Low-intensity transcranial ultrasound stimulation modulates neurovascular coupling in mouse models of Alzheimer's disease.

Neurovascular coupling plays an important role in the progression of Alzheimer's disease. However, it is unclear how ultrasound stimulation modulates neurovascular coupling in Alzheimer's disease. Here, we found that (i) transcranial ultrasound stimulation modulates the time domain and frequency domain characteristics of cerebral blood oxygen metabolism in Alzheimer's disease mice; (ii) transcranial ultrasound stimulation can significantly modulate the relative power of theta and gamma frequency of local field potential in Alzheimer's disease mice; and (iii) transcranial ultrasound stimulation can significantly modulate the neurovascular coupling in time domain and frequency domain induced by forepaw electrical stimulation in Alzheimer's disease mice. It provides a research basis for the clinical application of transcranial ultrasound stimulation in Alzheimer's disease patients.

Reduced neurovascular coupling of the visual network in migraine patients with aura as revealed with arterial spin labeling MRI: is there a demand-supply mismatch behind the scenes?

BACKGROUND: Although neuroimaging investigations have consistently demonstrated that "hyperresponsive" and "hyperconnected" visual cortices may represent the functional substrate of cortical spreading depolarization in patients with migraine with aura, the mechanisms which underpin the brain "tendency" to ignite the cortical spreading depolarization and, consequently, aura phenomenon are still matter of debate. Considering that triggers able to induce aura phenomenon constrain brain to increase global (such as physical activity, stressors and sleep abnormalities) or local (such as bright light visual stimulations) energy demand, a vascular supply unable to satisfy the increased energy requirement could be hypothesized in these patients. METHODS: Twenty-three patients with migraine with aura, 25 patients with migraine without aura and 20 healthy controls underwent a 3-Tesla MRI study. Cerebral blood flow and local functional connectivity (regional homogeneity) maps were obtained and registered to the MNI space where 100 cortical regions were derived using a functional local-global normative parcellation. A surrogate estimate of the regional neurovascular coupling for each subject was obtained at each parcel from the correlation coefficient between the z-scored ReHo map and the z-scored cerebral blood flow maps. RESULTS: A significantly higher regional cerebral blood flow across the visual cortex of both hemispheres (i.e. fusiform and lingual gyri) was detected in migraine with aura patients when compared to patients with migraine without aura (p < 0.05, corrected for multiple comparisons). Concomitantly, a significantly reduced neurovascular coupling (p < 0.05, false discovery rate corrected) in the primary visual cortex parcel (VIS-4) of the large-scale visual network was observed in the left hemisphere of patients with migraine with aura (0.23±0.03), compared to both patients with migraine without aura (0.32±0.05) and healthy controls (0.29±0.05). CONCLUSIONS: Visual cortex neurovascular "decoupling" might represent the "link" between the exposure to trigger factors and aura phenomenon ignition. While physiological vascular oversupply may compensate neurovascular demand-supply at rest, it becomes inadequate in case of increased energy demand (e.g. when patients face with trigger factors) paving the way to the aura phenomenon ignition in patients with migraine with aura. Whether preventive treatments may exert their therapeutic activity on migraine with aura restoring the energy demands and cerebral blood flow trade-off within the visual network should be further investigated.

Association between neurovascular coupling and neural signals in the resting state as revealed by a combined fMRI and magnetoencephalography study in humans.

The blood oxygenation level-dependent (BOLD) activation reflects hemodynamic events mediated by neurovascular coupling. During task performance, the BOLD hemodynamic response in a relevant area is mainly driven by the high levels of synaptic activity (reflected in local field potentials, LFPs) but, in contrast, during a task-free, resting state, the contribution to BOLD of such neural events is small, as expected by the comparatively (to the task state) low level of neural events. Concomitant recording of BOLD and LFP at rest in animal experiments has estimated the neural contribution to BOLD to ∼10%. Such experiments have not been performed in humans. As an approximation, we recorded (in the same subject, n = 57 healthy participants) at a task-free, resting state the BOLD signal and, in a different session, the magnetoencephalographic (MEG) signal, which reflects purely neural (synaptic) events. We then calculated the turnover of these signals by computing the successive moment-to-moment difference in the BOLD and MEG time series and retaining the median of the absolute value of the differenced series (BOLD and TMEG, respectively). The correlation between normalized turnovers of BOLD (TBOLD) and turnovers of MEG (TMEG) was r = 0.336 (r2 = 0.113; P = 0.011). These results estimate that 11.3% of the variance in TBOLD can be explained by the variance in TMEG. This estimate is close to the aforementioned estimate obtained by direct recordings in animal experiments. NEW & NOTEWORTHY Here, we report on a weak positive association between turnovers of blood oxygenation level-dependent (TBOLD) and magnetoencephalographic (TMEG) signals in 57 healthy human subjects in a resting, task-free state. More specifically, we found that the purely neural TMEG accounted for 11.1% of the TBOLD, a percentage remarkably close to that found between resting-state local field potentials (LFPs) and BOLD recorded concurrently in animal experiments.

