Journal articles on the topic 'Neurovascular coupling (NVC)'
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Teskey, G. Campbell, and Cam Ha T. Tran. "Neurovascular Coupling in Seizures." Neuroglia 2, no. 1 (October 11, 2021): 36–47. http://dx.doi.org/10.3390/neuroglia2010005.
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Neurovascular coupling is a key control mechanism in cerebral blood flow (CBF) regulation. Importantly, this process was demonstrated to be affected in several neurological disorders, including epilepsy. Neurovascular coupling (NVC) is the basis for functional brain imaging, such as PET, SPECT, fMRI, and fNIRS, to assess and map neuronal activity, thus understanding NVC is critical to properly interpret functional imaging signals. However, hemodynamics, as assessed by these functional imaging techniques, continue to be used as a surrogate to map seizure activity; studies of NVC and cerebral blood flow control during and following seizures are rare. Recent studies have provided conflicting results, with some studies showing focal increases in CBF at the onset of a seizure while others show decreases. In this brief review article, we provide an overview of the current knowledge state of neurovascular coupling and discuss seizure-related alterations in neurovascular coupling and CBF control.
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Balbi, Matilde, Masayo Koide, George C. Wellman, and Nikolaus Plesnila. "Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo." Journal of Cerebral Blood Flow & Metabolism 37, no. 11 (January 23, 2017): 3625–34. http://dx.doi.org/10.1177/0271678x16686595.
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Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation. Recent findings ex vivo suggest neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, is also impaired after SAH. The aim of the current study was to investigate whether this occurs also in vivo. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Twenty-four hours later NVC was tested by forepaw stimulation and CO2 reactivity by inhalation of 10% CO2. Vessel diameter was assessed in vivo by two-photon microscopy. NVC was also investigated ex vivo using brain slices. Cerebral arterioles of sham-operated mice dilated to 130% of baseline upon CO2 inhalation or forepaw stimulation and cerebral blood flow (CBF) increased. Following SAH, however, CO2 reactivity was completely lost and the majority of cerebral arterioles showed paradoxical constriction in vivo and ex vivo resulting in a reduced CBF response. As previous results showed intact NVC 3 h after SAH, the current findings indicate that impairment of NVC after cerebral hemorrhage occurs secondarily and is progressive. Since neuronal activity-induced vasoconstriction (inverse NVC) is likely to further aggravate SAH-induced cerebral ischemia and subsequent brain damage, inverse NVC may represent a novel therapeutic target after SAH.
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Sundqvist, Nicolas, Sebastian Sten, Peter Thompson, Benjamin Jan Andersson, Maria Engström, and Gunnar Cedersund. "Mechanistic model for human brain metabolism and its connection to the neurovascular coupling." PLOS Computational Biology 18, no. 12 (December 22, 2022): e1010798. http://dx.doi.org/10.1371/journal.pcbi.1010798.
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The neurovascular and neurometabolic couplings (NVC and NMC) connect cerebral activity, blood flow, and metabolism. This interconnection is used in for instance functional imaging, which analyses the blood-oxygen-dependent (BOLD) signal. The mechanisms underlying the NVC are complex, which warrants a model-based analysis of data. We have previously developed a mechanistically detailed model for the NVC, and others have proposed detailed models for cerebral metabolism. However, existing metabolic models are still not fully utilizing available magnetic resonance spectroscopy (MRS) data and are not connected to detailed models for NVC. Therefore, we herein present a new model that integrates mechanistic modelling of both MRS and BOLD data. The metabolic model covers central metabolism, using a minimal set of interactions, and can describe time-series data for glucose, lactate, aspartate, and glutamate, measured after visual stimuli. Statistical tests confirm that the model can describe both estimation data and predict independent validation data, not used for model training. The interconnected NVC model can simultaneously describe BOLD data and can be used to predict expected metabolic responses in experiments where metabolism has not been measured. This model is a step towards a useful and mechanistically detailed model for cerebral blood flow and metabolism, with potential applications in both basic research and clinical applications.
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Toth, Adam Nyul, Tabea Wiedenhoeft, Stefano Tarantini, Tamas Csipo, Priya Balasubramanian, Anna Csiszar, Agnes Csiszar, and Zoltan Ungvari. "Fusogenic Liposomes Deliver Resveratrol to Brain Microcirculation and Improve Neurovascular Coupling in Aged Mice." Innovation in Aging 4, Supplement_1 (December 1, 2020): 120. http://dx.doi.org/10.1093/geroni/igaa057.394.
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Abstract Adjustment of cerebral blood flow (CBF) to the increased oxygen and nutrient demands of active brain regions via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In advanced age, cerebromicrovascular oxidative stress and endothelial dysfunction impair neurovascular coupling, contributing to age-related cognitive decline. Recently we developed a resveratrol (3,4′,5- trihydroxystilbene)-containing fusogenic liposome (FL-RSV)-based molecular delivery system that can effectively target cultured cerebromicrovascular endothelial cells, attenuating age-related oxidative stress. To assess the cerebromicrovascular protective effects of FL-RSV in vivo, aged (24-monthold) C57BL/6 mice were treated with FL-RSV for four days. To demonstrate effective cellular uptake of FL-RSV, accumulation of the lipophilic tracer dyes in cells of the neurovascular unit was confirmed using two-photon imaging (through a chronic cranial window). NVC was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with FL-RSV significantly improved NVC responses by increasing NO-mediated vasodilation. These findings are paralleled by the protective effects of FL-RSV on endothelium-dependent relaxation in the aorta. Thus, treatment with FL-RSV rescues endothelial function and NVC responses in aged mice. We propose that resveratrol containing fusogenic liposomes could also be used for combined delivery of various anti-geronic factors, including proteins, small molecules, DNA vectors and mRNAs targeting key pathways involved in microvascular aging and neurovascular dysfunction for the prevention/treatment of age-related cerebromicrovascular pathologies and development of vascular cognitive impairment (VCI) in aging.
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Lefferts, Wesley K., William E. Hughes, Corey N. White, Tom D. Brutsaert, and Kevin S. Heffernan. "Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia." Applied Physiology, Nutrition, and Metabolism 41, no. 2 (February 2016): 133–41. http://dx.doi.org/10.1139/apnm-2015-0400.
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The matching of oxygen supply to neural demand (i.e., neurovascular coupling (NVC)) is an important determinant of cognitive performance. The impact of hypoxia on NVC remains poorly characterized. NVC is partially modulated by nitric oxide (NO), which may initially decrease in hypoxia. This study investigated the effect of acute NO-donor (nitrate) supplementation on NVC and cognitive function in hypoxia. Twenty healthy men participated in this randomized, double-blind, crossover design study. Following normoxic cognitive/NVC testing, participants consumed either nitrate (NIT) or a NIT-depleted placebo (PLA). Participants then underwent 120 min of hypoxia (11.6% ± 0.1% O2) and all cognitive/NVC testing was repeated. NVC was assessed as change in middle cerebral artery (MCA) blood flow during a cognitive task (incongruent Stroop) using transcranial Doppler. Additional computerized cognitive testing was conducted separately to assess memory, executive function, attention, sensorimotor, and social cognition domains. Salivary nitrite significantly increased following supplementation in hypoxia for NIT (+2.6 ± 1.0 arbitrary units (AU)) compared with PLA (+0.2 ± 0.3 AU; p < 0.05). Memory performance (−6 ± 13 correct) significantly decreased (p < 0.05) in hypoxia while all other cognitive domains were unchanged in hypoxia for both PLA and NIT conditions (p > 0.05). MCA flow increased during Stroop similarly in normoxia (PLA +5 ± 6 cm·s−1, NIT +7 ± 7 cm·s−1) and hypoxia (PLA +5 ± 9 cm·s−1, NIT +6 ± 7 cm·s−1) (p < 0.05) and this increase was not altered by PLA or NIT (p > 0.05). In conclusion, acute hypoxia resulted in significant reductions in memory concomitant with preservation of executive function, attention, and sensorimotor function. Hypoxia had no effect on NVC. Acute NIT supplementation had no effect on NVC or cognitive performance in hypoxia.
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Kirton, Adam, Carolyn Gunraj, and Robert Chen. "TMS Neuro-Cardiovascular Coupling in Vascular Compression Cranial Neuropathy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 36, no. 1 (January 2009): 83–88. http://dx.doi.org/10.1017/s0317167100006363.
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Background:Neurovascular compression (NVC) may cause cranial mononeuropathy but lacks a definitive diagnostic investigation. We hypothesized that the arterial pressure wave (APW) would interact at the neurovascular interface in NVC to inhibit transmission of transcranial magnetic stimulation (TMS) stimuli to affected muscles.Methods:We report a novel neurophysiological method coupling cardiovascular physiology with TMS. The electrocardiogram (ECG) and arterial pressure wave (APW) were coupled to triggering of cortical TMS in a patient with NVC-induced spinal accessory (CNXI) mononeuropathy. Outcome measures included motor evoked potential (MEP) amplitudes and firing probabilities of normal and affected trapezieus (TPZ). Values at intervals in proximity to the APW (40/80/120/160ms) were compared to baseline (800ms) using ANOVA and student t-test.Results:Electrocardiogram triggered TMS of CNXI pathways with 100% reliability. MEP amplitudes were decreased in proximity to the APW, particularly at 120ms (0.21±0.04 mV versus 0.39±0.10mV, p=0.003). TPZ firing probabilities were similarly inhibited (43.8% versus 88.2%, p=0.009). No effect of APW proximity was observed on the unaffected side (p=0.868). Procedures were well tolerated.Conclusions:Vascular compression causes CNXI mononeuropathy. Transcranial magnetic stimulation-cardiovascular coupling may evaluate neurovascular junction interactions and non-invasively diagnose NVC.
