The brain corresponds to only 2% of the body weight but requires 15 to 25% of the cardiac output^1,2), with a cerebral blood flow (CBF) corresponding to 40–50 mL /100g of brain tissue/ min, for which oxygen and nutrients are supplied¹⁾. The cerebral autoregulation process consists of a homeostatic mechanism responsible for maintaining a constant and effective CBF based on blood pressure, to which the cerebral vessels react to contribute to said regulation³⁾. Due to the great cerebral metabolic demand, it is to be expected that most brain disorders and neurodegenerative diseases are due to alterations in the cerebral blood supply⁴⁾. In this review, concepts of interest in the physiology of the CSF will be pointed out, such as the self-regulation process and its neuronal mechanisms, as well as the alterations that the CSF can present in pathological situations. Table 1 summarizes the key differences between the two responses, focusing on their definitions.

Cushing’s triad is characterized by a classic set of symptoms that indicate increased ICP and potential brain herniation. The triad includes hypertension (Elevated blood pressure due to compensatory mechanisms as ICP increases), bradycardia (Slowing heart rate due to a reflex response to hypertension), and irregular or abnormal respirations, manifesting as Cheyne-Stokes respiration or other irregular patterns). The mechanism is that as there is an increase in ICP, cerebral structures, and blood vessels compress, leading to impaired cerebral perfusion reflecting in raised ICP with hypertension and, in response, bradycardia and abnormal respiration due to brainstem compression). The clinical relevance of Cushing's triad includes a significant brain injury or mass effect requiring immediate intervention. CNS Ischemic Response.

CNS Ischemic Response is a reflexive response of the central nervous system to reduce cerebral blood flow (CBF) during severe ischemia. It occurs when there is a significant drop in cerebral perfusion pressure (CPP), often due to systemic hypotension or increased ICP. There is associated increased sympathetic activity attempting to maintain cerebral perfusion by increasing systemic vascular resistance (SVR), leading to elevated blood pressure. In response to local metabolic needs, vasodilation in ischemic brain areas enhances blood flow, and an overall sympathetic tone can counteract it. Physiological responses include increased heart rate, elevated blood pressure, and possibly bradycardia as a late response to severe ischemia. The clinical relevance of these changes includes a critical state of cerebral hypoperfusion, requiring immediate medical intervention to restore blood flow. Cerebral blood flow, neurovascular coupling, and autoregulation.

CBF is understood as the percentage of blood that irrigates the brain tissue, which constantly changes the dynamics of its functioning due to factors such as body position, blood pressure, cardiac output, nerve stimulation, and neurovascular coupling^1,2,4,5). One of the most critical mechanisms when studying CBF is neurovascular coupling, defined as the relationship between metabolic demand and CBF, that is, the higher the energy consumption, the more significant the contribution of blood flow to brain tissue.^2,4,5) The metabolic consumption of cerebral oxygen (CMRO), which corresponds to a value between 4-6ml/100g/min, 40% being the basal energy expenditure (GEB), which is not modified by drugs, and the remaining 60%, functional energy expenditure (GEF), susceptible to pharmacological treatment. CMRO can also be influenced by cerebral vascular resistance (CVR) and cerebral perfusion pressure (CPP) ¹⁾.

CPP is defined as the difference between mean arterial pressure (MAP) and intracranial pressure (ICP), with values between 80 and 100 mmHg considered normal.¹⁾ Understanding that any condition that increases MAP or decreases ICP will alter CPP and, therefore, the irrigation of brain tissue. Oxygen and glucose are not determinants of increasing or decreasing CBF⁶⁾. On the other hand, the modification of the CVR, mediated by the astrocytes that come into direct contact with the endothelium of the cerebral arteries or arterioles, which release vasodilator substances such as nitric oxide (NO) that spread through the gap junctions to diffuse the signal and thus generalize a vasodilator response, can increase CBF^5,7). Said adaptation process is called self-regulation, whose main premise is the modification of the CVR, (2) taking metabolic demand as a trigger in this case. When MAP increases or decreases, the CVR is modified to dampen the changes in CBF^1,2). This is how hypotension promotes vasodilation⁸⁾ to perpetuate blood flow that reaches the brain.

One of the variables with the greatest impact on CBF is arterial blood gases, more specifically, CO₂ and O₂, because cerebral blood vessels are highly sensitive to fluctuations in these compounds—especially CO₂^5,8). Changes in the latter are mediated by the local action of CO₂ in this tissue through changes in extracellular pH⁵⁾. It must be clarified that even when the autoregulation due to changes in PaCO₂ is mediated by pH, its own or induced changes in the blood will not affect CBF⁸⁾. Hypercapnia induces vasodilatation and, with it, an increase in CBF and cerebral oxygen delivery (CDO). In contrast, in hypocapnia, there is vasoconstriction and, therefore, a decrease in CBF and CDO^1,2,5,8,9). On the other hand, hypoxia promotes vasodilation (6) and hyperoxia induces vasoconstriction^8,9). Substances such as prostaglandins (PGE₂), NO^2,9), prostacyclin I², and endothelium-derived hyperpolarizing factor (EDHF) promote vasodilation, while thromboxane A₂ and prostaglandin F2_a, induce vasoconstriction⁹⁾.

