Neurovascular Interactions in the Nervous System.

Molecular cross talk between the nervous and vascular systems is necessary to maintain the correct coupling of organ structure and function. Molecular pathways shared by both systems are emerging as major players in the communication of the neuronal compartment with the endothelium. Here we review different aspects of this cross talk and how vessels influence the development and homeostasis of the nervous system. Beyond the classical role of the vasculature as a conduit to deliver oxygen and metabolites needed for the energy-demanding neuronal compartment, vessels emerge as powerful signaling systems that control and instruct a variety of cellular processes during the development of neurons and glia, such as migration, differentiation, and structural connectivity. Moreover, a broad spectrum of mild to severe vascular dysfunctions occur in various pathologies of the nervous system, suggesting that mild structural and functional changes at the neurovascular interface may underlie cognitive decline in many of these pathological conditions.

Astrocyte Endfeet in Brain Function and Pathology: Open Questions.

Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte endfeet contain specialized organelles and proteins, including local protein translation machinery and highly organized scaffold proteins, which anchor channels, transporters, receptors, and enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by the loss of polarization of specific endfoot proteins, vascular dysregulation, BBB disruption, altered waste clearance, or, in extreme cases, loss of endfoot coverage. A role for astrocyte endfeet has been demonstrated or postulated in many of these conditions. This review provides an overview of the development, composition, function, and pathological changes of astrocyte endfeet and highlights the gaps in our knowledge that future research should address.

Functional Ultrasound Neuroimaging.

Functional ultrasound (fUS) is a neuroimaging method that uses ultrasound to track changes in cerebral blood volume as an indirect readout of neuronal activity at high spatiotemporal resolution. fUS is capable of imaging head-fixed or freely behaving rodents and of producing volumetric images of the entire mouse brain. It has been applied to many species, including primates and humans. Now that fUS is reaching maturity, it is being adopted by the neuroscience community. However, the nature of the fUS signal and the different implementations of fUS are not necessarily accessible to nonspecialists. This review aims to introduce these ultrasound concepts to all neuroscientists. We explain the physical basis of the fUS signal and the principles of the method, present the state of the art of its hardware implementation, and give concrete examples of current applications in neuroscience. Finally, we suggest areas for improvement during the next few years.

Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation.

Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure; 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO2)]; 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans); and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the interrelationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

Pericytes and the Control of Blood Flow in Brain and Heart.

Pericytes, attached to the surface of capillaries, play an important role in regulating local blood flow. Using optogenetic tools and genetically encoded reporters in conjunction with confocal and multiphoton imaging techniques, the 3D structure, anatomical organization, and physiology of pericytes have recently been the subject of detailed examination. This work has revealed novel functions of pericytes and morphological features such as tunneling nanotubes in brain and tunneling microtubes in heart. Here, we discuss the state of our current understanding of the roles of pericytes in blood flow control in brain and heart, where functions may differ due to the distinct spatiotemporal metabolic requirements of these tissues. We also outline the novel concept of electro-metabolic signaling, a universal mechanistic framework that links tissue metabolic state with blood flow regulation by pericytes and vascular smooth muscle cells, with capillary KATP and Kir2.1 channels as primary sensors. Finally, we present major unresolved questions and outline how they can be addressed.

Parvalbumin interneuron activity drives fast inhibition-induced vasoconstriction followed by slow substance P-mediated vasodilation.

The role of parvalbumin (PV) interneurons in vascular control is poorly understood. Here, we investigated the hemodynamic responses elicited by optogenetic stimulation of PV interneurons using electrophysiology, functional magnetic resonance imaging (fMRI), wide-field optical imaging (OIS), and pharmacological applications. As a control, forepaw stimulation was used. Stimulation of PV interneurons in the somatosensory cortex evoked a biphasic fMRI response in the photostimulation site and negative fMRI signals in projection regions. Activation of PV neurons engaged two separable neurovascular mechanisms in the stimulation site. First, an early vasoconstrictive response caused by the PV-driven inhibition is sensitive to the brain state affected by anesthesia or wakefulness. Second, a later ultraslow vasodilation lasting a minute is closely dependent on the sum of interneuron multiunit activities, but is not due to increased metabolism, neural or vascular rebound, or increased glial activity. The ultraslow response is mediated by neuropeptide substance P (SP) released from PV neurons under anesthesia, but disappears during wakefulness, suggesting that SP signaling is important for vascular regulation during sleep. Our findings provide a comprehensive perspective about the role of PV neurons in controlling the vascular response.