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Csipo, Tamas, Agnes Lipecz, Peter Mukli, Dhay Bahadli, Osamah Abdulhussein, Cameron D. Owens, Stefano Tarantini, et al. "Increased cognitive workload evokes greater neurovascular coupling responses in healthy young adults." PLOS ONE 16, no. 5 (May 19, 2021): e0250043. http://dx.doi.org/10.1371/journal.pone.0250043.
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Understanding how the brain allocates resources to match the demands of active neurons under physiological conditions is critically important. Increased metabolic demands of active brain regions are matched with hemodynamic responses known as neurovascular coupling (NVC). Several methods that allow noninvasive assessment of brain activity in humans detect NVC and early detection of NVC impairment may serve as an early marker of cognitive impairment. Therefore, non-invasive NVC assessments may serve as a valuable tool to detect early signs of cognitive impairment and dementia. Working memory tasks are routinely employed in the evaluation of cognitive task-evoked NVC responses. However, recent attempts that utilized functional near-infrared spectroscopy (fNIRS) or transcranial Doppler sonography (TCD) while using a similar working memory paradigm did not provide convincing evidence for the correlation of the hemodynamic variables measured by these two methods. In the current study, we aimed to compare fNIRS and TCD in their performance of differentiating NVC responses evoked by different levels of working memory workload during the same working memory task used as cognitive stimulation. Fourteen healthy young individuals were recruited for this study and performed an n-back cognitive test during TCD and fNIRS monitoring. During TCD monitoring, the middle cerebral artery (MCA) flow was bilaterally increased during the task associated with greater cognitive effort. fNIRS also detected significantly increased activation during a more challenging task in the left dorsolateral prefrontal cortex (DLPFC), and in addition, widespread activation of the medial prefrontal cortex (mPFC) was also revealed. Robust changes in prefrontal cortex hemodynamics may explain the profound change in MCA blood flow during the same cognitive task. Overall, our data support our hypothesis that both TCD and fNIRS methods can discriminate NVC evoked by higher demand tasks compared to baseline or lower demand tasks.
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Anfray, Antoine, Antoine Drieu, Vincent Hingot, Yannick Hommet, Mervé Yetim, Marina Rubio, Thomas Deffieux, Mickael Tanter, Cyrille Orset, and Denis Vivien. "Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors." Journal of Cerebral Blood Flow & Metabolism 40, no. 10 (October 30, 2019): 2038–54. http://dx.doi.org/10.1177/0271678x19883599.
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The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).
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Tarantini, Stefano, Andriy Yabluchanskiy, Praveen Ballabh, Eszter Farkas, Joseph Baur, David Sinclair, Anna Csiszar, and Zoltan Ungvari. "NMN Rescues Endothelial Function and Neurovascular Coupling, Improving Cognitive Function in Aged Mice." Innovation in Aging 4, Supplement_1 (December 1, 2020): 121. http://dx.doi.org/10.1093/geroni/igaa057.399.
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Abstract Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).
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Samora, Milena, Lauro C. Vianna, Jake C. Carmo, Victor Macedo, Matthew Dawes, Aaron A. Phillips, Julian F. R. Paton, and James P. Fisher. "Neurovascular coupling is not influenced by lower body negative pressure in humans." American Journal of Physiology-Heart and Circulatory Physiology 319, no. 1 (July 1, 2020): H22—H31. http://dx.doi.org/10.1152/ajpheart.00076.2020.
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Visual stimulation evoked a robust increase in posterior cerebral artery velocity and a modest increase in vertebral artery blood flow, i.e., neurovascular coupling (NVC), which was unaffected by lower body negative pressure in humans (LBNP). In addition, although LBNP induced a mild hypocapnia, this degree of hypocapnia in the absence of LBNP failed to modify the NVC response.
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Jor’dan, Azizah J., Brad Manor, Ikechukwu Iloputaife, Daniel A. Habtemariam, Jonathan F. Bean, Farzaneh A. Sorond, and Lewis A. Lipsitz. "Diminished Locomotor Control Is Associated With Reduced Neurovascular Coupling in Older Adults." Journals of Gerontology: Series A 75, no. 8 (January 8, 2019): 1516–22. http://dx.doi.org/10.1093/gerona/glz006.
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Abstract Background Walking, especially while dual-tasking, requires functional activation of cognitive brain regions and their connected neural networks. This study examined the relationship between neurovascular coupling (NVC), as measured by the change in cerebral blood flow in response to performing a cognitive executive task, and dual-task walking performance. Methods Seventy community-dwelling older adults aged 84 ± 5 years within the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly (MOBILIZE) Boston Study were divided into LOW (n = 35) and HIGH (n = 35) NVC. NVC was quantified by transcranial Doppler ultrasound and stratified by the median change in cerebral blood flow velocity of the middle cerebral artery induced by the performance of the n-back task of executive function. Walking metrics included walking speed, step width, stride length, stride time, stride time variability, and double-support time from single- and dual-task walking conditions, as well as the “cost” of dual-tasking. Results During both single- and dual-task walking, older adults with LOW NVC displayed narrower step width (p = .02 and p = .02), shorter stride length (p = .01 and p = .02), and longer double-support time (p = .03 and p = .002) when compared with the HIGH group. During single-task walking only, LOW NVC was also linked to slower walking speed (p = .02). These associations were independent of age, height, hypertension, atrial fibrillation, and assistive device. The LOW and HIGH NVC groups did not differ in dual-task costs to walking performance. Conclusion In older adults, diminished capacity to regulate cerebral blood flow in response to an executive function task is linked to worse walking performance under both single- and dual-task conditions, but not necessarily dual-task costs.
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Lefferts, Wesley K., Jacob P. DeBlois, Tiago V. Barreira, and Kevin S. Heffernan. "Neurovascular coupling during cognitive activity in adults with controlled hypertension." Journal of Applied Physiology 125, no. 6 (December 1, 2018): 1906–16. http://dx.doi.org/10.1152/japplphysiol.00100.2018.
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Hypertension, even when controlled, may accelerate arterial stiffening and impair the ability of the cerebrovasculature to increase blood flow to support neural activity, i.e., neurovascular coupling (NVC). Optimal NVC depends on continuous, nonpulsatile flow, which is partially determined by extra- and intracranial vessel function. We sought to compare extra- and intracranial hemodynamics during cognitive activity (Stroop task) in 30 middle-aged, well-controlled medicated hypertensive and 30 age-, sex-, and body mass index (BMI)-matched nonhypertensive adults (56 ± 6 years, 28.2 ± 2.9 kg/m2 BMI; 32 men). Aortic and carotid (single point) pulse wave velocity (PWV) were assessed via tonometry and ultrasound, respectively. Carotid and middle cerebral artery (MCA) blood velocity pulsatility were measured via ultrasound and Doppler. Prefrontal cortex (PFC) oxygenation was measured via tissue saturation index (TSI) using near-infrared spectroscopy. Accuracy and reaction times were computed to assess cognitive performance. Stroop performance was similar between groups ( P > 0.01). Aortic and carotid PWV increased, carotid flow pulsatility decreased ( P < 0.01), and MCA flow pulsatility and PFC TSI were maintained during Stroop ( P > 0.01). Our findings indicate that middle-age adults with medically controlled hypertension and adults without hypertension demonstrate similar intra- and extracranial cerebrovascular reactivity during cognitive engagement. Despite increases in large artery stiffness, middle-aged adults with controlled hypertension and without hypertension exhibit reductions in extracranial flow pulsatility during cognitive engagement that may be part of a concerted cerebrovascular response to support downstream cerebral oxygenation and overall NVC. NEW & NOTEWORTHY Hypertension is associated with accelerated arterial stiffening, which may alter extra- and intracranial vascular reactivity during cognitive activity and impair neurovascular coupling. Middle-aged adults with medicated hypertension exhibit similar neurovascular coupling and extra-/intracranial vascular reactivity during sustained cognitive activity. Extracranial modulation of central hemodynamics may be an important component of optimal neurovascular coupling.
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Yamaguchi, Yuji, Tsukasa Ikemura, and Naoyuki Hayashi. "Exhaustive Exercise Attenuates the Neurovascular Coupling by Blunting the Pressor Response to Visual Stimulation." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/671063.
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Neurovascular coupling (NVC) is assessed as an increase response to visual stimulation, and is monitored by blood flow of the posterior cerebral artery (PCA). To investigate whether exhaustive exercise modifies NVC, and more specifically, the relative contributions of vasodilatation in the downstream of PCA and the pressor response on NVC, we measured blood flow velocity in the PCA (PCAv) in 13 males using transcranial Doppler ultrasound flowmetry during a leg-cycle exercise at 75% of maximal heart rate until exhaustion. NVC was estimated as the relative change in PCAv from the mean value obtained during 20-s with the eyes closed to the peak value obtained during 40-s of visual stimulation involving looking at a reversed checkerboard. Conductance index (CI) was calculated by dividing PCAv by mean arterial pressure (MAP) to evaluate the vasodilatation. At exhaustion, PCAv was significantly decreased relative to baseline measurements, and the PCAv response to visual stimulation significantly decreased. Compared to baseline, exhaustive exercise significantly suppressed the increase in MAP to visual stimulation, while the CI response did not significantly change by the exercise. These results suggest that exhaustive exercise attenuates the magnitude of NVC by blunting the pressor response to visual stimulation.
