Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia.

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.

[1]  Jamie R. Blackwell,et al.  Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation , 2015, Physiology & Behavior.

[2]  Yojiro Ogawa,et al.  Decreased steady-state cerebral blood flow velocity and altered dynamic cerebral autoregulation during 5-h sustained 15% O2 hypoxia. , 2010, Journal of applied physiology.

[3]  M. Wolf.  Functional TCD: regulation of cerebral hemodynamics--cerebral autoregulation, vasomotor reactivity, and neurovascular coupling. , 2015, Frontiers of neurology and neuroscience.

[4]  L. Brush,et al.  McDonaldʼs Blood Flow in Arteries , 1991 .

[5]  K. Heffernan,et al.  Effect of acute nitrate ingestion on central hemodynamic load in hypoxia. , 2016, Nitric oxide : biology and chemistry.

[6]  Chiao-Chi V. Chen,et al.  Neurovascular abnormalities in brain disorders: highlights with angiogenesis and magnetic resonance imaging studies , 2013, Journal of Biomedical Science.

[7]  Peng Li,et al.  Training-dependent cognitive advantage is suppressed at high altitude , 2012, Physiology & Behavior.

[8]  M. van Buchem,et al.  Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. , 2002, Journal of applied physiology.

[9]  J. Donnelly,et al.  Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation , 2014, The Journal of physiology.

[10]  Bencie Woll,et al.  Stimulus rate increases lateralisation in linguistic and non-linguistic tasks measured by functional transcranial Doppler sonography , 2015, Neuropsychologia.

[11]  W. Nichols,et al.  McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles , 1998 .

[12]  G. Vingerhoets,et al.  Lateralization of cerebral blood flow velocity changes during cognitive tasks. A simultaneous bilateral transcranial Doppler study. , 1999, Stroke.

[13]  K. Przyklenk.  Ischemic Preconditioning , 2004, Journal of Thrombosis and Thrombolysis.

[14]  B. Mallick,et al.  High altitude memory impairment is due to neuronal apoptosis in hippocampus, cortex and striatum , 2008, Journal of Chemical Neuroanatomy.

[15]  P. Brugger,et al.  Cognitive and emotional processing at high altitude. , 2005, Aviation, space, and environmental medicine.

[16]  M. Molinari,et al.  Inability to Process Negative Emotions in Cerebellar Damage: a Functional Transcranial Doppler Sonographic Study , 2015, The Cerebellum.

[17]  C. Iadecola.  Neurovascular regulation in the normal brain and in Alzheimer's disease , 2004, Nature Reviews Neuroscience.

[18]  Cognitive and emotional functioning in BED , 2016 .

[19]  Darren P. Casey,et al.  Acute dietary nitrate supplementation enhances compensatory vasodilation during hypoxic exercise in older adults. , 2015, Journal of applied physiology.

[20]  E. Gordon,et al.  THE TEST-RETEST RELIABILITY OF A STANDARDIZED NEUROCOGNITIVE AND NEUROPHYSIOLOGICAL TEST BATTERY: “NEUROMARKER” , 2005, The International journal of neuroscience.

[21]  Jamie R. Blackwell,et al.  Influence of dietary nitrate supplementation on physiological and cognitive responses to incremental cycle exercise , 2014, Respiratory Physiology & Neurobiology.

[22]  A. Van Schepdael,et al.  Dietary nitrate improves muscle but not cerebral oxygenation status during exercise in hypoxia. , 2012, Journal of applied physiology.

[23]  R. Milner,et al.  Defining the critical hypoxic threshold that promotes vascular remodeling in the brain , 2015, Experimental Neurology.

[24]  S. Gaydos,et al.  Hypoxic hypoxia at moderate altitudes: review of the state of the science. , 2012, Aviation, space, and environmental medicine.

[25]  B. A. Conway,et al.  The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models , 2015 .

[26]  B. Whipp,et al.  The role of nitrogen oxides in human adaptation to hypoxia , 2011, Scientific reports.