Pericyte Control of Blood Flow Across Microvascular Zones in the Central Nervous System.

The vast majority of the brain's vascular length is composed of capillaries, where our understanding of blood flow control remains incomplete. This review synthesizes current knowledge on the control of blood flow across microvascular zones by addressing issues with nomenclature and drawing on new developments from in vivo optical imaging and single-cell transcriptomics. Recent studies have highlighted important distinctions in mural cell morphology, gene expression, and contractile dynamics, which can explain observed differences in response to vasoactive mediators between arteriole, transitional, and capillary zones. Smooth muscle cells of arterioles and ensheathing pericytes of the arteriole-capillary transitional zone control large-scale, rapid changes in blood flow. In contrast, capillary pericytes downstream of the transitional zone act on slower and smaller scales and are involved in establishing resting capillary tone and flow heterogeneity. Many unresolved issues remain, including the vasoactive mediators that activate the different pericyte types in vivo, the role of pericyte-endothelial communication in conducting signals from capillaries to arterioles, and how neurological disease affects these mechanisms.

Transcranial ultrasound stimulation selectively affects cortical neurovascular coupling across neuronal types and LFP frequency bands.

Previous studies have affirmed that transcranial ultrasound stimulation (TUS) can influence cortical neurovascular coupling across low-frequency (0-2 Hz)/high-frequency (160-200 Hz) neural oscillations and hemodynamics. Nevertheless, the selectivity of this coupling triggered by transcranial ultrasound stimulation for spike activity (> 300 Hz) and additional frequency bands (4-150 Hz) remains elusive. We applied transcranial ultrasound stimulation to mice visual cortex while simultaneously recording total hemoglobin concentration, spike activity, and local field potentials. Our findings include (1) a significant increase in coupling strength between spike firing rates of putative inhibitory neurons/putative excitatory neurons and total hemoglobin concentration post-transcranial ultrasound stimulation; (2) an ~ 2.1-fold higher Pearson correlation coefficient between putative inhibitory neurons and total hemoglobin concentration compared with putative excitatory neurons and total hemoglobin concentration (*P < 0.05); (3) a notably greater cross-correlation between putative inhibitory neurons and total hemoglobin concentration than that between putative excitatory neurons and total hemoglobin concentration (*P < 0.05); (4) an enhancement of Pearson correlation coefficient between the relative power of γ frequency band (30-80 Hz), hγ frequency band (80-150 Hz) and total hemoglobin concentration following transcranial ultrasound stimulation (*P < 0.05); and (5) strongest cross-correlation observed at negative delay for θ frequency band, and positive delay for α, ß, γ, hγ frequency bands. Collectively, these results demonstrate that cortical neurovascular coupling evoked by transcranial ultrasound stimulation exhibits selectivity concerning neuronal types and local field potential frequency bands.

The significance and limited influence of cerebrovascular reactivity on age and sex effects in task- and resting-state brain activity.

Functional MRI measures the blood-oxygen-level dependent signals, which provide an indirect measure of neural activity mediated by neurovascular responses. Cerebrovascular reactivity affects both task-induced and resting-state blood-oxygen-level dependent activity and may confound inter-individual effects, such as those related to aging and biological sex. We examined a large dataset containing breath-holding, checkerboard, and resting-state tasks. We used the breath-holding task to measure cerebrovascular reactivity, used the checkerboard task to obtain task-based activations, and quantified resting-state activity with amplitude of low-frequency fluctuations and regional homogeneity. We hypothesized that cerebrovascular reactivity would be correlated with blood-oxygen-level dependent measures and that accounting for these correlations would result in better estimates of age and sex effects. We found that cerebrovascular reactivity was correlated with checkerboard task activations in the visual cortex and with amplitude of low-frequency fluctuations and regional homogeneity in widespread fronto-parietal regions, as well as regions with large vessels. We also found significant age and sex effects in cerebrovascular reactivity, some of which overlapped with those observed in amplitude of low-frequency fluctuations and regional homogeneity. However, correcting for the effects of cerebrovascular reactivity had very limited influence on the estimates of age and sex. Our results highlight the limitations of accounting for cerebrovascular reactivity with the current breath-holding task.