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Salinet, Angela SM, Nathália CC Silva, Juliana Caldas, Daniel S. de Azevedo, Marcelo de-Lima-Oliveira, Ricardo C. Nogueira, Adriana B. Conforto, et al. "Impaired cerebral autoregulation and neurovascular coupling in middle cerebral artery stroke: Influence of severity?" Journal of Cerebral Blood Flow & Metabolism 39, no. 11 (August 17, 2018): 2277–85. http://dx.doi.org/10.1177/0271678x18794835.
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We aimed to assess cerebral autoregulation (CA) and neurovascular coupling (NVC) in stroke patients of differing severity comparing responses to healthy controls and explore the association between CA and NVC with functional outcome. Patients admitted with middle cerebral artery (MCA) stroke and healthy controls were recruited. Stroke severity was defined by the National Institutes of Health Stroke Scale (NIHSS) scores: ≤4 mild, 5–15 moderate and ≥16 severe. Transcranial Doppler ultrasound and Finometer recorded MCA cerebral blood flow velocity (CBFv) and blood pressure, respectively, over 5 min baseline and 1 min passive movement of the elbow to calculate the autoregulation index (ARI) and CBFv amplitude responses to movement. All participants were followed up for three months. A total of 87 participants enrolled in the study, including 15 mild, 27 moderate and 13 severe stroke patients, and 32 control subjects. ARI was lower in the affected hemisphere (AH) of moderate and severe stroke groups. Decreased NVC was seen bilaterally in all stroke groups. CA and NVC correlated with stroke severity and functional outcome. CBFv regulation is significantly impaired in acute stroke, and further compromised with increasing stroke severity. Preserved CA and NVC in the acute period were associated with improved three-month functional outcome.
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Maggio, Paola, Angela S. M. Salinet, Ronney B. Panerai, and Thompson G. Robinson. "Does hypercapnia-induced impairment of cerebral autoregulation affect neurovascular coupling? A functional TCD study." Journal of Applied Physiology 115, no. 4 (August 15, 2013): 491–97. http://dx.doi.org/10.1152/japplphysiol.00327.2013.
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Neurovascular coupling (NVC) and dynamic cerebral autoregulation (dCA) are both impaired in the acute phase of ischemic stroke, but their reciprocal interactions are difficult to predict. To clarify these aspects, the present study explored NVC in a healthy volunteer population during a surrogate state of impaired dCA induced by hypercapnia. This study aimed to test whether hypercapnia leads to a depression of NVC through an impairment of dCA. Continuous recordings of middle cerebral arteries cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 were performed in 19 right-handed subjects (aged >45 yr) before, during, and after 60 s of a passive paradigm during normocapnia and hypercapnia. The CBFv response was broken down into subcomponents describing the relative contributions of BP (VBP), critical closing pressure (VCrCP), and resistance area product (VRAP). VRAP reflects myogenic activity in response to BP changes, whereas VCrCP is more indicative of metabolic control. The results revealed that hypercapnia significantly affected NVC, with significant reductions in the relative contribution of VCrCP to the paradigm-induced increase in CBFv. The present study suggests that hypercapnia impairs both dCA and NVC, probably acting through an impairment of the metabolic component of CBF control.
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Tarantini, Stefano, Peter Hertelendy, Zsuzsanna Tucsek, M. Noa Valcarcel-Ares, Nataliya Smith, Akos Menyhart, Eszter Farkas, et al. "Pharmacologically-Induced Neurovascular Uncoupling is Associated with Cognitive Impairment in Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 11 (July 15, 2015): 1871–81. http://dx.doi.org/10.1038/jcbfm.2015.162.
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There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.
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Lecrux, C., and E. Hamel. "Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1705 (October 5, 2016): 20150350. http://dx.doi.org/10.1098/rstb.2015.0350.
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Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as ‘neurovascular coupling (NVC)’. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.
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Chalak, Lina F., and Rong Zhang. "New Wavelet Neurovascular Bundle for Bedside Evaluation of Cerebral Autoregulation and Neurovascular Coupling in Newborns with Hypoxic-Ischemic Encephalopathy." Developmental Neuroscience 39, no. 1-4 (2017): 89–96. http://dx.doi.org/10.1159/000457833.
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Neonatal encephalopathy (NE) resulting from birth asphyxia constitutes a major global public health burden for millions of infants every year, and despite therapeutic hypothermia, half of these neonates have poor neurological outcomes. As new neuroprotective interventions are being studied in clinical trials, there is a critical need to establish physiological surrogate markers of therapeutic efficacy, to guide patient selection and/or to modify the therapeutic intervention. The challenge in the field of neonatal brain injury has been the difficulty of clinically discerning NE severity within the short therapeutic window after birth or of analyzing the dynamic aspects of the cerebral circulation in sick NE newborns. To address this roadblock, we have recently developed a new “wavelet neurovascular bundle” analytical system that can measure cerebral autoregulation (CA) and neurovascular coupling (NVC) at multiple time scales under dynamic, nonstationary clinical conditions. This wavelet analysis may allow noninvasive quantification at the bedside of (1) CA (combining metrics of blood pressure and cerebral near-infrared spectroscopy, NIRS) and (2) NVC (combining metrics obtained from NIRS and EEG) in newborns with encephalopathy without mathematical assumptions of linear and stationary systems. In this concept paper, we present case examples of NE using the proposed physiological wavelet metrics of CA and NVC. The new approach, once validated in large NE studies, has the potential to optimize the selection of candidates for therapeutic decision-making, and the prediction of neurocognitive outcomes.
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Gagliano, Giuseppe, Anita Monteverdi, Stefano Casali, Umberto Laforenza, Claudia A. M. Gandini Wheeler-Kingshott, Egidio D’Angelo, and Lisa Mapelli. "Non-Linear Frequency Dependence of Neurovascular Coupling in the Cerebellar Cortex Implies Vasodilation–Vasoconstriction Competition." Cells 11, no. 6 (March 19, 2022): 1047. http://dx.doi.org/10.3390/cells11061047.
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Neurovascular coupling (NVC) is the process associating local cerebral blood flow (CBF) to neuronal activity (NA). Although NVC provides the basis for the blood oxygen level dependent (BOLD) effect used in functional MRI (fMRI), the relationship between NVC and NA is still unclear. Since recent studies reported cerebellar non-linearities in BOLD signals during motor tasks execution, we investigated the NVC/NA relationship using a range of input frequencies in acute mouse cerebellar slices of vermis and hemisphere. The capillary diameter increased in response to mossy fiber activation in the 6–300 Hz range, with a marked inflection around 50 Hz (vermis) and 100 Hz (hemisphere). The corresponding NA was recorded using high-density multi-electrode arrays and correlated to capillary dynamics through a computational model dissecting the main components of granular layer activity. Here, NVC is known to involve a balance between the NMDAR-NO pathway driving vasodilation and the mGluRs-20HETE pathway driving vasoconstriction. Simulations showed that the NMDAR-mediated component of NA was sufficient to explain the time course of the capillary dilation but not its non-linear frequency dependence, suggesting that the mGluRs-20HETE pathway plays a role at intermediate frequencies. These parallel control pathways imply a vasodilation–vasoconstriction competition hypothesis that could adapt local hemodynamics at the microscale bearing implications for fMRI signals interpretation.
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Sten, Sebastian, Henrik Podéus, Nicolas Sundqvist, Fredrik Elinder, Maria Engström, and Gunnar Cedersund. "A quantitative model for human neurovascular coupling with translated mechanisms from animals." PLOS Computational Biology 19, no. 1 (January 6, 2023): e1010818. http://dx.doi.org/10.1371/journal.pcbi.1010818.
Full textAbstract:
Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied both experimentally and using mathematical models; various combinations of blood volume and flow, local field potential (LFP), hemoglobin level, blood oxygenation level-dependent response (BOLD), and optogenetics have been measured and modeled in rodents, primates, or humans. However, these data have not been brought together into a unified quantitative model. We now present a mathematical model that describes all such data types and that preserves mechanistic behaviors between experiments. For instance, from modeling of optogenetics and microscopy data in mice, we learn cell-specific contributions; the first rapid dilation in the vascular response is caused by NO-interneurons, the main part of the dilation during longer stimuli is caused by pyramidal neurons, and the post-peak undershoot is caused by NPY-interneurons. These insights are translated and preserved in all subsequent analyses, together with other insights regarding hemoglobin dynamics and the LFP/BOLD-interplay, obtained from other experiments on rodents and primates. The model can predict independent validation-data not used for training. By bringing together data with complementary information from different species, we both understand each dataset better, and have a basis for a new type of integrative analysis of human data.
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Panerai, Ronney B., Martha F. Hanby, Thompson G. Robinson, and Victoria J. Haunton. "Alternative representation of neural activation in multivariate models of neurovascular coupling in humans." Journal of Neurophysiology 122, no. 2 (August 1, 2019): 833–43. http://dx.doi.org/10.1152/jn.00175.2019.