The mechanisms of the nervous system to regulate blood flow could be better perceptible and, in some cases, unclear^5,7,8,10). However, sympathetic stimulation certainly plays a fundamental role in regulating CBF, but the mechanism by which it does so has not yet been fully elucidated^2,5). The effect of catecholamines on CBF is more related to homeostatic side effects due to the presence of the neurotransmitter in the circulation and not to a direct effect on the cells of the blood vessel since the blood-brain barrier limits the passage of catecholamines to the CBF—smooth muscle of the vessel wall⁸⁾. Other neurotransmitters such as histamine, acetylcholine, and vasoactive intestinal peptide (VIP) have been studied in vitro without being able to do so in human models. Acetylcholine and VIP produce a relaxation or dilation of the cerebral blood vessels, in contrast to histamine, which generates a contraction of these⁸⁾. Sympathetic stimulation has a slight or almost zero effect when intervening in the dynamics of the CBF^5,8,10). Conversely, cholinergic stimulation seems to modulate vasodilation when faced with a hypercapnic and/or hypoxic stimulus⁸⁾.

Certain drugs can enhance or inhibit stimuli involved in the autoregulation of CBF, influenced by the functional energy expenditure of CMRO. This allows the efficacy or necessity of specific compounds or mechanisms to be assessed when initiating a response that alters CBF. The inhibition of the enzyme nitric oxide synthase and, therefore, the synthesis of NO, with N-monomethyl-L-arginine (L-NMMA) did not alter the vasodilator response to these stimuli in young adults⁹⁾, allowing us to understand that this substance helps in the process, but is not essential for its realization. The cyclooxygenase enzyme, responsible for producing prostaglandins, prostacyclins, and thromboxanes, is selectively and non-selectively inhibited by celecoxib and indomethacin, respectively. However, cyclooxygenase does not produce a response to hypoxia. Indomethacin decreases the response to hypercapnia⁹⁾, suggesting that, although these two conditions have similar responses, their mechanism of action has certain differences. Adenosine, another potent vasodilator, favors the relaxation of blood vessels when applied in vitro to human and animal models. However, in dogs and cats, its effect on CBF is diminished by the blood-brain barrier that controls the entry of this nucleoside. This, in addition, can be inhibited by theophylline⁸⁾. Nimodipine is a drug that blocks L-type calcium channels (important in vasodilation). Although it does not appear to modify the effects of CBF⁹⁾, it has been shown to have beneficial effects on morbidity and mortality after subarachnoid hemorrhage that could end in an ischemic stroke¹⁰⁾. The vasoreactivity to arterial gases can be positively modified when a lymph node blockade occurs with trimetaphan^5,10), in this way, stimuli that were previously weak, such as the sympathetic, can be potentiated to even attenuate or stop response to hypercapnia.

In contrast, administering an alpha-agonist, such as ephedrine, or an alpha/beta antagonist, such as labetalol, does not impact vasoreactivity⁵⁾. The administration of a non-selective alpha blocker such as phentolamine slows down the autoregulatory response to different stimuli¹⁰⁾. Finally, a drug such as clonidine, an alpha-adrenergic receptor agonist, can delay the accelerated rise of natural CBF to hypercapnia¹⁰⁾.

The CBF can be altered in various physiological situations such as aging, adaptation to environmental changes, movement, or physical exercise^5,11-14). In fact, the cerebral vascular anatomy with the presence of curvatures and bifurcations in the arteries are the ones that most frequently alter the CBF, generating a loss of energy¹⁵⁾. It can also be affected in many pathologies such as neurodegenerative, neurological, and chronic diseases or in situations of hypoxia^9,16-19).

Cerebral blood flow gradually decreases in women and men during the normal aging process. This decrease can be related to a reduction in cerebral consumption of nutrients such as oxygen and glucose, as well as an alteration in cerebrovascular function²⁰⁾. Normally 15% of CO₂ is distributed to the brain in adults, however in older adults a decreasing proportion of CO₂ is attributed, causing a great vasodilatation of the cerebral arteries and arterioles which leads to an increase of the CBF secondary to the increase in blood velocity^12,20). Under resting conditions, the reduction in heart rate and mean arterial pressure causes a reduction in CBF in the elderly; on the contrary, in situations of greater cardiac output, it causes an increase in CBF, which is greater in the elderly than in young adults. , this increase indicates a concurrent decrease in cerebrovascular regulatory capacity and increased hemodynamic stress on the cerebral circulation in the elderly^12,20).