Insulin regulates neurovascular coupling through astrocytes.

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.

The oxygen initial dip in the brain of anesthetized and awake mice.

An ongoing controversy in brain metabolism is whether increases in neural activity cause a local and rapid decrease in oxygen concentration (i.e., the "initial dip") preceding functional hyperemia. This initial dip has been suggested to cause a transient increase in vascular deoxyhemoglobin with several imaging techniques and stimulation paradigms, but not consistently. Here, we investigate contributors to this initial dip in a distinct neuronal network, an olfactory bulb (OB) glomerulus most sensitive to a specific odorant (ethyl tiglate [ET]) and a site of strong activation and energy consumption upon ET stimulation. Combining two-photon fluorescence and phosphorescence lifetime microscopy, and calcium, blood flow, and pO2 measurements, we characterized this initial dip in pO2 in mice chronically implanted with a glass cranial window, during both awake and anesthetized conditions. In anesthetized mice, a transient dip in vascular pO2 was detected in this glomerulus when functional hyperemia was slightly delayed, but its amplitude was minute (0.3 SD of resting baseline). This vascular pO2 dip was not observed in other glomeruli responding nonspecifically to ET, and it was poorly influenced by resting pO2. In awake mice, the dip in pO2 was absent in capillaries as well as, surprisingly, in the neuropil. These high-resolution pO2 measurements demonstrate that in awake mice recovered from brain surgery, neurovascular coupling was too fast and efficient to reveal an initial dip in pO2.

Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma.

Reduced blood flow and impaired neurovascular coupling are recognized features of glaucoma, the leading cause of irreversible blindness worldwide, but the mechanisms underlying these defects are unknown. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). Using two-photon microscope live imaging of the mouse retina, we found reduced capillary diameter and impaired blood flow at pericyte locations in eyes with high intraocular pressure, the most important risk factor to develop glaucoma. We show that IP-TNTs are structurally and functionally damaged by ocular hypertension, a response that disrupted light-evoked neurovascular coupling. Pericyte-specific inhibition of excessive Ca2+ influx rescued hemodynamic responses, protected IP-TNTs and neurovascular coupling, and enhanced retinal neuronal function as well as survival in glaucomatous retinas. Our study identifies pericytes and IP-TNTs as potential therapeutic targets to counter ocular pressure-related microvascular deficits, and provides preclinical proof of concept that strategies aimed to restore intrapericyte calcium homeostasis rescue autoregulatory blood flow and prevent neuronal dysfunction.

Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Relating Pupil Diameter and Blinking to Cortical Activity and Hemodynamics across Arousal States.

Arousal state affects neural activity and vascular dynamics in the cortex, with sleep associated with large changes in the local field potential and increases in cortical blood flow. We investigated the relationship between pupil diameter and blink rate with neural activity and blood volume in the somatosensory cortex in male and female unanesthetized, head-fixed mice. We monitored these variables while the mice were awake, during periods of rapid eye movement (REM), and non-rapid eye movement (NREM) sleep. Pupil diameter was smaller during sleep than in the awake state. Changes in pupil diameter were coherent with both gamma-band power and blood volume in the somatosensory cortex, but the strength and sign of this relationship varied with arousal state. We observed a strong negative correlation between pupil diameter and both gamma-band power and blood volume during periods of awake rest and NREM sleep, although the correlations between pupil diameter and these signals became positive during periods of alertness, active whisking, and REM. Blinking was associated with increases in arousal and decreases in blood volume when the mouse was asleep. Bilateral coherence in gamma-band power and in blood volume dropped following awake blinking, indicating a reset of neural and vascular activity. Using only eye metrics (pupil diameter and eye motion), we could determine the arousal state of the mouse ('Awake,' 'NREM,' 'REM') with >90% accuracy with a 5 s resolution. There is a strong relationship between pupil diameter and hemodynamics signals in mice, reflecting the pronounced effects of arousal on cerebrovascular dynamics.SIGNIFICANCE STATEMENT Determining arousal state is a critical component of any neuroscience experiment. Pupil diameter and blinking are influenced by arousal state, as are hemodynamics signals in the cortex. We investigated the relationship between cortical hemodynamics and pupil diameter and found that pupil diameter was strongly related to the blood volume in the cortex. Mice were more likely to be awake after blinking than before, and blinking resets neural activity. Pupil diameter and eye motion can be used as a reliable, noninvasive indicator of arousal state. As mice transition from wake to sleep and back again over a timescale of seconds, monitoring pupil diameter and eye motion permits the noninvasive detection of sleep events during behavioral or resting-state experiments.