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Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and [Formula: see text], rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. The simultaneous effects of neural stimulation, BP, and [Formula: see text] on CBFV were expressed with a dynamic multivariate model, using BP, EtCO2, and stimulation [ s( t)] as inputs. Two versions of s( t) were considered: a gate function [ sG( t)] or an orthogonal decomposition [ sO( t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO2 reactivity [vasomotor reactivity step response (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO( t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10−5) and was correlated with the CBFV change ( r = 0.73, P = 0.0001). The sO( t) explained a greater fraction of CBFV variance (~50%) than sG( t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for sG( t), and 6.9 and 7.4 for sO( t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO2 in response to sensorimotor stimulation, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO2 reactivity, and NVC in humans. NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 ([Formula: see text]) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or [Formula: see text]. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, [Formula: see text] and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions.
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Aires, Ana, António Andrade, Elsa Azevedo, Filipa Gomes, José Paulo Araújo, and Pedro Castro. "Neurovascular Coupling Impairment in Heart Failure with Reduction Ejection Fraction." Brain Sciences 10, no. 10 (October 7, 2020): 714. http://dx.doi.org/10.3390/brainsci10100714.
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The hemodynamic consequences of a persistent reduced ejection fraction and unknown cardiac output on the brain have not been thoroughly studied. We sought to explore the status of the mechanisms of cerebrovascular regulation in patients with heart failure with reduced (HFrEF) and recovered (HFrecEF) ejection fraction. We monitored cerebral blood flow velocity (CBFV) with transcranial Doppler and blood pressure. Cerebral autoregulation, assessed by transfer function from the spontaneous oscillations of blood pressure to CBFV and neurovascular coupling (NVC) with visual stimulation were compared between groups of HFrEF, HFrecEF and healthy controls. NVC was significantly impaired in HFrEF patients with reduced augmentation of CBFV during stimulation (overshoot systolic CBFV 19.11 ± 6.92 vs. 22.61 ± 7.78 vs. 27.92 ± 6.84, p = 0.04), slower upright of CBFV (rate time to overshoot: 1.19 ± 3.0 vs. 3.06 (4.30) vs. 2.90 ± 3.84, p = 0.02); p = 0.023) and reduced arterial oscillatory properties (natural frequency 0.17 ± 0.06 vs. 0.20 ± 0.09 vs. 0.24 ± 0.07, p = 0.03; attenuation 0.34 ± 0.24 vs. 0.48 ± 0.35 vs. 0.50 ± 0.23, p = 0.05). Cerebral autoregulation was preserved. The neurovascular unit of subjects with chronically reduced heart pumping capability is severely dysfunctional. Dynamic testing with transcranial Doppler could be useful in these patients, but whether it helps in predicting cognitive impairment must be addressed in future prospective studies.
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Salinet, Angela S. M., Thompson G. Robinson, and Ronney B. Panerai. "Active, passive, and motor imagery paradigms: component analysis to assess neurovascular coupling." Journal of Applied Physiology 114, no. 10 (May 15, 2013): 1406–12. http://dx.doi.org/10.1152/japplphysiol.01448.2012.
Full textAbstract:
The association between neural activity and cerebral blood flow (CBF) has been used to assess neurovascular coupling (NVC) in health and diseases states, but little attention has been given to the contribution of simultaneous changes in peripheral covariates. We used an innovative approach to assess the contributions of arterial blood pressure (BP), PaCO2, and the stimulus itself to changes in CBF velocities (CBFv) during active (MA), passive (MP), and motor imagery (MI) paradigms. Continuous recordings of CBFv, beat-to-beat BP, heart rate, and breath-by-breath end-tidal CO2 (EtCO2) were performed in 17 right-handed subjects before, during, and after motor-cognitive paradigms performed with the right arm. A multivariate autoregressive-moving average model was used to calculate the separate contributions of BP, EtCO2, and the neural activation stimulus (represented by a metronome on-off signal) to the CBFv response during paradigms. Differences were found in the bilateral CBFv responses to MI compared with MA and MP, due to the contributions of stimulation ( P < 0.05). BP was the dominant contributor to the initial peaked CBFv response in all paradigms with no significant differences between paradigms, while the contribution of the stimulus explained the plateau phase and extended duration of the CBFv responses. Separating the neural activation contribution from the influences of other covariates, it was possible to detect differences between three paradigms often used to assess disease-related NVC. Apparently similar CBFv responses to different motor-cognitive paradigms can be misleading due to the contributions from peripheral covariates and could lead to inaccurate assessment of NVC, particularly during MI.
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Haider, Ameer A., Tonia S. Rex, and Lauren K. Wareham. "cGMP Signaling in the Neurovascular Unit—Implications for Retinal Ganglion Cell Survival in Glaucoma." Biomolecules 12, no. 11 (November 11, 2022): 1671. http://dx.doi.org/10.3390/biom12111671.
Full textAbstract:
Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often progresses. Hence, effective clinical targets for the treatment of glaucoma remain elusive. Glaucoma shares comorbidities with a multitude of vascular diseases, and evidence in humans and animal models demonstrates an association between vascular dysfunction of the retina and glaucoma pathology. Integral to the survival of retinal ganglion cells (RGCs) is functional neurovascular coupling (NVC), providing RGCs with metabolic support in response to neuronal activity. NVC is mediated by cells of the neurovascular unit (NVU), which include vascular cells, glial cells, and neurons. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling is a prime mediator of NVC between endothelial cells and neurons, but emerging evidence suggests that cGMP signaling is also important in the physiology of other cells of the NVU. NO-cGMP signaling has been implicated in glaucomatous neurodegeneration in humans and mice. In this review, we explore the role of cGMP signaling in the different cell types of the NVU and investigate the potential links between cGMP signaling, breakdown of neurovascular function, and glaucoma pathology.
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Beishon, Lucy C., Kannakorn Intharakham, Victoria J. Haunton, Thompson G. Robinson, and Ronney B. Panerai. "The Interaction of Dynamic Cerebral Autoregulation and Neurovascular Coupling in Cognitive Impairment." Current Alzheimer Research 18, no. 14 (December 2021): 1067–76. http://dx.doi.org/10.2174/1567205019666211227102936.
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Background: Dynamic cerebral autoregulation (dCA) remains intact in both ageing and dementia, but studies of neurovascular coupling (NVC) have produced mixed findings. Objective: We investigated the effects of task-activation on dCA in healthy older adults (HOA), and patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). Methods: Resting and task-activated data from thirty HOA, twenty-two MCI, and thirty-four AD were extracted from a database. The autoregulation index (ARI) was determined at rest and during five cognitive tasks from transfer function analysis. NVC responses were present where group-specific thresholds of cross-correlation peak function and variance ratio were exceeded. Cumulative response rate (CRR) was the total number of positive responses across five tasks and two hemispheres. Results: ARI differed between groups in dominant (p=0.012) and non-dominant (p=0.042) hemispheres at rest but not during task-activation (p=0.33). ARI decreased during language and memory tasks in HOA (p=0.002) but not in MCI or AD (p=0.40). There was a significant positive correlation between baseline ARI and CRR in all groups (r=0.26, p=0.018), but not within sub-groups. Conclusion: dCA efficiency was reduced in task-activation in healthy but not cognitively impaired participants. These results indicate differences in neurovascular processing in healthy older adults relative to cognitively impaired individuals.
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Nowak-Flück, Daniela, Philip N. Ainslie, Anthony R. Bain, Amar Ahmed, Kevin W. Wildfong, Laura E. Morris, Aaron A. Phillips, and James P. Fisher. "Effect of healthy aging on cerebral blood flow, CO2 reactivity, and neurovascular coupling during exercise." Journal of Applied Physiology 125, no. 6 (December 1, 2018): 1917–30. http://dx.doi.org/10.1152/japplphysiol.00050.2018.
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We sought to make the first comparisons of duplex Doppler ultrasonography-derived measures of cerebral blood flow during exercise in young and older individuals and to assess whether healthy aging influences the effect of exercise on neurovascular coupling (NVC) and cerebral vascular reactivity to changes in carbon dioxide (CVRco2). In 10 healthy young (23 ± 2 yr; mean ± SD) and 9 healthy older (66 ± 3 yr) individuals, internal carotid artery (ICA) and vertebral artery (VA) blood flows were concurrently measured, along with middle and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean). Measures were made at rest and during leg cycling (75 W and 35% maximum aerobic workload). ICA and VA blood flow during dynamic exercise, undertaken at matched absolute (ICA: young 336 ± 95, older 352 ± 155; VA: young 95 ± 43, older 100 ± 30 ml/min) and relative (ICA: young 355 ± 125, older 323 ± 153; VA: young 115 ± 48, older 110 ± 32 ml/min) intensities, were not different between groups ( P > 0.670). The PCAvmean responses to visual stimulation (NVC) were blunted in older versus younger group at rest (16 ± 6% vs. 23 ± 7%, P < 0.026) and exercise; however, these responses were not changed from rest to exercise in either group. The ICA and VA CVRco2 were comparable in both groups and unaltered during exercise. Collectively, our findings suggest that 1) ICA and VA blood flow responses to dynamic exercise are similar in healthy young and older individuals, 2) NVC is blunted in healthy older individuals at rest and exercise but is not different between rest to exercise in either group, and 3) CVRco2 is similar during exercise in healthy young and older groups. NEW & NOTEWORTHY Internal carotid artery and vertebral artery blood flow responses to dynamic exercise are similar in healthy young and older individuals. Neurovascular coupling and cerebrovascular carbon dioxide reactivity, two key mechanisms mediating the cerebral blood flow responses to exercise, are generally unaffected by exercise in both healthy young and older individuals.