[27]  A. Schechter,et al.  The role of nitrite in neurovascular coupling , 2011, Brain Research.

[28]  S. Singh,et al.  Differential temporal response of hippocampus, cortex and cerebellum to hypobaric hypoxia: A biochemical approach , 2007, Neurochemistry International.

[29]  Andrew M. Jones,et al.  Effects of short-term dietary nitrate supplementation on blood pressure, O2 uptake kinetics, and muscle and cognitive function in older adults. , 2013, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  M. Joyner,et al.  Local control of skeletal muscle blood flow during exercise: influence of available oxygen. , 2011, Journal of applied physiology.

[31]  P. Bärtsch,et al.  Remote ischemic preconditioning delays the onset of acute mountain sickness in normobaric hypoxia , 2015, Physiological reports.

[32]  Geoff Der,et al.  The effects of high altitude on choice reaction time mean and intra-individual variability: Results of the Edinburgh Altitude Research Expedition of 2008. , 2010, Neuropsychology.

[33]  Wenjing Luo,et al.  Effects of acetazolamide on cognitive performance during high-altitude exposure. , 2013, Neurotoxicology and teratology.

[34]  C. Sartori,et al.  Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. , 2000, American journal of respiratory and critical care medicine.

[35]  E. Gordon,et al.  Development and validation of a World-Wide-Web-based neurocognitive assessment battery: WebNeuro , 2007, Behavior research methods.

[36]  M. Joyner,et al.  Failure of Systemic Hypoxia to Blunt α‐Adrenergic Vasoconstriction in the Human Forearm , 2003 .

[37]  S. Agarwal,et al.  A new approach to hypobaric hypoxia induced cognitive impairment , 2012, The Indian journal of medical research.

[38]  N. Ayas,et al.  Dynamic cerebral autoregulation during and following acute hypoxia: role of carbon dioxide. , 2013, Journal of applied physiology.

[39]  E. Plautz,et al.  Quantification of neurovascular protection following repetitive hypoxic preconditioning and transient middle cerebral artery occlusion in mice. , 2015, Journal of visualized experiments : JoVE.

[40]  M. Poulin,et al.  Indexes of flow and cross-sectional area of the middle cerebral artery using doppler ultrasound during hypoxia and hypercapnia in humans. , 1996, Stroke.

[41]  D. Attwell,et al.  Glial and neuronal control of brain blood flow , 2022 .

[42]  Paul Ma,et al.  Performance during mild acute hypoxia. , 1994 .

[43]  C. Pedlar,et al.  A single dose of beetroot juice enhances cycling performance in simulated altitude. , 2014, Medicine and science in sports and exercise.

[44]  C. Piérard,et al.  Working memory impairment in pilots exposed to acute hypobaric hypoxia. , 2013, Aviation, space, and environmental medicine.

[45]  Joseph Donnelly,et al.  Influence of cerebral blood flow on breathing stability , 2009 .

[46]  M. D’Esposito,et al.  The Effect of Normal Aging on the Coupling of Neural Activity to the Bold Hemodynamic Response , 1999, NeuroImage.

[47]  Ashley R. Morgan,et al.  Acute effect of a high nitrate diet on brain perfusion in older adults. , 2011, Nitric oxide : biology and chemistry.

[48]  D. Arciniegas,et al.  Cognitive sequelae of hypoxic-ischemic brain injury: a review. , 2010, NeuroRehabilitation.

[49]  G. Mitchell,et al.  Carotid artery stiffness and hemodynamic pulsatility during cognitive engagement in healthy adults: a pilot investigation. , 2015, American journal of hypertension.

[50]  Joseph A Fisher,et al.  Integrative regulation of human brain blood flow , 2014, The Journal of physiology.

[51]  J. Cleland.  Effects of Acetazolamide , 1969 .

[52]  P. Pradat-Diehl,et al.  Neurological sequelae after cerebral anoxia , 2010, Brain injury.