Altered Neurovascular Coupling for Multidisciplinary Intensive Rehabilitation in Parkinson's Disease.

Effective rehabilitation in Parkinson's disease (PD) is related to brain reorganization with restoration of cortico-subcortical networks and compensation of frontoparietal networks; however, further neural rehabilitation evidence from a multidimensional perspective is needed. To investigate how multidisciplinary intensive rehabilitation treatment affects neurovascular coupling, 31 PD patients (20 female) before and after treatment and 30 healthy controls (17 female) underwent blood oxygenation level-dependent functional magnetic resonance imaging and arterial spin labeling scans. Cerebral blood flow (CBF) was used to measure perfusion, and fractional amplitude of low-frequency fluctuation (fALFF) was used to measure neural activity. The global CBF-fALFF correlation and regional CBF/fALFF ratio were calculated as neurovascular coupling. Dynamic causal modeling (DCM) was used to evaluate treatment-related alterations in the strength and directionality of information flow. Treatment reduced CBF-fALFF correlations. The altered CBF/fALFF exhibited increases in the left angular gyrus and the right inferior parietal gyrus and decreases in the bilateral thalamus and the right superior frontal gyrus. The CBF/fALFF alteration in right superior frontal gyrus showed correlations with motor improvement. Further, DCM indicated increases in connectivity from the superior frontal gyrus and decreases from the thalamus to the inferior parietal gyrus. The benefits of rehabilitation were reflected in the dual mechanism, with restoration of executive control occurring in the initial phase of motor learning and compensation of information integration occurring in the latter phase. These findings may yield multimodal insights into the role of rehabilitation in disease modification and identify the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD.SIGNIFICANCE STATEMENT Although rehabilitation has been proposed as a promising supplemental treatment for PD as it results in brain reorganization, restoring cortico-subcortical networks and eliciting compensatory activation of frontoparietal networks, further multimodal evidence of the neural mechanisms underlying rehabilitation is needed. We measured the ratio of perfusion and neural activity derived from arterial spin labeling and blood oxygenation level-dependent fMRI data and found that benefits of rehabilitation seem to be related to the dual mechanism, restoring executive control in the initial phase of motor learning and compensating for information integration in the latter phase. We also identified the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD patients.

Nimodipine Protects Vascular and Cognitive Function in an Animal Model of Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.

Network response of brain microvasculature to neuronal stimulation.

Neurovascular coupling (NVC), or the adjustment of blood flow in response to local increases in neuronal activity is a hallmark of healthy brain function, and the physiological foundation for functional magnetic resonance imaging (fMRI). However, it remains only partly understood due to the high complexity of the structure and function of the cerebrovascular network. Here we set out to understand NVC at the network level, i.e. map cerebrovascular network reactivity to activation of neighbouring neurons within a 500×500×500 µm3 cortical volume (∼30 high-resolution 3-nL fMRI voxels). Using 3D two-photon fluorescence microscopy data, we quantified blood volume and flow changes in the brain vessels in response to spatially targeted optogenetic activation of cortical pyramidal neurons. We registered the vessels in a series of image stacks acquired before and after stimulations and applied a deep learning pipeline to segment the microvascular network from each time frame acquired. We then performed image analysis to extract the microvascular graphs, and graph analysis to identify the branch order of each vessel in the network, enabling the stratification of vessels by their branch order, designating branches 1-3 as precapillary arterioles and branches 4+ as capillaries. Forty-five percent of all vessels showed significant calibre changes; with 85 % of responses being dilations. The largest absolute CBV change was in the capillaries; the smallest, in the venules. Capillary CBV change was also the largest fraction of the total CBV change, but normalized to the baseline volume, arterioles and precapillary arterioles showed the biggest relative CBV change. From linescans along arteriole-venule microvascular paths, we measured red blood cell velocities and hematocrit, allowing for estimation of pressure and local resistance along these paths. While diameter changes following neuronal activation gradually declined along the paths; the pressure drops from arterioles to venules increased despite decreasing resistance: blood flow thus increased more than local resistance decreases would predict. By leveraging functional volumetric imaging and high throughput deep learning-based analysis, our study revealed distinct hemodynamic responses across the vessel types comprising the microvascular network. Our findings underscore the need for large, dense sampling of brain vessels for characterization of neurovascular coupling at the network level in health and disease.