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Filosa, Jessica A., and Jennifer A. Iddings. "Astrocyte regulation of cerebral vascular tone." American Journal of Physiology-Heart and Circulatory Physiology 305, no. 5 (September 1, 2013): H609—H619. http://dx.doi.org/10.1152/ajpheart.00359.2013.
Full textAbstract:
Cerebral blood flow is controlled by two crucial processes, cerebral autoregulation (CA) and neurovascular coupling (NVC) or functional hyperemia. Whereas CA ensures constant blood flow over a wide range of systemic pressures, NVC ensures rapid spatial and temporal increases in cerebral blood flow in response to neuronal activation. The focus of this review is to discuss the cellular mechanisms by which astrocytes contribute to the regulation of vascular tone in terms of their participation in NVC and, to a lesser extent, CA. We discuss evidence for the various signaling modalities by which astrocytic activation leads to vasodilation and vasoconstriction of parenchymal arterioles. Moreover, we provide a rationale for the contribution of astrocytes to pressure-induced increases in vascular tone via the vasoconstrictor 20-HETE (a downstream metabolite of arachidonic acid). Along these lines, we highlight the importance of the transient receptor potential channel of the vanilloid family (TRPV4) as a key molecular determinant in the regulation of vascular tone in cerebral arterioles. Finally, we discuss current advances in the technical tools available to study NVC mechanisms in the brain as it relates to the participation of astrocytes.
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Salinet, Angela S. M., Thompson G. Robinson, and Ronney B. Panerai. "Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation." Journal of Applied Physiology 118, no. 2 (January 15, 2015): 170–77. http://dx.doi.org/10.1152/japplphysiol.00620.2014.
Full textAbstract:
Cerebral blood flow (CBF) regulation can be impaired in acute ischemic stroke but the combined effects of dynamic cerebral autoregulation (CA), CO2 cerebrovascular reactivity (CVR), and neurovascular coupling (NVC), obtained from simultaneous measurements, have not been described. CBF velocity in the middle cerebral artery (MCA) (CBFv, transcranial Doppler), blood pressure (BP, Finometer), and end-tidal Pco2 (PetCO2, infrared capnography) were recorded during a 1-min passive movement of the arm in 27 healthy controls [mean age (SD) 61.4 (6.0) yr] and 27 acute stroke patients [age 63 (11.7) yr]. A multivariate autoregressive-moving average model was used to separate the contributions of BP, arterial Pco2 (PaCO2), and the neural activation to the CBFv responses. CBFv step responses for the BP, CO2, and stimulus inputs were also obtained. The contribution of the stimulus to the CBFv response was highly significant for the difference between the affected side [area under the curve (AUC) 104.5 (4.5)%] and controls [AUC 106.9 (4.3)%; P = 0.008]. CBFv step responses to CO2 [affected hemisphere 0.39 (0.7), unaffected 0.55 (0.8), controls 1.39 (0.9)%/mmHg; P = 0.01, affected vs. controls; P = 0.025, unaffected vs. controls] and motor stimulus inputs [affected hemisphere 0.20 (0.1), unaffected 0.22 (0.2), controls 0.37 (0.2) arbitrary units; P = 0.009, affected vs. controls; P = 0.02, unaffected vs. controls] were reduced in the stroke group compared with controls. The CBFv step responses to the BP input at baseline and during the paradigm were not different between groups ( P = 0.07), but PetCO2 was lower in the stroke group ( P < 0.05). These results provide new insights into the interaction of CA, CVR, and NVC in both health and disease states.
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Phillips, Aaron A., Darren ER Warburton, Philip N. Ainslie, and Andrei V. Krassioukov. "Regional Neurovascular Coupling and Cognitive Performance in Those with Low Blood Pressure Secondary to High-Level Spinal Cord Injury: Improved by Alpha-1 Agonist Midodrine Hydrochloride." Journal of Cerebral Blood Flow & Metabolism 34, no. 5 (January 29, 2014): 794–801. http://dx.doi.org/10.1038/jcbfm.2014.3.
Full textAbstract:
Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI > T6 spinal segment, and 10 age- and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha1-agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70 ± 10 versus 92 ± 14 mm Hg; P<0.05); however, PCAv conductance was higher (0.56 ± 0.13 versus 0.39 ± 0.15 cm/second/mm Hg; P<0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent ( P<0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function ( P<0.05). Improvements in BP were related to improved cognitive function in those with SCI ( r2 = 0.52; P<0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI.
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Merchant, Sana, Marvin S. Medow, Paul Visintainer, Courtney Terilli, and Julian M. Stewart. "Oscillatory lower body negative pressure impairs working memory task-related functional hyperemia in healthy volunteers." American Journal of Physiology-Heart and Circulatory Physiology 312, no. 4 (April 1, 2017): H672—H680. http://dx.doi.org/10.1152/ajpheart.00438.2016.
Full textAbstract:
Neurovascular coupling (NVC) describes the link between an increase in task-related neural activity and increased cerebral blood flow denoted “functional hyperemia.” We previously showed induced cerebral blood flow oscillations suppressed functional hyperemia; conversely functional hyperemia also suppressed cerebral blood flow oscillations. We used lower body negative pressure (OLBNP) oscillations to force oscillations in middle cerebral artery cerebral blood flow velocity (CBFv). Here, we used N-back testing, an intellectual memory challenge as a neural activation task, to test the hypothesis that OLBNP-induced oscillatory cerebral blood flow can reduce functional hyperemia and NVC produced by a working memory task and can interfere with working memory. We used OLBNP (−30 mmHg) at 0.03, 0.05, and 0.10 Hz and measured spectral power of CBFv at all frequencies. Neither OLBNP nor N-back, alone or combined, affected hemodynamic parameters. 2-Back power and OLBNP individually were compared with 2-back power during OLBNP. 2-Back alone produced a narrow band increase in oscillatory arterial pressure (OAP) and oscillatory cerebral blood flow power centered at 0.0083 Hz. Functional hyperemia in response to 2-back was reduced to near baseline and 2-back memory performance was decreased by 0.03-, 0.05-, and 0.10-Hz OLBNP. OLBNP alone produced increased oscillatory power at frequencies of oscillation not suppressed by added 2-back. However, 2-back preceding OLBNP suppressed OLBNP power. OLBNP-driven oscillatory CBFv blunts NVC and memory performance, while memory task reciprocally interfered with forced CBFv oscillations. This shows that induced cerebral blood flow oscillations suppress functional hyperemia and functional hyperemia suppresses cerebral blood flow oscillations. NEW & NOTEWORTHY We show that induced cerebral blood flow oscillations suppress functional hyperemia produced by a working memory task as well as memory task performance. We conclude that oscillatory cerebral blood flow produces causal reductions of memory task neurovascular coupling and memory task performance. Reductions of functional hyperemia are constrained by autoregulation.
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Moshkforoush, Arash, Baarbod Ashenagar, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Mark T. Nelson, and Nikolaos M. Tsoukias. "The capillary Kir channel as sensor and amplifier of neuronal signals: Modeling insights on K+-mediated neurovascular communication." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16626–37. http://dx.doi.org/10.1073/pnas.2000151117.
Full textAbstract:
Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K+(Kir) channels can sense neuronally evoked increases in interstitial K+and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive. Here, we utilize mathematical modeling to investigate how small outward currents in stimulated cECs can elicit physiologically relevant spread of vasodilatory signals within the highly interconnected brain microvascular network to increase local CBF. Our model shows that the Kir channel can act as an “on–off” switch in cECs to hyperpolarize the cell membrane as extracellular K+increases. A local hyperpolarization can be amplified by the voltage-dependent activation of Kir in neighboring cECs. Sufficient Kir density enables robust amplification of the hyperpolarizing stimulus and produces responses that resemble action potentials in excitable cells. This Kir-mediated excitability can remain localized in the stimulated region or regeneratively propagate over significant distances in the microvascular network, thus dramatically increasing the efficacy of K+for eliciting local hyperemia. Modeling results show how changes in cEC transmembrane current densities and gap junctional resistances can affect K+-mediated NVC and suggest a key role for Kir as a sensor of neuronal activity and an amplifier of retrograde electrical signaling in the cerebral vasculature.
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Pearson, Andrew G., Kathleen B. Miller, Adam T. Corkery, Nicole A. Eisenmann, Anna J. Howery, Alexandra E. Carl, Marlowe W. Eldridge, and Jill N. Barnes. "Impact of age and cyclooxygenase inhibition on the hemodynamic response to acute cognitive challenges." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 321, no. 2 (August 1, 2021): R208—R219. http://dx.doi.org/10.1152/ajpregu.00048.2021.
Full textAbstract:
Structural and functional changes in the cerebral vasculature occur with advancing age, which may lead to impaired neurovascular coupling (NVC) and cognitive decline. Cyclooxygenase (COX) inhibition abolishes age-related differences in cerebrovascular reactivity, but it is unclear if COX inhibition impacts NVC. The purpose of this study was to examine the influence of aging on NVC before and after COX inhibition. Twenty-three young (age = 25 ± 4 yr) and 21 older (age = 64 ± 5 yr) adults completed two levels of difficulty of the Stroop and n-back tests before and after COX inhibition. Middle cerebral artery blood velocity (MCAv) was measured using transcranial Doppler ultrasound and mean arterial blood pressure (MAP) was measured using a finger cuff. Hemodynamic variables were measured at rest and in response to cognitive challenges. During the Stroop test, older adults demonstrated a greater increase in MCAv (young: 2.2 ± 6.8% vs. older: 5.9 ± 5.8%; P = 0.030) and MAP (young: 2.0 ± 4.9% vs. older: 4.8 ± 4.9%; P = 0.036) compared with young adults. There were no age-related differences during the n-back test. COX inhibition reduced MCAv by 30% in young and 26% in older adults ( P < 0.001 for both). During COX inhibition, there were no age-related differences in the percent change in MCAv or MAP in response to the cognitive tests. Our results show that older adults require greater increases in MCAv and MAP during a test of executive function compared with young adults and that any age-related differences in NVC were abolished during COX inhibition. Collectively, this suggests that aging is associated with greater NVC necessary to accomplish a cognitive task.