Fronto-parietal activity changes associated with changes in working memory load: Evidence from simultaneous electroencephalography and functional near-infrared spectroscopy analysis.

Working memory (WM) involves the capacity to maintain and manipulate information over short periods. Previous research has suggested that fronto-parietal activities play a crucial role in WM. However, there remains no agreement on the effect of working memory load (WML) on neural activities and haemodynamic responses. Here, our study seeks to examine the effect of WML through simultaneous electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). In this study, a delay change detection task was conducted on 23 healthy volunteers. The task included three levels: one item, three items and five items. The EEG and fNIRS were simultaneously recorded during the task. Neural activities and haemodynamic responses at prefrontal and parietal regions were analysed using time-frequency analysis and weighted phase-lag index (wPLI). We observed a significant enhancement in prefrontal and parietal ß suppression as WML increased. Furthermore, as WML increased, there was a notable enhancement in fronto-parietal connectivity (FPC), as evidenced by both EEG and fNIRS. Correlation analysis indicated that as WML increased, there was a potential for enhancement of neurovascular coupling (NVC) of FPC.

In vitro modelling of the neurovascular unit for ischemic stroke research: Emphasis on human cell applications and 3D model design.

Ischemic stroke has garnered global medical attention as one of the most serious cerebrovascular diseases. The mechanisms involved in both the development and recovery phases of ischemic stroke are complex, involving intricate interactions among different types of cells, each with its own unique functions. To better understand the possible pathogenesis, neurovascular unit (NVU), a concept comprising neurons, endothelial cells, mural cells, glial cells, and extracellular matrix components, has been used in analysing various brain diseases, particularly in ischemic stroke, aiming to depict the interactions between cerebral vasculature and neural cells. While in vivo models often face limitations in terms of reproducibility and the ability to precisely mimic human pathophysiology, it is now important to establish in vitro NVU models for ischemic stroke research. In order to accurately portray the pathological processes occurring within the brain, a diverse array of NVU 2D and 3D in vitro models, each possessing unique characteristics and advantages, have been meticulously developed. This review presents a comprehensive overview of recent advancements in in vitro models specifically tailored for investigating ischemic stroke. Through a systematic categorization of these developments, we elucidate the intricate links between NVU components and the pathogenesis of ischemic stroke. Furthermore, we explore the distinct advantages offered by innovative NVU models, notably 3D models, which closely emulate in vivo conditions. Additionally, an examination of current therapeutic modalities for ischemic stroke developed utilizing in vitro NVU models is provided. Serving as a valuable reference, this review aids in the design and implementation of effective in vitro models for ischemic stroke research.

The effect of posture on the age dependence of neurovascular coupling.

Previous studies report contradicting age-related neurovascular coupling (NVC). Few studies assess postural effects, but less investigate relationships between age and NVC within different postures. Therefore, this study investigated the effect of age on NVC in different postures with varying cognitive stimuli. Beat-to-beat blood pressure, heart rate and end-tidal carbon dioxide were assessed alongside middle and posterior cerebral artery velocities (MCAv and PCAv, respectively) using transcranial Doppler ultrasonography in 78 participants (31 young-, 23 middle- and 24 older-aged) with visuospatial (VST) and attention tasks (AT) in various postures at two timepoints (T2 and T3). Between-group significance testing utilized one-way analysis-of-variance (ANOVA) (Tukey post-hoc). Mixed three-way/one-way ANOVAs explored task, posture, and age interactions. Significant effects of posture on NVC were driven by a 3.8% increase from seated to supine. For AT, mean supine %MCAv increase was greatest in younger (5.44%) versus middle (0.12%) and older-age (0.09%) at T3 (p = 0.005). For VST, mean supine %PCAv increase was greatest at T2 and T3 in middle (10.99%/10.12%) and older-age (17.36%/17.26%) versus younger (9.44%/8.89%) (p = 0.004/p = 0.002). We identified significant age-related NVC effects with VST-induced hyperactivation. This may reflect age-related compensatory processes in supine. Further work is required, using complex stimuli while standing/walking, examining NVC, aging and falls.

