CBF & Exercise Hemodynamics

Question 1

What is cerebral blood flow (CBF)?

Answer 1

Cerebral blood flow (CBF) refers to the amount of blood passing through a given amount of brain tissue per unit of time. It is essential for delivering oxygen and nutrients to brain tissues and removing metabolic waste products. Proper CBF is critical for maintaining normal brain function and overall neuronal health (Shaw, 2002; Meaney & Smith, 2011).

Question 2

What are the 3 major arteries in the brain, and which regions do they perfuse?

Answer 2

• Anterior cerebral artery (ACA):
  ○ Anterior corpus callosum: communication between hemispheres.
  ○ Anterior cingulate cortex: emotional regulation, decision-making, and autonomic functions.
  ○ Medial prefrontal cortex: cognitive processes, such as planning, decision-making, and social behavior.
• Middle cerebral artery (MCA):
  ○ Primary motor cortex: voluntary movements of the body.
  ○ Primary sensory cortex: Sensory information processing, such as touch, pressure, and proprioception.
  ○ Broca’s area: speech production and language processing.
  ○ Wernicke’s area: language comprehension.
  ○ Auditory cortex: auditory information, hearing and interpreting sounds.
  ○ Lateral prefrontal cortex: executive functions, such as working memory, cognitive flexibility, and decision-making.
• Posterior cerebral artery (PCA):
  ○ Primary visual cortex: visual information from the eyes.
  ○ Visual association areas: object recognition and spatial processing.
  ○ Hippocampus: memory formation, consolidation, and spatial navigation.
  ○ Inferior temporal lobe: visual object recognition and memory.

Question 3

Describe the relationship between CBF and the metabolic demands of the body. Touch on neurovascular coupling and cerebral autoregulation

Answer 3

• CBF is tightly regulated to match the brain’s metabolic demands. During increased neuronal activity, such as during cognitive tasks or physical exercise, the brain’s need for oxygen and glucose rises, leading to an increase in CBF. This relationship is mediated by cerebral autoregulation mechanisms, which adjust vessel diameter to maintain consistent perfusion despite systemic blood pressure changes (Giza & Hovda, 2014).
• Neurovascular coupling: The brain’s metabolic demands are directly linked to neuronal activity. When a specific brain region is activated during a cognitive task or physical activity, the neurons in that area require more energy. This increased energy demand triggers a process called neurovascular coupling, where the local blood vessels dilate, allowing more blood to flow to the active brain region. This mechanism ensures that the active neurons receive the necessary oxygen and glucose to function optimally (Attwell et al., 2010).
• Cerebral autoregulation: CBF is maintained relatively constant within a wide range of systemic blood pressures through a process called cerebral autoregulation. This mechanism ensures that the brain receives a consistent blood supply despite fluctuations in blood pressure. Cerebral autoregulation is achieved by adjusting the diameter of the blood vessels in response to changes in blood pressure. When blood pressure increases, the blood vessels constrict to maintain a steady CBF; conversely, when blood pressure decreases, the blood vessels dilate to maintain adequate perfusion (Paulson, Strandgaard, & Edvinsson, 1990).
• Metabolic demands during exercise: During physical exercise, the body’s metabolic demands increase significantly. The brain must work harder to coordinate movement, maintain balance, and regulate autonomic functions such as heart rate and breathing. As a result, the brain’s metabolic demands also increase during exercise. To meet these increased demands, CBF increases globally, with some regional variations depending on the type and intensity of the exercise (Smith & Ainslie, 2017).
  Regional differences in metabolic demands: Different brain regions have varying metabolic demands based on their functions and activity levels. For example, the primary visual cortex has a higher metabolic demand compared to other cortical areas due to its constant activity in processing visual information. Similarly, during cognitive tasks that engage specific brain regions, such as the prefrontal cortex during working memory tasks, those regions exhibit increased metabolic demands and, consequently, increased CBF (Raichle & Gusnard, 2002).

Question 4

Are there any biological sex differences in CBF and perfusion levels in a healthy population?

