Neurovascular Coupling

[SNT Gatchaman]

Neurovascular coupling is the concept that in the CNS, organ function is tightly associated with blood flow, moreso than in other organs. Theoretical background and latest thinking —

From the introduction in The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease (2017, Neuron) —

The brain, an organ of unparalleled sophistication, seems to have a fundamental design glitch: it consumes a large amount of energy but lacks a reservoir to store fuel for use when needed. Therefore, the brain receives energy substrates, primarily oxygen and glucose, "on the fly" through its blood supply.

There has been a long-standing interest in how the brain regulates its own blood supply, driven not only by the desire to gain a better understanding of the harmful effects of cerebrovascular insufficiency but also by the early realization that regional changes in cerebral blood flow (CBF) may provide a window on brain function. This large body of work spanning over almost two centuries revealed a remarkable complexity in the interaction between the brain and its vessels that is unmatched by the vasculature in other organs.

Overcoming "dualistic thinking" —

Although the vital importance of cerebral blood vessels in brain health had long been appreciated, hard-core neuroscientists considered brain cells and cerebral blood vessels distinct entities. Such a dichotomy led to the tacit assumption that, unless the delivery of blood flow to the brain was critically compromised, neurons had little to do with the vasculature and vice versa. Similarly, a rigid distinction was placed between "neurodegenerative diseases" (e.g., Alzheimer’s disease) and cerebrovascular diseases (e.g., stroke), so that these conditions were considered mutually exclusive and mechanistically unrelated.

The NVU [neurovascular unit] concept challenged these assumptions and emphasized the symbiotic relationship between brain cells and cerebral blood vessels, calling attention to their developmental, structural, and functional interdependence in health and disease.

The neuroscience community embraced the concept enthusiastically, and the NVU has drawn increasing interest, as attested by the dramatic rise in the number of yearly citations over the past decade. New technologies have enabled investigators to delve deeper into the functions of the NVU in health and disease. Consequently, the NVU has taken center stage in all facets of normal brain function and in the pathobiology of a wide variety of brain diseases.

Neurovascular coupling underlies functional MRI which uses Blood Oxgygen Level-Dependent (BOLD) imaging, whereby measured regional increase in O2 levels in the blood corresponds to specific areas of brain activation. Oxygen levels rise much more than brain tissue can use, which has been a long-standing paradox.

Down the rabbit hole of complex brain biochemistry, relating oxidative phosphorylation, anaerobic glycolysis and lactate generation under a situation of no capillary recruitment to metabolic challenge...

From the abstract for Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2, and pO2 (2023, Journal of Neurochemistry) —

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2) resulting in blood hyperoxygenation, the basis of BOLD fMRI contrast. Explanations for the high CBF vs. CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintainenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise.

Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2).

In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0.

Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain’s high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Expanding with —

The apparent paradox of a high n and low OF, might be explained, at least in part, by CBF removing lactate and protons produced by the nonoxidative processing of glucose and glycogen through glycolysis and glycogenolysis, respectively. Under non-activated conditions, glycogen is not significantly used and >90% of blood-borne glucose is oxidized to CO2, in the mitochondria for ATP synthesis, with 5-8% of glucose being converted to lactate via nonoxidative glycolysis.

In contrast, during activation the incremental rate of nonoxidative glycolysis and glycogenolysis leading to lactate production is 3 times greater than the corresponding increase in oxidative metabolism [...]. We reasoned that the increase in the rate of proton production during activation (as a result of nonoxidative glucose processing coupled to ATP hydrolysis), if not matched by enhanced clearance via CBF, could lead to a decrease in blood and brain tissue pH and an associated increase in pCO2, due to the carbonic anhydrase (CA) catalyzed reaction, with a potential impairment of brain function.

We therefore hypothesize that rather than optimizing a single parameter, the neurovascular coupling and capillary O2, and CO2 mass transfer are co-regulated to simultaneously maintain homeostasis of pH, pCO2, and pO2.

The physiological importance of neurovascular coupling in maintaining homeostasis of pH, pCO2, and pO2 depends upon the sensitivity of brain function to these parameters. The critical importance of pCO2 homeostasis for brain cognitive and electrical function has been long known from patient studies.