Neurovascular coupling and CO2 interrogate distinct vascular regulations.

Neurovascular coupling (NVC), which mediates rapid increases in cerebral blood flow in response to neuronal activation, is commonly used to map brain activation or dysfunction. Here we tested the reemerging hypothesis that CO2 generated by neuronal metabolism contributes to NVC. We combined functional ultrasound and two-photon imaging in the mouse barrel cortex to specifically examine the onsets of local changes in vessel diameter, blood flow dynamics, vascular/perivascular/intracellular pH, and intracellular calcium signals along the vascular arbor in response to a short and strong CO2 challenge (10 s, 20%) and whisker stimulation. We report that the brief hypercapnia reversibly acidifies all cells of the arteriole wall and the periarteriolar space 3-4 s prior to the arteriole dilation. During this prolonged lag period, NVC triggered by whisker stimulation is not affected by the acidification of the entire neurovascular unit. As it also persists under condition of continuous inflow of CO2, we conclude that CO2 is not involved in NVC.

Orchestrating Blood Flow in the Retina: Interpericyte Tunnelling Nanotube Communication.

The retina transforms light into electrical signals, which are sent to the brain via the optic nerve to form our visual perception. This complex signal processing is performed by the retinal neuron and requires a significant amount of energy. Since neurons are unable to store energy, they must obtain glucose and oxygen from the bloodstream to produce energy to match metabolic needs. This process is called neurovascular coupling (NVC), and it is based on a precise mechanism that is not totally understood. The discovery of fine tubular processes termed tunnelling nanotubes (TNTs) set a new type of cell-to-cell communication. TNTs are extensions of the cellular membrane that allow the transfer of material between connected cells. Recently, they have been reported in the brain and retina of living mice, where they connect pericytes, which are vascular mural cells that regulate vessel diameter. Accordingly, these TNTs were termed interpericyte tunnelling nanotubes (IPTNTs), which showed a vital role in blood delivery and NVC. In this chapter, we review the involvement of TNTs in NVC and discuss their implications in retinal neurodegeneration.

Spatiotemporal relationships between neuronal, metabolic, and hemodynamic signals in the awake and anesthetized mouse brain.

Neurovascular coupling (NVC) and neurometabolic coupling (NMC) provide the basis for functional magnetic resonance imaging and positron emission tomography to map brain neurophysiology. While increases in neuronal activity are often accompanied by increases in blood oxygen delivery and oxidative metabolism, these observations are not the rule. This decoupling is important when interpreting brain network organization (e.g., resting-state functional connectivity [RSFC]) because it is unclear whether changes in NMC/NVC affect RSFC measures. We leverage wide-field optical imaging in Thy1-jRGECO1a mice to map cortical calcium activity in pyramidal neurons, flavoprotein autofluorescence (representing oxidative metabolism), and hemodynamic activity during wake and ketamine/xylazine anesthesia. Spontaneous dynamics of all contrasts exhibit patterns consistent with RSFC. NMC/NVC relative to excitatory activity varies over the cortex. Ketamine/xylazine profoundly alters NVC but not NMC. Compared to awake RSFC, ketamine/xylazine affects metabolic-based connectomes moreso than hemodynamic-based measures of RSFC. Anesthesia-related differences in NMC/NVC timing do not appreciably alter RSFC structure.

Impairments of neurovascular coupling after stroke lower glymphatic system function and lead to depressive symptom: A longitudinal cohort study.