Answer 4

• Yes, biological sex differences exist in CBF and perfusion levels, with women generally exhibiting higher resting CBF compared to men. These differences are influenced by hormonal factors, particularly estrogen, and can vary across brain regions. Cerebrovascular reactivity also differs between sexes, with women showing higher reactivity. These differences may have implications for the prevalence and outcomes of neurological disorders.
• Higher CBF in women: Women generally have higher resting CBF compared to men. This difference has been observed in both global and regional CBF measurements. A meta-analysis by Gur and Gur (1990) found that women had approximately 13% higher CBF than men, after controlling for factors such as age and brain size. This difference was most pronounced in younger adults and decreased with age.
• Hormonal influences: The higher CBF in women is likely influenced by hormonal factors, particularly estrogen. Estrogen has vasodilatory effects on cerebral blood vessels, which can increase CBF. In premenopausal women, CBF fluctuates throughout the menstrual cycle, with higher levels observed during the follicular phase when estrogen levels are high (Brackley et al., 1999).
• Regional differences: Sex differences in CBF are not uniform across all brain regions. Some studies have found that women have higher perfusion in specific areas, such as the limbic system and the parietal lobes (Liu et al., 2012). These regional differences may be related to sex-specific cognitive and emotional processing.
• Cerebrovascular reactivity: Biological sex also influences cerebrovascular reactivity, which is the ability of blood vessels to dilate or constrict in response to changes in blood CO2 levels. Women have been shown to have higher cerebrovascular reactivity compared to men, particularly during the follicular phase of the menstrual cycle (Kastrup et al., 1999). This increased reactivity may provide a protective effect against ischemic injury.

Question 5

What is cerebrovascular reactivity and what causes some to be more reactive than others

Answer 5

Cerebrovascular reactivity (CVR) refers to the ability of the blood vessels in the brain to respond and adapt to changes in the level of carbon dioxide (CO2) in the blood. It is a measure of the brain’s ability to regulate its blood flow in response to changes in CO2levels.

Factors that can influence cerebrovascular reactivity:

1. Age:
   
   • Older individuals tend to have decreased cerebrovascular reactivity compared to younger individuals.
   • This is thought to be due to age-related changes in the structure and function of the blood vessels in the brain.
2. Sex:
   
   • Females generally have higher cerebrovascular reactivity compared to males.
   • This may be due to differences in hormonal factors and vascular anatomy between genders.
3. Cardiovascular health:
   
   • Individuals with cardiovascular diseases, such as hypertension, atherosclerosis, or stroke, often have impaired cerebrovascular reactivity.
   • Cardiovascular conditions can lead to structural and functional changes in the brain’s blood vessels, reducing their ability to respond to changes in CO2 levels.
4. Neurological conditions:
   
   • Certain neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury, have been associated with altered cerebrovascular reactivity.
   • These conditions can affect the brain’s vascular function and the ability to regulate blood flow.
5. Lifestyle factors:
   
   • Smoking, physical inactivity, and poor dietary habits can contribute to decreased cerebrovascular reactivity.
   • These factors can impact the overall vascular health and function.
6. Genetic factors:
   
   • Some individuals may have a genetic predisposition to having higher or lower cerebrovascular reactivity.
   • Genetic variations can influence the structure and function of the brain’s blood vessels.

Individuals with higher cerebrovascular reactivity are better able to adjust their blood flow in response to changes in CO2 levels, which is important for maintaining optimal brain function and oxygenation. Decreased cerebrovascular reactivity, on the other hand, can be a marker of impaired vascular function and may contribute to the development or progression of various neurological and cardiovascular conditions.

Question 6

Are there biological sex differences in CBF responses and alterations in response to an SRC?