[53]  P. Williams.  A single dose , 2008, BDJ.

[54]  Mark Kohler,et al.  Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies , 2014, BMC Neurology.

[55]  M. Joyner,et al.  The catecholamines strike back. What NO does not do. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[56]  Farzaneh A. Sorond,et al.  Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people , 2013, Neurology.

[57]  D. Asmaro,et al.  Cognition at altitude: impairment in executive and memory processes under hypoxic conditions. , 2013, Aviation, space, and environmental medicine.

[58]  M. Gladwin,et al.  The Nitrate–Nitrite–Nitric Oxide Pathway in Mammals , 2011 .

[59]  P. K. Banerjee,et al.  Hypobaric hypoxia induces oxidative stress in rat brain , 2006, Neurochemistry International.

[60]  Arne Møller,et al.  A NO way to BOLD?: Dietary nitrate alters the hemodynamic response to visual stimulation , 2013, NeuroImage.

[61]  W. Nichols,et al.  Comprar Mcdonald's blood flow in arteries. Theoretical, experimental and clinical principles | W. Nichols | 9780340985014 | Hodder Education , 2011 .

[62]  Tobias M. Merz,et al.  Cognitive performance in high-altitude climbers: a comparative study of saccadic eye movements and neuropsychological tests , 2013, European Journal of Applied Physiology.

[63]  Guy Vingerhoets,et al.  Transcranial Doppler Ultrasonography Monitoring of Cerebral Hemodynamics During Performance of Cognitive Tasks: A Review , 2000, Neuropsychology Review.

[64]  Yan Li,et al.  Blood flow pattern in the middle cerebral artery in relation to indices of arterial stiffness in the systemic circulation. , 2012, American journal of hypertension.

[65]  P. FosterGary,et al.  Ischemic preconditioning improves oxygen saturation and attenuates hypoxic pulmonary vasoconstriction at high altitude. , 2014 .

[66]  M. Joyner,et al.  Failure of systemic hypoxia to blunt alpha-adrenergic vasoconstriction in the human forearm. , 2003, The Journal of physiology.

[67]  Moors Pieter,et al.  Test-retest reliability. , 2014 .

[68]  Ruikang K. Wang,et al.  Responses of Peripheral Blood Flow to Acute Hypoxia and Hyperoxia as Measured by Optical Microangiography , 2011, PloS one.

[69]  P. Ainslie,et al.  Effect of acute hypoxia on regional cerebral blood flow: effect of sympathetic nerve activity. , 2014, Journal of applied physiology.

[70]  Mark T. Gladwin,et al.  The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics , 2008, Nature Reviews Drug Discovery.

[71]  M. Meyerand,et al.  Regional heterogeneity in the brain's response to hypoxia measured using BOLD MR imaging , 1999, Magnetic resonance in medicine.

[72]  M. Joyner,et al.  Impaired modulation of sympathetic α‐adrenergic vasoconstriction in contracting forearm muscle of ageing men , 2005, The Journal of physiology.

[73]  Marc J. Poulin,et al.  Cerebrovascular responses to altitude , 2007, Respiratory Physiology & Neurobiology.

[74]  C. Pedlar,et al.  The effects of a single dose of concentrated beetroot juice on performance in trained flatwater kayakers. , 2013, International journal of sport nutrition and exercise metabolism.

[75]  P. Luiten,et al.  Cerebral microvascular pathology in aging and Alzheimer's disease , 2001, Progress in Neurobiology.

[76]  Effects of physiological aging and cerebrovascular risk factors on the hemodynamic response to brain activation: a functional transcranial Doppler study , 2007 .

[77]  G. Buela-Casal,et al.  Neuropsychological Functioning Associated with High-Altitude Exposure , 2004, Neuropsychology Review.

[78]  N. Bryan,et al.  Food sources of nitrates and nitrites: the physiologic context for potential health benefits. , 2009, The American journal of clinical nutrition.