Neurovascular coupling in eye-open-eye-close task and resting state: Spectral correspondence between concurrent EEG and fMRI.

Neurovascular coupling serves as an essential neurophysiological mechanism in functional neuroimaging, which is generally presumed to be robust and invariant across different physiological states, encompassing both task engagement and resting state. Nevertheless, emerging evidence suggests that neurovascular coupling may exhibit state dependency, even in normal human participants. To investigate this premise, we analyzed the cross-frequency spectral correspondence between concurrently recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data, utilizing them as proxies for neurovascular coupling during the two conditions: an eye-open-eye-close (EOEC) task and a resting state. We hypothesized that given the state dependency of neurovascular coupling, EEG-fMRI spectral correspondences would change between the two conditions in the visual system. During the EOEC task, we observed a negative phase-amplitude-coupling (PAC) between EEG alpha-band and fMRI visual activity. Conversely, in the resting state, a pronounced amplitude-amplitude-coupling (AAC) emerged between EEG and fMRI signals, as evidenced by the spectral correspondence between the EEG gamma-band of the midline occipital channel (Oz) and the high-frequency fMRI signals (0.15-0.25 Hz) in the visual network. This study reveals distinct scenarios of EEG-fMRI spectral correspondence in healthy participants, corroborating the state-dependent nature of neurovascular coupling.

Neurovascular coupling alteration in drug-naïve Parkinson's disease: The underlying molecular mechanisms and levodopa's restoration effects.

BACKGROUND: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. MATERIAL AND METHODS: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. RESULTS: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value <0.0006). The distribution of NVC differences correlated with the density of dopaminergic, serotonin, MU-opioid, and cholinergic receptors/transporters. Additionally, levodopa ameliorated abnormal NVC in most of these regions, where there were primarily ALFF changes with limited CBF modifications. CONCLUSION: Patients exhibited NVC dysfunction primarily in the striato-thalamo-cortical circuit and motor control regions, which could be driven by dopaminergic and nondopaminergic systems, and levodopa therapy mainly restored abnormal NVC by modulating neuronal activity.

Analysis of potassium ion diffusion from neurons to capillaries: Effects of astrocyte endfeet geometry.

Neurovascular coupling (NVC) refers to a local increase in cerebral blood flow in response to increased neuronal activity. Mechanisms of communication between neurons and blood vessels remain unclear. Astrocyte endfeet almost completely cover cerebral capillaries, suggesting that astrocytes play a role in NVC by releasing vasoactive substances near capillaries. An alternative hypothesis is that direct diffusion through the extracellular space of potassium ions (K+ ) released by neurons contributes to NVC. Here, the goal is to determine whether astrocyte endfeet present a barrier to K+ diffusion from neurons to capillaries. Two simplified 2D geometries of extracellular space, clefts between endfeet, and perivascular space are used: (i) a source 1 µm from a capillary; (ii) a neuron 15 µm from a capillary. K+ release is modelled as a step increase in [K+ ] at the outer boundary of the extracellular space. The time-dependent diffusion equation is solved numerically. In the first geometry, perivascular [K+ ] approaches its final value within 0.05 s. Decreasing endfeet cleft width or increasing perivascular space width slows the rise in [K+ ]. In the second geometry, the increase in perivascular [K+ ] occurs within 0.5 s and is insensitive to changes in cleft width or perivascular space width. Predicted levels of perivascular [K+ ] are sufficient to cause vasodilation, and the rise time is within the time for flow increase in NVC. These results suggest that direct diffusion of K+ through the extracellular space is a possible NVC signalling mechanism.