Answer 6

• Yes, there is evidence to suggest that biological sex differences in cerebral blood flow (CBF) and perfusion exist in concussed populations. Although research in this specific area is limited, several studies have investigated sex differences in CBF following concussions.
• Acute post-concussion period: A study by Fakhran et al. (2014) used CT perfusion imaging to examine sex differences in CBF within 72 hours of a concussion. They found that concussed females had significantly higher CBF compared to concussed males in the acute post-concussion period. This difference was most pronounced in the frontotemporal regions and was associated with more severe symptoms in females.
• Chronic post-concussion period: Sex differences in CBF have also been observed in the chronic post-concussion period. A study by Barlow et al. (2017) used arterial spin labeling (ASL) MRI to measure CBF in male and female adolescents at 1-month post-concussion. They found that concussed females had higher regional CBF compared to concussed males in several brain regions, including the right fusiform gyrus, right precentral gyrus, and left inferior temporal gyrus.
• Longitudinal changes: A longitudinal study by Militana et al. (2016) investigated changes in CBF using ASL MRI in male and female athletes at baseline (pre-concussion), 1-day, 1-week, and 1-month post-concussion. They found that concussed females had higher CBF at 1-day post-concussion compared to concussed males. However, these differences were not significant at later time points, suggesting that sex differences in CBF may be most pronounced in the acute post-concussion period.
• Relationship with symptoms: Sex differences in CBF following concussions have been associated with differences in symptom severity and duration. The study by Fakhran et al. (2014) found that higher CBF in concussed females was associated with more severe symptoms, particularly in the domains of fatigue and cognition. Similarly, the study by Barlow et al. (2017) found that higher regional CBF in concussed females was associated with more severe symptoms and longer recovery times.

Question 7

If the Neurometabolic Cascade by Giza & Hovda states that CBF decreases within the first 10 days postinjury, why do some studies show elevated CBF, and particularly in females?

Answer 7

• The neurometabolic cascade of concussion, as described by Giza and Hovda (2014), suggests that there is a period of reduced CBF in the acute post-concussion period, typically lasting up to 10 days. This reduction in CBF is thought to be due to the mismatch between increased energy demand and decreased energy supply following a concussion.
• The findings of higher CBF in concussed females compared to males in the acute post-concussion period may seem contradictory to this model. However, there are several potential explanations for this apparent discrepancy:
• Timing of CBF measurements: The timing of CBF measurements in studies examining sex differences may not capture the initial period of reduced CBF described in the neurometabolic cascade. For example, the study by Fakhran et al. (2014) measured CBF within 72 hours of a concussion, which may be outside the window of maximum CBF reduction.
• Severity of concussion: The severity of the concussion may influence the degree and duration of CBF reduction. If females tend to have milder concussions compared to males, they may have a shorter period of reduced CBF or a faster return to baseline CBF levels. However, the relationship between concussion severity and CBF is not well understood and requires further research.
• Baseline sex differences in CBF: Females have higher baseline CBF compared to males. This higher baseline CBF may influence the post-concussion CBF response. Even if females experience a reduction in CBF following a concussion, their absolute CBF levels may still be higher than males due to their higher baseline values.
• Hormonal influences: Hormonal factors, particularly estrogen, may modulate the CBF response following a concussion. Estrogen has been shown to have neuroprotective effects and may attenuate the reduction in CBF following a concussion (Roof & Hall, 2000). The higher estrogen levels in females may contribute to their higher CBF in the acute post-concussion period.
• Limitations of the neurometabolic cascade model: The neurometabolic cascade of concussion is a simplified model of a complex pathophysiological process. It may not fully capture the heterogeneity of concussion responses and the influence of individual factors such as sex. More research is needed to refine this model and incorporate sex-specific differences in CBF and other physiological parameters.

Question 8

Describe CBF changes throughout the menstrual cycle.

Answer 8

• Cerebral blood flow (CBF) fluctuates throughout the menstrual cycle due to hormonal changes, particularly in estrogen and progesterone levels:
• Menstrual phase (days 1-5): Both estrogen and progesterone levels are low, and CBF may be relatively lower compared to other phases.
• Follicular phase (days 1-14): Estrogen levels gradually rise, peaking just before ovulation. Estrogen’s vasodilatory effects lead to increased CBF, which can be up to 20% higher compared to the early follicular phase.
• Ovulatory phase (around day 14): Estrogen levels reach their peak, while progesterone remains low. CBF is likely to be at its highest during this brief 24-48 hour phase.
• Luteal phase (days 15-28): Progesterone levels rise and become dominant. Progesterone’s vasoconstrictive properties may lead to a decrease in CBF, but the effects are less well-established and may be influenced by the estrogen-to-progesterone ratio.
  These CBF changes have been observed in various brain regions and are linked to alterations in cognitive function, emotional processing, and susceptibility to certain neurological disorders.