BACKGROUND: Respective changes in neurovascular coupling (NVC) and glymphatic function have been reported in post-stroke depression (PSD). Recent studies have found a link between NVC and waste clearance by the glymphatic system, which has not been illustrated in PSD. METHOD: We prospectively recruited ninety-six stroke patients and forty-four healthy controls (HC), with fifty-nine patients undergoing a second MRI scan. NVC metrics were investigated by exploring Pearson correlation coefficients and ratios between cerebral blood flow (CBF) and BOLD-derived quantitative maps (ALFF, fALFF, REHO maps). Diffusion tensor imaging along the perivascular (DTI-ALPS) index was used to reflect glymphatic function. We first analyzed the altered NVC metrics in stroke patients relative to the HC group. Then, we explored the relationship between NVC metrics, ALPS index and depressive symptoms at baseline and during the follow-up period through correlation and mediation analyses. RESULTS: Stroke patients exhibited significantly lower global CBF-fALFF coupling and ALPS index. At the regional level, abnormal NVC alterations in brain regions involved in cognition, emotion, and sensorimotor function in PSD. Baseline analyses showed that ALPS index exhibited positive associations with both global and local NVC and abnormal regional NVC may contribute to generation of PSD by reducing glymphatic function (ß = -0.075, p < 0.05, CI = [-0.169 to -0.012]). Longitudinal analyses similarly showed that ALPS index changes were positively associated with changes in NVC and mediated improvements in depressive symptoms. CONCLUSION: Our findings suggest that NVC abnormalities leading to impaired glymphatic system function may be a potential neurobiological mechanism of PSD.

Hypoxic Signal Transduction and Compensatory Mechanisms in the Neurovascular Unit.

Hypoxic hypoxia arises from an inadequate oxygen supply to the blood, resulting in reduced arterial oxygen partial pressure and a consequent decline in oxygen diffusion into tissue cells for utilization. This condition is characterized by diminished oxygen content in the blood, while the supply of other nutrients within the blood remains normal. The brain is particularly sensitive to oxygen deficiency, with varying degrees of hypoxic hypoxia resulting in different levels of neural functional disorder. Since the brain has a specific threshold range for the perception of hypoxic hypoxia, mild hypoxic hypoxia can trigger compensatory protective responses in the brain without affecting neural function. These hypoxic compensatory responses enable the maintenance of an adequate oxygen supply and energy substrates for neurons, thereby ensuring normal physiological functions. To further understand the hypoxic compensatory mechanisms of the central nervous system (CNS), this article explores the structural features of the brain's neurovascular unit model, hypoxic signal transduction, and compensatory mechanisms.

The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow.

Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then to exert tight control over a much broader range of processes, including neurotransmitter release, neuronal excitability, and synaptic plasticity. Endothelial NO synthase (eNOS) is usually far from the mind of synaptic neurophysiologists, who have focused most of their attention on neuronal NO synthase (nNOS) as the primary source of NO at the neurovascular unit (NVU). Nevertheless, the available evidence suggests that eNOS could also contribute to generating the burst of NO that, serving as volume intercellular messenger, is produced in response to neuronal activity in the brain parenchyma. Herein, we review the role of eNOS in both the regulation of cerebral blood flow and of synaptic plasticity and discuss the mechanisms by which cerebrovascular endothelial cells may transduce synaptic inputs into a NO signal. We further suggest that eNOS could play a critical role in vascular-to-neuronal communication by integrating signals converging onto cerebrovascular endothelial cells from both the streaming blood and active neurons.

Vascular Function and Ion Channels in Alzheimer's Disease.

This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aß) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.

Sensor-Assisted Analysis of Autonomic and Cerebrovascular Dysregulation following Concussion in an Individual with a History of Ten Concussions: A Case Study.

INTRODUCTION: Concussion is known to cause transient autonomic and cerebrovascular dysregulation that generally recovers; however, few studies have focused on individuals with an extensive concussion history. METHOD: The case was a 26-year-old male with a history of 10 concussions, diagnosed for bipolar type II disorder, mild attention-deficit hyperactivity disorder, and a history of migraines/headaches. The case was medicated with Valproic Acid and Escitalopram. Sensor-based baseline data were collected within six months of his injury and on days 1-5, 10, and 14 post-injury. Symptom reporting, heart rate variability (HRV), neurovascular coupling (NVC), and dynamic cerebral autoregulation (dCA) assessments were completed using numerous biomedical devices (i.e., transcranial Doppler ultrasound, 3-lead electrocardiography, finger photoplethysmography). RESULTS: Total symptom and symptom severity scores were higher for the first-week post-injury, with physical and emotional symptoms being the most impacted. The NVC response showed lowered activation in the first three days post-injury, while autonomic (HRV) and autoregulation (dCA) were impaired across all testing visits occurring in the first 14 days following his concussion. CONCLUSIONS: Despite symptom resolution, the case demonstrated ongoing autonomic and autoregulatory dysfunction. Larger samples examining individuals with an extensive history of concussion are warranted to understand the chronic physiological changes that occur following cumulative concussions through biosensing devices.