During aerobic exercise, the CBF must ensure an adequate amount of oxygen and nutrients, in addition to taking care of the control of blood pressure; therefore, the values of blood pressure, heart rate, cardiac output, oxygen consumption, and metabolism increase¹⁴⁾. However, during moderate-intensity exercise, CBF increases in brain areas responsible for movement due to increased brain metabolism. On the other hand, during high-intensity exercises, CBF decreases due to local hyperventilation and vasoconstriction of areas with activity in the lower part of the brain^13,14). The study by Hiura et al. used positron emission tomography (PET) to assess the changes in CBF during dynamic exercise, it was evaluated at different stages of the exercise: at the beginning, during, and after the exercise; finding that at the beginning of the exercise the global CBF increased by 13% compared to the rest, and compared to rest the regional FCS increased in the brain stem, insular cortex and basal ganglia. After exercise, the phenomenon of post-exercise hypotension occurs. Therefore, the regional CBF decreases¹¹⁾. Due to the poor absorption of glucose and the increase in lactate during exercise, the CBF can be altered; hyperthermia during exercise can generate central fatigue and hypoglycemia¹³⁾.

Chronic diseases such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and Arterial Hypertension (AHT) can generate alterations that affect brain perfusion and function^9,18,21). CKD is characterized by its repercussions on blood pressure and hematopoiesis, which can significantly affect brain function. CKD is also associated with ischemic disease in adults and with neurocognitive and brain development alterations in children^18,22). In patients with CKD, due to the decrease in the production of erythropoietin, chronic anemia is generated, which in turn can cause damage at the endothelial level due to an increase in flow and greater metabolic demand^18,23). In addition to global CBF alterations, there are also regional CBF alterations, which have been associated with changes in neurocognitive performance. Other studies have reported reduced glomerular filtration rate and increased CBF in patients with CKD¹⁸⁾. The regulation of CBF is very important in hypoxic situations; cerebrovascular sensitivity to hypoxia is evaluated as the change in heart rate during a hypoxic event and shows the ability of the brain vessels to compensate for the lack of oxygen (O₂). This capacity is reduced in patients with COPD^9,24). During hypoxia, the partial pressures of oxygen (PO₂) decrease; therefore, those of carbon dioxide (PaCO₂) increase, both PO₂ and PaCO₂ act as regulators of the CBF; in situations of hypercapnia, the CBF increases perfusion due to to the lack of O₂^9,25). It is known that increasing PaCO₂ directly increases CBF. However, it is still not entirely clear about the impact of hypercapnia and hypoxia on CBF in people with COPD⁹⁾.

CBF alterations have been evaluated in patients with neurodegenerative diseases^16,26), Kapitan et al. reported regional CBF alterations in subjects with Parkinson's using ^{99m Tc-ECD} cerebral single-photon emission computed tomography (SPECT), a significant decrease in perfusion of brain regions such as the premotor cortex and cortex was detected. Posterior parietal in both hemispheres, due to disease-related motor disorders and deafferentation of the connections between the parietal and motor cortex, rectifies the reduction of dopamine neurons in the substantia nigra region, characteristic of the pathophysiology of the disease^16,27). Hypoperfusion has also been reported in the thalamus, subthalamic regions, and areas of the basal ganglia, but this was more significant in the advanced stages of the disease²⁷⁾. As a compensatory mechanism for movement disorders and involvement of the nigro -striatal circuit, an increase in cerebral perfusion was found in areas of the cerebellum, the cerebellar dentate nucleus, the left insula, and paralimbic structures, which have important connections with the dopaminergic system¹⁶⁾. Significant hypoperfusion of posterior temporal and bilateral parietal areas has been found in patients with Alzheimer's; this decrease reflects the presence of cognitive impairment¹⁶⁾. In the study by Arias et al. the differences in the regional CBF between patients with mild cognitive impairment (MCI) and healthy people (control group) were characterized, the CBF was evaluated through cerebral SPECT and it was found that in the group with MCI there was decreased blood flow when compared with the results of the control group (P<0.05), especially in the left temporal regions: the upper and middle temporal pole, in the hippocampus and Heschl's gyrus; Hypoperfusion was also observed in limbic areas such as the left parahippocampus and right posterior cingulate. In this structure, the evaluation of the regional CBF is important due to the possibility of transition from MCI to Alzheimer's disease^26,28). Left parietal areas, such as the inferior and supramarginal parietal zone and the left insula, also decreased CBF²⁶⁾.

The CNS ischemic response and Cushing's triad are critical physiological responses associated with increased intracranial pressure (ICP) and brain ischemia, but they involve different mechanisms and clinical implications. It is important to know the mechanisms the brain requires for self-regulation and provision of oxygen and nutrients. On the other hand, thanks to the advancement of biotechnology, it has been possible to implement neuromonitoring methods for the evaluation of CBF, to demonstrate alterations at the regional level in various pathological situations, as well as to increase knowledge of its dynamic alterations in situations changing physiological conditions such as aging or physical exercise.