Question 9

Describe hypoxia and its relationship with CBF.

Answer 9

• Hypoxia refers to a state of reduced oxygen supply to the tissues. In the context of the brain, hypoxia occurs when there is a decrease in the partial pressure of oxygen (PaO2) in the arterial blood. When the brain experiences hypoxia, it triggers a compensatory response to increase CBF in order to maintain adequate oxygen delivery to the brain tissue.
• The increase in CBF during hypoxia is mediated by several mechanisms, including:
• Dilation of cerebral blood vessels: Hypoxia causes the release of vasodilatory substances, such as nitric oxide and adenosine, which relax the smooth muscles of cerebral blood vessels, leading to increased CBF.
• Decreased cerebrovascular resistance: Hypoxia reduces the resistance of cerebral blood vessels, allowing for greater blood flow.
• Increased cardiac output: Hypoxia can stimulate the cardiovascular system to increase cardiac output, which contributes to increased CBF.
• The extent of CBF increase during hypoxia varies depending on the severity and duration of the hypoxic episode. Acute and severe hypoxia can lead to a more pronounced increase in CBF compared to chronic and mild hypoxia.

Question 10

Describe hypercapnia and its relationship with CBF.

Answer 10

• Hypercapnia: Hypercapnia refers to an elevated level of carbon dioxide (CO2) in the blood. CO2 is a potent vasodilator, and an increase in arterial CO2 partial pressure (PaCO2) leads to a significant increase in CBF.
• The relationship between PaCO2 and CBF is nearly linear within the physiological range. For every 1 mmHg increase in PaCO2, CBF increases by approximately 2-4%.
  This response is mediated by the following mechanisms:
• Decreased pH: CO2 readily diffuses across the blood-brain barrier and forms carbonic acid, which dissociates into hydrogen ions (H+) and bicarbonate (HCO3-). The increased H+ concentration lowers the pH of the cerebral extracellular fluid, causing vasodilation and increased CBF.
• Activation of chemoreceptors: Central chemoreceptors in the brainstem detect changes in pH and PaCO2, triggering a vasodilatory response to increase CBF.

The CBF response to hypercapnia is rapid, occurring within seconds of the increase in PaCO2. This response is an important regulatory mechanism that helps maintain pH homeostasis and ensures adequate blood supply to the brain during conditions that increase CO2 production, such as exercise.

Question 11

Describe one study that proves that an increase in CBF is a candidate mechanism for a post-exercise improvement in EF

Answer 11

A study by Tari et al., (2020) investigated the mechanism behind improved executive function after aerobic exercise. Participants completed sessions of exercise, hypercapnia, and control conditions. The hypercapnic condition was included because it produces an increase in CBF independent of metabolic demands. An estimate of CBF was achieved via TCD and NIRs that provided measures of middle cerebral artery blood velocity (BV) and deoxygenated hemoglobin (HHb), respectively. Exercise and hypercapnia showed comparable changes in CBF metrics and improved reaction times in antisaccades. Accordingly, results evince that an increase in CBF represents a candidate mechanism for a postexercise improvement in executive function

Question 12

What physiological conditions disrupt regular CBF?

Answer 12

• Several physiological conditions can disrupt regular cerebral blood flow (CBF), leading to various consequences:
• Hypertension (high blood pressure): This condition can impair cerebral autoregulation, the brain’s ability to maintain constant blood flow despite changes in blood pressure. Chronic hypertension can lead to structural changes in cerebral blood vessels, increasing the risk of cerebrovascular damage, such as stroke or aneurysms.
• Hypotension (low blood pressure): When blood pressure drops significantly, it reduces perfusion pressure, which is the force driving blood through the cerebral vasculature. Inadequate perfusion pressure can lead to cerebral ischemia, where brain tissue receives insufficient blood flow, potentially causing neuronal damage or dysfunction.
• Hypercapnia (elevated blood CO2 levels) and Hypocapnia (low blood CO2 levels): Carbon dioxide is a potent vasodilator in the cerebral vasculature. Elevated CO2 levels cause cerebral blood vessels to dilate, increasing CBF. Conversely, low CO2 levels lead to vasoconstriction, reducing CBF. Extreme changes in blood CO2 levels can disrupt normal CBF regulation.
  Hypoxia (low blood oxygen levels): When the brain senses a decrease in blood oxygen levels, it triggers vasodilation to enhance oxygen delivery to brain tissue. However, severe or prolonged hypoxia can disrupt normal CBF regulation and lead to neuronal injury.