There are multiple mechanisms that may explain the deleterious effects of elevated tissue pCO2 on brain function. [...] It has been shown both in vitro and in vivo that changes in cellular and interstitial pH can alter neuronal signaling through the modulation of multiple receptors, ion channels, and metabolic enzymes. Additionally, there is experimental evidence for a direct effect of CO2, on brain function independent of pH. Changes in pH and pCO2, also directly impact metabolic reactions that involve protons and CO2, leading to changes in the concentration of glutamate and other metabolite/neurotransmitter pools, the phosphocreatine/creatine ratio, and metabolic fluxes such as glycolysis. Regulation of extracellular pH is particularly critical for neurotransmitter receptor function, as protons reduce both glutamate and GABA ionotropic receptor conductance. [...] Furthermore, astrocytic gap junctions, potassium-induced stimulation of glutamate uptake, and neuronal acetylcholine receptors all work more efficiently at slightly alkaline pH.

 

[SNT Gatchaman]

More papers on theories and mechanisms —

Neurovascular Uncoupling Is Linked to Microcirculatory Dysfunction in Regions Outside the Ischemic Core Following Ischemic Stroke (2023, Journal of the American Heart Association)
Emerging Links between Cerebral Blood Flow Regulation and Cognitive Decline: A Role for Brain Microvascular Pericytes (2022, Aging and disease)
Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease (2022, Brain) - linked above by @livinglighter
Revisiting the neurovascular unit (2021, Nature Neuroscience)
Interpericyte tunnelling nanotubes regulate neurovascular coupling (2020, Nature)
Caveolae in CNS arterioles mediate neurovascular coupling (2020, Nature)
Glial and neuronal control of brain blood flow (2010, Nature)

 

[SNT Gatchaman]

Evidence suggesting abnormalities of neurovascular coupling in ME/CFS/LC —

Altered brain connectivity in Long Covid during cognitive exertion: a pilot study (2023, Frontiers in Neuroscience)
Changes in Brain Activation Pattern During Working Memory Tasks in People With Post-COVID Condition and Persistent Neuropsychiatric Symptoms (2023, Neurology)
Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Frontiers in Neuroscience)
Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS: a systematic review (2020, Journal of Translational Medicine)
Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome (2018, Brain Connectivity)
Brain function characteristics of chronic fatigue syndrome: A task fMRI study (2018, NeuroImage: Clinical)

 

[livinglighter]

Thank you very much for putting this thread together @SNT Gatchaman

 

[livinglighter]

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Frontiers in Neuroscience)

Chronic fatigue syndrome had blunted activity throughout the cerebrum compared to controls before and after exercise except for within the mPFC. Increased signal in the mPFC has been associated with the fatigue in TBI and during processing of fatigue as a sensation (Pardini et al., 2010; Tajima et al., 2010). A similar finding of elevated anterior DMN activation during a low cognitive load task following exercise was also found in Gulf War Illness (GWI) (Rayhan et al., 2019). GWI is a chronic disease affecting approximately 25% of the veterans who served in the 1991 Persian Gulf War (Fukuda et al., 1998; Steele, 2000; White et al., 2016). CFS and GWI have similar symptoms of fatigue, cognitive dysfunction and post-exertional malaise (Rayhan et al., 2019; Washington et al., 2020a, b).

I think I am late to the party, but I didn't know it had been said that pwGWI also suffer from PEM.

 

[SNT Gatchaman]

See BOLD signal changes can oppose oxygen metabolism across the human cortex (2025) —

CMRO2 is cerebral metabolism of oxygen
CBF is cerebral blood flow
CBV is cerebral blood volume
OED is oxygen extraction fraction
GM is grey matter

The canonical haemodynamic response is as above: that increased neuronal activity requires increased oxygen and is directly correlated with increased regional blood flow.

n-ratio is the positive neurovascular coupling, ie ∆CBF/∆CMRO2. BOLD imaging relies on blood flow increase with more oxygen than is needed to indicate the increased neuronal activity, ie the n-ratio is >1.

From that paper —

The Davis model predicts BOLD signal amplitudes for realistic ranges of ∆CMRO2 and ∆CBF in the human brain. Despite it being published more than 20 years ago, no study has examined the model’s accuracy across the human cortex. Intriguingly, the Davis model predicts a range of discordant positive and negative ΔBOLD for biologically plausible ΔCBF in relation to ΔCMRO2.