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Intharakham, Kannakorn, Ronney B. Panerai, and Thompson G. Robinson. "The scalability of common paradigms for assessment of cognitive function: A functional transcranial Doppler study." PLOS ONE 17, no. 3 (March 28, 2022): e0266048. http://dx.doi.org/10.1371/journal.pone.0266048.
Full textAbstract:
Cognitive paradigms induce changes in cerebral blood flow (CBF) associated with increased metabolic demand, namely neurovascular coupling (NVC). We tested the hypothesis that the effect of complexity and duration of cognitive paradigms will either enhance or inhibit the NVC response. Bilateral CBF velocity (CBFV) in the middle cerebral arteries (MCAs) via transcranial Doppler ultrasound (TCD), blood pressure (BP), electrocardiogram (ECG) and end-tidal CO2 (EtCO2) of 16 healthy participants (aged 21–71 years) were simultaneously recorded at rest and during randomized paradigms of different complexities (naming words beginning with P-,R-,V- words and serial subtractions of 100–2,100–7,1000–17), and durations (5s, 30s and 60s). CBFV responses were population mean normalized from a 30-s baseline period prior to task initiation. A significant increase in bilateral CBFV response was observed at the start of all paradigms and provided a similar pattern in most responses, irrespective of complexity or duration. Although significant inter-hemispherical differences were found during performance of R-word and all serial subtraction paradigms, no lateralisation was observed in more complex naming word tasks. Also, the effect of duration was manifested at late stages of 100–7, but not for other paradigms. CBFV responses could not distinguish different levels of complexity or duration with a single presentation of the cognitive paradigm. Further studies of the ordinal scalability of the NVC response are needed with more advanced modelling techniques, or different types of neural stimulation.
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Zhang, Cong, Maryam Tabatabaei, Samuel Bélanger, Hélène Girouard, Mohammad Moeini, Xuecong Lu, and Frédéric Lesage. "Astrocytic endfoot Ca2+ correlates with parenchymal vessel responses during 4-AP induced epilepsy: An in vivo two-photon lifetime microscopy study." Journal of Cerebral Blood Flow & Metabolism 39, no. 2 (August 9, 2017): 260–71. http://dx.doi.org/10.1177/0271678x17725417.
Full textAbstract:
Neurovascular coupling (NVC) underlying the local increase in blood flow during neural activity forms the basis of functional brain imaging and is altered in epilepsy. Because astrocytic calcium (Ca2+) signaling is involved in NVC, this study investigates the role of this pathway in epilepsy. Here, we exploit 4-AP induced epileptic events to show that absolute Ca2+ concentration in cortical astrocyte endfeet in vivo correlates with the diameter of precapillary arterioles during neural activity. We simultaneously monitored free Ca2+ concentration in astrocytic endfeet with the Ca2+-sensitive indicator OGB-1 and diameter of adjacent arterioles in the somatosensory cortex of adult mice by two-photon fluorescence lifetime measurements following 4-AP injection. Our results reveal that, regardless of the mechanism by which astrocytic endfoot Ca2+ was elevated during epileptic events, increases in Ca2+ associated with vasodilation for each individual ictal event in the focus. In the remote area, increases in Ca2+ correlated with vasoconstriction at the onset of seizure and vasodilation during the later part of the seizure. Furthermore, a slow increase in absolute Ca2+ with time following multiple seizures was observed, which in turn, correlated with a trend of arteriolar constriction both at the epileptic focus and remote areas.
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Beishon, Lucy, Rebecca H. Clough, Meeriam Kadicheeni, Tamara Chithiramohan, Ronney B. Panerai, Victoria J. Haunton, Jatinder S. Minhas, and Thompson G. Robinson. "Vascular and haemodynamic issues of brain ageing." Pflügers Archiv - European Journal of Physiology 473, no. 5 (January 13, 2021): 735–51. http://dx.doi.org/10.1007/s00424-020-02508-9.
Full textAbstract:
AbstractThe population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing “normal” ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.
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Claassen, Jurgen A. H. R., Dick H. J. Thijssen, Ronney B. Panerai, and Frank M. Faraci. "Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation." Physiological Reviews 101, no. 4 (October 1, 2021): 1487–559. http://dx.doi.org/10.1152/physrev.00022.2020.
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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.
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Van Skike, Candice E., Stacy A. Hussong, Andy Banh, and Veronica Galvan. "NITRIC OXIDE SYNTHASE DYSFUNCTION UNDERLIES CEREBROVASCULAR DEFICITS IN A MOUSE MODEL OF TAUOPATHY." Innovation in Aging 3, Supplement_1 (November 2019): S91. http://dx.doi.org/10.1093/geroni/igz038.346.
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Abstract We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer’s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer’s disease and potentially other tauopathies.
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Paney, Christiane, Marci Johnson, Alina Fong, and Mark Allen. "fNCI-directed treatment of sports related post-concussion syndrome ion syndrome." Neurology 91, no. 23 Supplement 1 (December 4, 2018): S21.1—S21. http://dx.doi.org/10.1212/01.wnl.0000550611.90268.73.
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PurposeWe propose that our individualized Enhanced Performance in Cognition (EPIC) Treatment can effectively address PCS in sports-related concussions by employing functional NeuroCognitive imaging (fNCI) in conjunction with post-concussion symptom scale measurements to inform and direct treatment modalities. fNCI is a specialized application of fMRI that utilizes a normative reference sample and biomarkers for concussion to provide sensitive and specific predictive diagnostic values. The fNCI addresses neurovascular coupling (NVC) dysregulation that commonly arises in PCS. These results inform individualized EPIC Treatment to restore normal NVC function with a treatment protocol that strategically integrates cardiovascular therapies with cognitive training.MethodsTwo hundred four sports concussion patients were assessed pre- and post-treatment using both objective (fNCI) and subjective Post-Concussion Symptom Scale (PCSS) measures, establishing pre-treatment benchmarks to measure therapeutic effectiveness. Patients underwent EPIC Treatment, which is a week-long, multiple treatments per day period consisting of cognitive, occupational, and neuromuscular therapy informed by fNCI and standardized PCSS findings.ResultsfNCI Severity Index Score (SIS) reported an average 80 percent reduction in objective measurements from the pre-treatment scan. Subjective measurements from the Post-Concussion Symptoms Scale (PCSS) reveal 59 percent reduction of symptoms as described by patient report. The SIS measurements are stable in follow-up scans 1-year post-treatment.ConclusionWe provide evidence that fNCI can be used in assessment and treatment of chronic PCS resulting from SRC. Furthermore, the results provide evidence that our fNCI-guided treatment has positive outcomes in both objective and subjective measurements. This supports the hypothesis that our treatment effectively addresses PCS symptoms resulting from SRC. Follow-up fNCI scans indicate that improvements are stable following treatment.SignificanceSRC patients suffering from chronic PCS who were assessed by fNCI and underwent EPIC treatment report immediate, sustainable, and longitudinal reduction in symptoms resulting in significant improvements to quality of life and functionality.
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Matenchuk, Brittany A., Marina James, Rachel J. Skow, Paige Wakefield, Christina MacKay, Craig D. Steinback, and Margie H. Davenport. "Longitudinal study of cerebral blood flow regulation during exercise in pregnancy." Journal of Cerebral Blood Flow & Metabolism 40, no. 11 (November 21, 2019): 2278–88. http://dx.doi.org/10.1177/0271678x19889089.
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Cerebrovascular adaptation to pregnancy is poorly understood. We sought to assess cerebrovascular regulation in response to visual stimulation, hypercapnia and exercise across the three trimesters of pregnancy. Using transcranial Doppler (TCD) ultrasound, middle and posterior cerebral artery mean blood velocities (MCAvmean and PCAvmean) were measured continuously at rest and in response to (1) visual stimulation to assess neurovascular coupling (NVC); (2) a modified Duffin hyperoxic CO2 rebreathe test, and (3) an incremental cycling exercise test to volitional fatigue in non-pregnant ( n = 26; NP) and pregnant women (first trimester [ n = 13; TM1], second trimester [ n = 21; TM2], and third trimester [ n = 20; TM3]) in total 47 women. At rest, MCAvmean and PETCO2 were lower in TM2 compared to NP. PCAvmean was lower in TM2 but not TM1 or TM3 compared to NP. Cerebrovascular reactivity in MCAvmean and PCAvmean during the hypercapnic rebreathing test was not different between pregnant and non-pregnant women. MCAvmean continued to increase over the second half of the exercise test in TM2 and TM3, while it decreased in NP due to differences in ΔPETCO2 between groups. Pregnant women experienced a delayed decrease in MCAvmean in response to maximal exercise compared to non-pregnant controls which was explained by CO2 reactivity and PETCO2 level.