Adaptive Changes in Neurovascular Properties With Binocular Accommodation Functions in Myopic Participants by 3D Visual Training: An EEG and fNIRS Study.

Although three-dimensional visual training (3DVT) has been used for myopia intervention, its neural mechanisms remain largely unknown. In this study, visual function was examined before and after 3DVT, while resting-state EEG-fNIRS signals were recorded from 38 myopic participants. A graph theoretical analysis was applied to compute the neurovascular properties, including static brain networks (SBNs), dynamic brain networks (DBNs), and dynamic neurovascular coupling (DNC). Correlations between the changes in neurovascular properties and the changes in visual functions were calculated. After 3DVT, the local efficiency and node efficiency in the frontal lobes increased in the SBNs constructed from EEG δ -band; the global efficiency and node efficiency in the frontal-parietal lobes decreased in the DBNs variability constructed from EEG δ -band. For the DNC constructed with EEG α -band and oxyhemoglobin (HbO), the local efficiency decreased, for EEG α -band and deoxyhemoglobin (HbR), the node efficiency in the frontal-occipital lobes decreased. For the SBNs constructed from HbO, the functional connectivity (FC) between the frontal-occipital lobes increased. The DNC constructed between the FC of the frontal-parietal lobes from EEG ß -band and the FC of the frontal-occipital lobes from HbO increased, and between the FC of the frontal-occipital lobes from EEG ß -band and the FC of the inter-frontal lobes from HbR increased. The neurovascular properties were significantly correlated with the amplitude of accommodation and accommodative facility. The result indicated the positive effects of 3DVT on myopic participants, including improved efficiency of brain networks, increased FC of SBNs and DNC, and enhanced binocular accommodation functions.

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain.

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.

The effect of CO2 on the age dependence of neurovascular coupling.

Prior studies have identified variable effects of aging on neurovascular coupling (NVC). Carbon dioxide (CO2) affects both cerebral blood velocity (CBv) and NVC, but the effects of age on NVC under different CO2 conditions are unknown. Therefore, we investigated the effects of aging on NVC in different CO2 states during cognitive paradigms. Seventy-eight participants (18-78 yr), with well-controlled comorbidities, underwent continuous recordings of CBv by bilateral insonation of middle (MCA) and posterior (PCA) cerebral arteries (transcranial Doppler), blood pressure, end-tidal CO2, and heart rate during poikilocapnia, hypercapnia (5% CO2 inhalation), and hypocapnia (paced hyperventilation). Neuroactivation via visuospatial (VS) and attention tasks (AT) was used to stimulate NVC. Peak percentage and absolute change in MCAv/PCAv, were compared between CO2 conditions and age groups (≤30, 31-60, and >60 yr). For the VS task, in poikilocapnia, younger adults had a lower NVC response compared with older adults [mean difference (MD): -7.92% (standard deviation (SD): 2.37), P = 0.004], but comparable between younger and middle-aged groups. In hypercapnia, both younger [MD: -4.75% (SD: 1.56), P = 0.009] and middle [MD: -4.58% (SD: 1.69), P = 0.023] age groups had lower NVC responses compared with older adults. Finally, in hypocapnia, both older [MD: 5.92% (SD: 2.21), P = 0.025] and middle [MD: 5.44% (SD: 2.27), P = 0.049] age groups had greater NVC responses, compared with younger adults. In conclusion, the magnitude of NVC response suppression from baseline during hyper- and hypocapnia, did not differ significantly between age groups. However, the middle age group demonstrated a different NVC response while under hypercapnic conditions, compared with hypocapnia.NEW & NOTEWORTHY This study describes the effects of age on neurovascular coupling under altered CO2 conditions. We demonstrated that both hypercapnia and hypocapnia suppress neurovascular coupling (NVC) responses. Furthermore, that middle age exhibits an NVC response comparable with younger adults under hypercapnia, and older adults under hypocapnia.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.