Question 13

Describe the relationship between heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP).

Answer 13

• Heart Rate (HR): This refers to the number of times the heart beats per minute. Heart rate directly influences cardiac output, which is the volume of blood pumped by the heart per minute. An increase in heart rate, such as during exercise or stress, leads to an increase in cardiac output, which can subsequently affect blood pressure and CBF.
• Systolic Blood Pressure (SBP): SBP is the maximum pressure exerted on the arterial walls during the contraction phase of the cardiac cycle (systole). It reflects the force with which the heart pumps blood into the arteries. SBP is determined by the volume of blood ejected from the left ventricle and the elasticity of the arterial walls. Factors that increase SBP include increased cardiac output, increased peripheral resistance, and reduced arterial compliance.
• Diastolic Blood Pressure (DBP): DBP is the minimum pressure in the arteries between heartbeats, during the relaxation phase of the cardiac cycle (diastole). It indicates the resistance to blood flow within the blood vessels. DBP is influenced by the resistance in the peripheral arteries and the ability of the arteries to return to their original shape after being stretched during systole. Factors that increase DBP include increased peripheral resistance and reduced arterial elasticity.
• The relationship between HR, SBP, and DBP determines overall blood flow and perfusion, including to the brain. When HR increases, it typically leads to an increase in both SBP and DBP, as more blood is being pumped into the arteries. However, the relative changes in SBP and DBP can vary depending on the underlying cause of the increased HR and the individual’s cardiovascular health.
• For example, during exercise, HR and SBP typically increase more than DBP, resulting in a widened pulse pressure (the difference between SBP and DBP). This is because the increased cardiac output during exercise is partially offset by a decrease in peripheral resistance due to vasodilation in the exercising muscles.

Question 14

What is the average SBP and DBP in a healthy population? What would it mean if SBP and/or DBP is above and/or below average?

Answer 14

• The average SBP is around 120 mmHg, and the average DBP is around 80 mmHg in a healthy population. Elevated SBP and/or DBP indicate hypertension, increasing the risk of cardiovascular diseases and cerebrovascular events. Lower than average SBP and/or DBP suggest hypotension, which can lead to inadequate perfusion of organs and potentially cause dizziness or shock in severe cases (Giza & Hovda, 2014).

Question 15

What can cause a rapid change in SBP and DBP readings?

Answer 15

• Rapid changes in SBP and DBP can result from:
• Physical Activity: Increases heart rate and cardiac output, elevating blood pressure.
• Stress: Triggers adrenaline release, raising blood pressure.
• Postural Changes: Standing up quickly can cause transient blood pressure drops (orthostatic hypotension).
• Medications: Some drugs can rapidly alter blood pressure.
• Dehydration: Reduces blood volume, potentially lowering blood pressure.
  Acute Medical Conditions: Conditions like heart attack or severe infections can cause sudden blood pressure changes (Giza & Hovda, 2014).

Question 16

How and in what ways do the following factors influence CBF: exercise type (i.e., aerobic, non-aerobic), exercise intensity, exercise duration, and cardiovascular fitness?