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Higashimori, Haruki, Víctor M. Blanco, Vengopal Raju Tuniki, John R. Falck, and Jessica A. Filosa. "Role of epoxyeicosatrienoic acids as autocrine metabolites in glutamate-mediated K+ signaling in perivascular astrocytes." American Journal of Physiology-Cell Physiology 299, no. 5 (November 2010): C1068—C1078. http://dx.doi.org/10.1152/ajpcell.00225.2010.
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Epoxyeicosatrienoic acids (EETs), synthesized and released by astrocytes in response to glutamate, are known to play a pivotal role in neurovascular coupling. In vascular smooth muscle cells (VSMC), EETs activate large-conductance, Ca2+-activated K+ (BK) channels resulting in hyperpolarization and vasodilation. However, the functional role and mechanism of action for glial-derived EETs are still to be determined. In this study, we evaluated the effect of the synthetic EET analog 11-nonyloxy-undec-8(Z)-enoic acid (NUD-GA) on outward K+ currents mediated by calcium-activated K+ channels. Addition of NUD-GA significantly increased intracellular Ca2+ and outward K+ currents in perivascular astrocytes. NUD-GA-induced currents were significantly inhibited by BK channel blockers paxilline and tetraethylammonium (TEA) (23.4 ± 2.4%; P < 0.0005). Similarly, NUD-GA-induced currents were also significantly inhibited in the presence of the small-conductance Ca2+-activated K+ channel inhibitor apamin along with a combination of blockers against glutamate receptors (12.8 ± 2.70%; P < 0.05). No changes in outward currents were observed in the presence of the channel blocker for intermediate-conductance K+ channels TRAM-34. Blockade of the endogenous production of EETs with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) significantly blunted ( dl)-1-aminocyclopentane-trans-1,3-dicarboxylic acid ( t-ACPD)-induced outward K+ currents ( P < 0.05; n = 6). Both NUD-GA and t-ACPD significantly increased BK channel single open probability; the later was blocked following MS-PPOH incubation. Our data supports the idea that EETs are potent K+ channel modulators in cortical perivascular astrocytes and further suggest that these metabolites may participate in NVC by modulating the levels of K+ released at the gliovascular space.
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Tsurugizawa, Tomokazu, Yoshifumi Abe, and Denis Le Bihan. "Water apparent diffusion coefficient correlates with gamma oscillation of local field potentials in the rat brain nucleus accumbens following alcohol injection." Journal of Cerebral Blood Flow & Metabolism 37, no. 9 (January 6, 2017): 3193–202. http://dx.doi.org/10.1177/0271678x16685104.
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Ethanol is a vasoactive agent as well as psychoactive drug. The neurovascular response, coupled with neuronal activity, can be disturbed by alcohol intake. Hence, blood oxygenation level-dependent (BOLD) fMRI, which relies on neurovascular coupling, might not be reliable to reflect alcohol-induced neuronal responses. Recently, diffusion fMRI has been shown to be more sensitive to neural activity than BOLD fMRI even when neurovascular coupling is disrupted. Especially, the apparent diffusion coefficient (ADC) is sensitive to changes occurring in the cellular tissue structure upon activation. In the present study, we compared BOLD fMRI signals, ADC, and local field potentials (LFPs) in the nucleus accumbens (NAc) following injection of an ethanol solution (0.4 g/kg body weight) in rats under medetomidine anesthesia. An increase in the gamma oscillation power of LFP and an ADC decrease were observed 5 min after the injection of EtOH. The BOLD signals showed a negative slow drift, similar to mean arterial pressure with a peak approximately 10 min after the injection. These results confirm that DfMRI can be a better marker of the neuronal activity than BOLD fMRI, especially when the brain hemodynamic status is changed by vasoactive drugs such as ethanol.
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Tabansky, Inna, Yupu Liang, Maya Frankfurt, Martin A. Daniels, Matthew Harrigan, Sarah Stern, Teresa A. Milner, et al. "Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal." Proceedings of the National Academy of Sciences 115, no. 29 (July 2, 2018): E6900—E6909. http://dx.doi.org/10.1073/pnas.1806123115.
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Neurons of the medullary reticular nucleus gigantocellularis (NGC) and their targets have recently been a focus of research on mechanisms supporting generalized CNS arousal (GA) required for proper cognitive functions. Using the retro-TRAP method, we characterized transcripts enriched in NGC neurons which have projections to the thalamus. The unique expression and activation of the endothelial nitric oxide (eNOS) signaling pathway in these cells and their intimate connections with blood vessels indicate that these neurons exert direct neurovascular coupling. Production of nitric oxide (NO) within eNOS-positive NGC neurons increases after environmental perturbations, indicating a role for eNOS/NO in modulating environmentally appropriate levels of GA. Inhibition of NO production causes dysregulated behavioral arousal after exposure to environmental perturbation. Further, our findings suggest interpretations for associations between psychiatric disorders and mutations in the eNOS locus.
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Bola, R. Aaron, and Eugene A. Kiyatkin. "Inflow of oxygen and glucose in brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses." Journal of Neurophysiology 119, no. 2 (February 1, 2018): 499–508. http://dx.doi.org/10.1152/jn.00692.2017.
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As an essential part of sympathetic activation that prepares the organism for “fight or flight,” peripheral norepinephrine (NE) plays an important role in regulating cardiac activity and the tone of blood vessels, increasing blood flow to the heart and the brain and decreasing blood flow to the organs not as necessary for immediate survival. To assess whether this effect is applicable to the brain, we used high-speed amperometry to measure the changes in nucleus accumbens (NAc) levels of oxygen and glucose induced by intravenous injections of NE in awake freely moving rats. We found that NE at low doses (2–18 μg/kg) induces correlative increases in NAc oxygen and glucose, suggesting local vasodilation and enhanced entry of these substances in brain tissue from the arterial blood. By using temperature recordings from the NAc, temporal muscle, and skin, we show that this central effect is associated with strong skin vasoconstriction and phasic increases in intrabrain heat production, indicative of metabolic neural activation. A tight direct correlation between NE-induced changes in metabolic activity and NAc levels of oxygen and glucose levels suggests that local cerebral vasodilation is triggered via a neurovascular coupling mechanism. Our data suggest that NE, by changing vascular tone and cardiac activity, triggers a visceral sensory signal that rapidly reaches the central nervous system via sensory nerves and induces neural activation. This neural activation leads to a chain of neurovascular events that promote entry of oxygen and glucose in brain tissue, thus preventing any possible metabolic deficit during functional activation. NEW & NOTEWORTHY Using high-speed amperometry and thermorecording in freely moving rats, we demonstrate that intravenous norepinephrine at physiological doses induces rapid correlative increases in nucleus accumbens oxygen and glucose levels coupled with increased intrabrain heat production. Although norepinephrine cannot cross the blood-brain barrier, by changing cardiac activity and vascular tone, it creates a sensory signal that reaches the central nervous system via sensory nerves, induces neural activation, and triggers a chain of neurovascular events that promotes intrabrain entry of oxygen and glucose.
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Solis, Ernesto, Anum Afzal, and Eugene A. Kiyatkin. "Opposing mechanisms underlying differential changes in brain oxygen and temperature induced by intravenous morphine." Journal of Neurophysiology 120, no. 5 (November 1, 2018): 2513–21. http://dx.doi.org/10.1152/jn.00445.2018.
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Morphine remains widely used in clinical settings due to its potent analgesic properties. However, one of the gravest risks of all opioids is their ability to induce respiratory depression and subsequent brain hypoxia that can lead to coma and death. Due to these life-threatening effects, our goal was to examine the effects of intravenous morphine at a wide range of doses (0.1–6.4 mg/kg) on changes in brain oxygen levels in freely moving rats. We used oxygen sensors coupled with high-speed amperometry and conducted measurements in the nucleus accumbens (NAc) and subcutaneous (SC) space, the latter serving as a proxy for blood oxygen levels that depend on respiratory activity. We also examined the effects of morphine on NAc, muscle, and skin temperature. Morphine induced dose-dependent decreases in SC oxygen levels, suggesting respiratory depression, but differential effects on NAc oxygen: increases at low and moderate doses (0.1–1.6 mg/kg) and decreases at the highest dose tested (6.4 mg/kg). Morphine also increased brain temperature at low and moderate doses but induced a biphasic, down-up change at high doses. The oxygen increases appear to result from a neurovascular coupling mechanism via local vasodilation and enhanced oxygen entry into brain tissue to compensate for blood oxygen drops caused by modest respiratory depression. At high morphine doses, this adaptive mechanism is unable to compensate for the enhanced respiratory depression, resulting in brain hypoxia. Hence, morphine appears to be safe when used as an analgesic at clinically relevant doses but poses great risks at high doses, likely to be abused by drug users. NEW & NOTEWORTHY With the use of oxygen sensors coupled with amperometry, we show that morphine induces differential effects on brain oxygen levels, slightly increasing them at low doses and strongly decreasing them at high doses. In contrast, morphine dose dependently decreases oxygen levels in the SC space. Therefore, morphine engages opposing mechanisms affecting brain oxygen levels, enhancing them through neurovascular coupling at low, clinically relevant doses and decreasing them due to dramatic respiratory depression at high doses, likely to be abused.
