrenoceptors in basal hindlimb vascular tone in obese rats. Furthermore, an augmented a-adrenoceptor-mediated vasoconstriction may not contribute to the impaired functional dilation in anaesthetized obese rats. [ABSTRACT FROM AUTHOR]

Perfusion pressure to the brain must remain relatively constant to provide rapid and efficient distribution of blood to metabolically active neurones. Both of these processes are regulated by the level of activation and tone of cerebral arterioles. The active state of cerebral arterial muscle is regulated, to a large extent, by the level of membrane potential. At physiological levels of arterial pressure, cerebral arterial muscle is maintained in an active state owing to membrane depolarization, compared with zero pressure load. As arterial pressure changes, so does membrane potential. The membrane is maintained in a relatively depolarized state because of, in part, inhibition of K+ channel activity. The activity of K+channels, especially the large conductance Ca2+-activated K+ channel (Kca) is dependent upon the level of 20-HETE produced by arterial muscle. As arterial pressure increases, so does cytochrome P450 (P4504A) activity. P4504A enzymes catalyse ω-hydroxylation of arachidonic acid and formation of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent inhibitor of Kca which maintains membrane depolarization and muscle cell activation. Astrocytes also metabolize AA via P450 enzymes of the 2C11 gene family to produce epoxyeicosatrienoic acids (EETs). Epoxyeicosatrienoic acids are released from astrocytes by glutamate which 'spills over' during neuronal activity. These locally released EETs shunt blood to metabolically active neurones providing substrate to support neuronal function. This short paper will discuss the findings which support the above scenario, the purpose of which is to provide a basis for future studies on the molecular mechanisms through which cerebral blood flow matches metabolism. [ABSTRACT FROM AUTHOR]