For all voxels with concordant positive and negative ∆BOLD, we observed a canonical hemodynamic response with average n-ratios of 2.0 and 1.6, respectively. Our data also confirm the presence of a substantial number of discordant voxels, comprising 31% of voxels with positive and 66% of voxels with negative ΔBOLD for CALC versus CTRL, and similarly for the REST and the MEM condition. Additionally, we recalculated ΔCMRO2 via the Davis model using parameters (α, M) derived from our own data, yielding a similar percentage and regional distribution of discordant voxels, along with comparable CMRO2 responses. In conclusion, these results strengthen the reliability of the mqBOLD approach, successfully validating the decades-old model parameters of the Davis model.

Discordant voxels occurred for both positive and negative ∆BOLD, as well as for ∆CMRO2 derived from Fick’s formula and the Davis model. The presence of both concordant and discordant responses within identical voxels implies different hemodynamic mechanisms serving varying oxygen demands.

According to Fick’s principle, a change in CMRO2 without CBF alteration arises from ∆OEF.

Fick's principle is VO2 = CO x [CaO2 - CvO2]. For cerebral metabolic oxygen calculations VO2 translates to CMRO2, CO translates to CBF and instead of the difference between arterial and venous O2 concentration, it uses the arterial concentration x the oxygen extraction fraction. The paper summarises as —

CMRO2 = OEF × CBF × CaO2
where CaO2 is CaO2 = 0.334 × Hct × 55.6 × O2sat
→ CMRO2 = OEF × CBF × 0.334 × Hct × 55.6 × O2sat

We hypothesized that baseline OEF varies across voxels with different hemodynamic response types, suggesting the presence of regionally varying oxygen buffers. Our findings confirmed significantly different baseline OEFs across three response types among ‘conjunction voxels’. Baseline OEF was lowest in ‘discordant only’ voxels and highest in ‘concordant only’ voxels, with ‘mixed’ voxels in between. We also observed a significant positive linear relationship between baseline CMRO2, CBF and OEF across voxels of all tasks, covering more than 50% of all GM voxels.

Multiple linear regression showed that OEF accounts for the majority of baseline CMRO2 variability (>68%), followed by CBF (>28%) and CBV (>1%) […] Collectively, our results suggest that OEF is a key modulator of baseline metabolism across the human cortex, potentially predicting regional hemodynamic responses during task.

In line with baseline results, multiple linear regression revealed that ∆OEF significantly contributes (58% of the total explained variance) to task-related oxygen demand in discordant voxels. Conversely, concordant voxels primarily accommodate ∆CMRO2 through ∆CBF (87%), supporting the canonical hemodynamic response.

In summary, OEF is a strong predictor of baseline metabolism across the cortex, and ∆OEF regulates oxygen demand in spatially distributed voxels.

Contrary to the canonical BOLD response model, we found that approximately 40% of brain voxels with significant ∆BOLD exhibited opposing changes in oxygen metabolism. Specifically, voxels with positive ∆BOLD showed decreased ∆CMRO2, whereas those with negative ∆BOLD exhibited increased ∆CMRO2. By measuring the BOLD signal, CBF, OEF and CMRO2 in the same session, we uncovered distinct neurovascular mechanisms in regions with concordant versus discordant responses. Discordant voxels primarily regulate oxygen demand via ∆OEF, whereas concordant voxels display a larger increase in ∆CBF, aligning with canonical predictions. Moreover, discordant voxels demonstrated lower baseline CMRO2 and OEF, indicating that their baseline oxygen supply is sufficient to meet higher metabolic demands. In conclusion, we identified two distinct hemodynamic responses to neuronal activity changes, influenced by baseline OEF and metabolism.

Reformatting their concluding paragraph —

Our study reveals spatial variability in hemodynamic changes across the human cortex, suggesting diverse underlying mechanisms.

• First, voxels primarily governed by ∆OEF exhibit a greater oxygen buffer, maintaining adequate oxygen pressure during tasks.
  
  
• Second, OEF regulation may indicate different signaling mechanisms, including astrocytic activity, shifts in excitatory/inhibitory signaling or neuromodulatory regulation.
  
  
• Third, our findings underscore the importance of quantitative mqBOLD fMRI for future research, particularly when examining groups with altered hemodynamics, such as in aging or neurodegenerative conditions.