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Nicolakakis, Nektaria, Tahar Aboulkassim, Antonio Aliaga, Xin-Kang Tong, Pedro Rosa-Neto, and Edith Hamel. "Intact Memory in TGF-β1 Transgenic Mice Featuring Chronic Cerebrovascular Deficit: Recovery with Pioglitazone." Journal of Cerebral Blood Flow & Metabolism 31, no. 1 (June 23, 2010): 200–211. http://dx.doi.org/10.1038/jcbfm.2010.78.
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The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-β1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-β1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-β1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl–cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was also administered to pups as a prophylactic 1-year treatment. Elderly TGF mice featured cerebrovascular dysfunction that was not remedied with NAC. In contrast, pioglitazone prevented or reversed this deficit, and rescued the impaired neurovascular coupling response to whisker stimulation, although it failed to normalize the vascular structure. In aged TGF mice, neuronal and cognitive indices—the stimulus-evoked neurometabolic response, cortical cholinergic innervation, and spatial memory in the Morris water maze—were intact. Our findings show that impaired brain hemodynamics and cerebrovascular function are not accompanied by memory impairment in this model. Conceivably in AD, they constitute aggravating factors against a background of aging and underlying pathology. Our data further highlight the ability of pioglitazone to protect the cerebrovasculature marked by TGF-β1 increase, aging, fibrosis, and antioxidant resistance, thus of high relevance for AD patients.
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Canna, Antonietta, Fabrizio Esposito, Gioacchino Tedeschi, Francesca Trojsi, Carla Passaniti, Irene di Meo, Rita Polito, et al. "Neurovascular coupling in patients with type 2 diabetes mellitus." Frontiers in Aging Neuroscience 14 (September 1, 2022). http://dx.doi.org/10.3389/fnagi.2022.976340.
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Functional and metabolic neural changes in Type 2 diabetes mellitus (T2DM) can be associated with poor cognitive performances. Here we analyzed the functional-metabolic neurovascular coupling (NVC) in the brain of T2DM patients. Thirty-three patients (70 ± 6 years, 15 males) with recent T2DM diagnosis and 18 healthy control (HC) subjects (65 ± 9 years, 9 males) were enrolled in a brain MRI study to identify the potential effects of T2DM on NVC. T2DM patients were either drug-naive (n = 19) or under treatment with metformin (n = 14) since less than 6 months. Arterial spin labeling and blood oxygen level dependent resting-state functional MRI (RS-fMRI) images were combined to derive NVC measures in brain regions and large-scale networks in a standard brain parcelation. Altered NVC values in T2DM patients were correlated with cognitive performances spanning several neurological domains using Spearman correlation coefficients. Compared to HC, T2DM patients had reduced NVC in the default mode network (DMN) and increased NVC in three regions of the dorsal (DAN) and salience-ventral (SVAN) attention networks. NVC abnormalities in DAN and SVAN were associated with reduced visuo-spatial cognitive performances. A spatial pattern of NVC reduction in the DMN, accompanied by isolated regional NVC increases in DAN and SVAN, could reflect the emergence of (defective) compensatory processes in T2DM patients in response to altered neurovascular conditions. Overall, this pattern is reminiscent of neural abnormalities previously observed in Alzheimer’s disease, suggesting that similar neurobiological mechanisms, secondary to insulin resistance and manifesting as NVC alterations, might be developing in T2DM pathology.
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Burma, Joel S., Rowan K. Van Roessel, Ibukunoluwa K. Oni, Jeff F. Dunn, and Jonathan D. Smirl. "Neurovascular coupling on trial: How the number of trials completed impacts the accuracy and precision of temporally derived neurovascular coupling estimates." Journal of Cerebral Blood Flow & Metabolism, February 25, 2022, 0271678X2210844. http://dx.doi.org/10.1177/0271678x221084400.
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Standard practices for quantifying neurovascular coupling (NVC) with transcranial Doppler ultrasound (TCD) require participants to complete one-to-ten repetitive trials. However, limited empirical evidence exists regarding how the number of trials completed influences the validity and reliability of temporally derived NVC metrics. Secondary analyses was performed on 60 young healthy participants (30 females/30 males) who completed eight cyclical eyes-closed (20-seconds), eyes-open (40-seconds) NVC trials, using the “Where’s Waldo?” visual paradigm. TCD data was obtained in posterior and middle cerebral arteries (PCA and MCA, respectively). The within-day (n = 11) and between-day ( n = 17) reliability were assessed at seven- and three-time points, respectively. Repeat testing from the reliability aims were also used for the concurrent validity analysis ( n = 160). PCA metrics (i.e., baseline, peak, percent increase, and area-under-the-curve) demonstrated five trials produced excellent intraclass correlation coefficient (ICC) 95% confidence intervals for validity and within-day reliability (>0.900), whereas between-day reliability was good-to-excellent (>0.750). Likewise, 95% confidence intervals for coefficient of variation (CoV) measures ranged from acceptable (<20%) to excellent (<5%) with five-or-more trials. Employing fewer than five trials produced poor/unacceptable ICC and CoV metrics. Future NVC, TCD-based research should therefore have participants complete a minimum of five trials when quantifying the NVC response with TCD via a “ Where’s Waldo?” paradigm.
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Vestergaard, Mark B., Jette L. Frederiksen, Henrik B. W. Larsson, and Stig P. Cramer. "Cerebrovascular Reactivity and Neurovascular Coupling in Multiple Sclerosis—A Systematic Review." Frontiers in Neurology 13 (June 1, 2022). http://dx.doi.org/10.3389/fneur.2022.912828.
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The inflammatory processes observed in the central nervous system in multiple sclerosis (MS) could damage the endothelium of the cerebral vessels and lead to a dysfunctional regulation of vessel tonus and recruitment, potentially impairing cerebrovascular reactivity (CVR) and neurovascular coupling (NVC). Impaired CVR or NVC correlates with declining brain health and potentially plays a causal role in the development of neurodegenerative disease. Therefore, we examined studies on CVR or NVC in MS patients to evaluate the evidence for impaired cerebrovascular function as a contributing disease mechanism in MS. Twenty-three studies were included (12 examined CVR and 11 examined NVC). Six studies found no difference in CVR response between MS patients and healthy controls. Five studies observed reduced CVR in patients. This discrepancy can be because CVR is mainly affected after a long disease duration and therefore is not observed in all patients. All studies used CO2 as a vasodilating stimulus. The studies on NVC demonstrated diverse results; hence a conclusion that describes all the published observations is difficult to find. Future studies using quantitative techniques and larger study samples are needed to elucidate the discrepancies in the reported results.
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Paquette, Thierry, Mathieu Piché, and Hugues Leblond. "Contribution of astrocytes to neurovascular coupling in the spinal cord of the rat." Journal of Physiological Sciences 71, no. 1 (May 28, 2021). http://dx.doi.org/10.1186/s12576-021-00800-6.
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AbstractFunctional magnetic resonance imaging (fMRI) of the spinal cord relies on the integrity of neurovascular coupling (NVC) to infer neuronal activity from hemodynamic changes. Astrocytes are a key component of cerebral NVC, but their role in spinal NVC is unclear. The objective of this study was to examine whether inhibition of astrocyte metabolism by fluorocitrate alters spinal NVC. In 14 rats, local field potential (LFP) and spinal cord blood flow (SCBF) were recorded simultaneously in the lumbosacral enlargement during noxious stimulation of the sciatic nerve before and after a local administration of fluorocitrate (N = 7) or saline (N = 7). Fluorocitrate significantly reduced SCBF responses (p < 0.001) but not LFP amplitude (p = 0.22) compared with saline. Accordingly, NVC was altered by fluorocitrate compared with saline (p < 0.01). These results support the role of astrocytes in spinal NVC and have implications for spinal cord imaging with fMRI for conditions in which astrocyte metabolism may be altered.
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Das, Yudhajit, Xinlong Wang, Srinivas Kota, Rong Zhang, Hanli Liu, and Lina F. Chalak. "Neurovascular coupling (NVC) in newborns using processed EEG versus amplitude-EEG." Scientific Reports 11, no. 1 (May 3, 2021). http://dx.doi.org/10.1038/s41598-021-88849-6.
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AbstractThere is a critical need for development of real time physiological biomarkers for birth asphyxia that constitutes a major global public health burden. Our recent study (Scientific Reports, V10:9183, 2020) established a novel non-invasive neurovascular coupling (NVC) assessment in newborns using dynamic wavelet transform coherence (WTC) analysis irrespective of different aEEG algorithms. As an extended study, the current paper examines whether the variability in processed EEG and amplitude-EEG (aEEG) outputs would impact the determination of NVC in newborns with encephalopathy. Concurrent processed EEG tracings and regional near infrared spectroscopy (NIRS)-based cerebral tissue oxygen saturation (SctO2) readings during a period of twenty hours in their first day of life were selected and processed in this study. After bandpass-filtered in 2–15 Hz, rectified, and down-sampled at 0.21 Hz, the processed EEG tracings along with NIRS-SctO2 (0.21 Hz) were used to perform WTC analysis, followed by comparison of WTC-metrics between SctO2-processed EEG coherence and SctO2-aEEG coherence using Bland–Altman statistics. Our results demonstrated high and significant correlation (R2 = 0.96, p < 0.001) between NVC assessments by SctO2-processed EEG and SctO2-aEEG coherence, confirming that band-passed, rectified, and down-sampled processed EEG, or aEEG, can be paired with NIRS-SctO2 to assess NVC in newborns with encephalopathy. Findings indicate the feasibility of a simpler approach to NVC in neonates by using directly processed EEG, instead of aEEG.