Answer 16

• Exercise Type: a. Aerobic exercise, such as running, cycling, or swimming, typically leads to a significant increase in CBF. This is primarily due to the elevated cardiac output and increased metabolic demands of the brain during aerobic activity. The increase in CBF helps to supply the brain with oxygen and glucose to maintain proper functioning during exercise. b. Non-aerobic exercise, such as resistance training or weightlifting, may have less pronounced effects on CBF compared to aerobic exercise. However, some studies have shown that resistance training can still lead to acute increases in CBF, particularly in the regions of the brain associated with motor control and planning.
• Exercise Intensity: a. Higher exercise intensities generally result in greater increases in CBF compared to lower intensities. This is because higher-intensity exercises place a greater demand on the cardiovascular system to supply oxygen and nutrients to the working muscles and the brain. b. As exercise intensity increases, there is a corresponding increase in cardiac output and blood pressure, which contributes to the elevation of CBF. The brain’s metabolic demands also rise with increasing exercise intensity, requiring a higher blood flow to maintain adequate oxygen and glucose delivery.
• Exercise Duration: a. Prolonged exercise sessions can sustain elevated CBF levels as long as the metabolic demands remain high. During continuous aerobic exercise, CBF typically increases within the first few minutes and then reaches a steady state that is maintained throughout the duration of the activity. b. However, if exercise duration is extended to the point of dehydration or exhaustion, CBF may decrease due to a reduction in cardiac output and blood pressure. This highlights the importance of proper hydration and pacing during prolonged exercise to maintain optimal CBF and brain function.
  Cardiovascular Fitness: a. Individuals with higher levels of cardiovascular fitness tend to have more efficient cardiovascular responses to exercise, including greater increases in CBF. This is because regular aerobic exercise leads to adaptations in the cardiovascular system, such as increased stroke volume, capillary density, and improved endothelial function. b. Higher fitness levels are also associated with better cerebral autoregulation, which is the brain’s ability to maintain relatively constant blood flow despite changes in blood pressure. This means that fitter individuals may have better CBF regulation during exercise and be less susceptible to fluctuations in blood pressure. c. Additionally, long-term engagement in aerobic exercise has been linked to structural changes in the brain, such as increased gray matter volume and improved white matter integrity, which may contribute to better overall brain health and function (Heath et al., 2016; 2017).

Question 17

Does cbf continuously rise with increasing duration and intensity of exercise, and if not, at which timepoint does it plateau and decrease and why?

Answer 17

No, cerebral blood flow (CBF) does not continuously rise with increasing duration and intensity of exercise. It typically exhibits a biphasic response:

Initial increase in CBF:

During the early stages of exercise, CBF increases to meet the higher metabolic demands of the brain.
This is driven by the increased production of vasodilatory substances, such as adenosine, lactate, and nitric oxide, which cause the brain’s blood vessels to dilate and increase blood flow.
Plateau and potential decrease in CBF:

After the initial rise, CBF typically reaches a plateau or even begins to decrease with prolonged or more intense exercise.
This plateau or decline in CBF is observed after approximately 10-20 minutes of sustained physical activity.
The reasons for the plateau or decrease in CBF during prolonged or intense exercise include:

a. Autoregulation:

The brain’s autoregulatory mechanisms aim to maintain a relatively constant CBF despite changes in blood pressure and metabolic demands.
As exercise progresses, the brain’s autoregulatory mechanisms may limit the further increase in CBF to prevent excessive perfusion and potential damage to the brain’s blood vessels.
b. Redistribution of blood flow:

During exercise, blood flow is preferentially directed to the working muscles, which have a higher metabolic demand.
This redistribution of blood flow can lead to a relative decrease in CBF as the body prioritizes blood flow to the exercising muscles.
c. Metabolic factors:

Prolonged or intense exercise can lead to the accumulation of metabolic byproducts, such as carbon dioxide and hydrogen ions, which can cause cerebral vasoconstriction and limit the further increase in CBF.
d. Hormonal factors:

Exercise can trigger the release of hormones, such as catecholamines (e.g., epinephrine, norepinephrine), which can have a mixed effect on cerebral vasculature, potentially contributing to the plateau or decrease in CBF.
The specific timepoint at which the plateau or decrease in CBF occurs can vary depending on the individual, the intensity and duration of the exercise, and the overall cardiovascular and cerebrovascular health.

Question 18

Does increasing exercise intensity elevate the post-exercise executive function benefit as a result of increased CBF?

Answer 18

• The magnitude of CBF change during exercise appears to have no significant impact on the magnitude of post-exercise executive function improvements.
• The study by Tari et al. (2021) investigated the relationship between exercise intensity, cerebral blood flow (CBF), and post-exercise executive function. The researchers aimed to test the hypothesis that increasing exercise intensity would lead to greater improvements in executive function due to increased CBF (i.e., drive theory). In the study, participants completed four experimental sessions: a V̇O2peak test to determine cardiorespiratory fitness and estimated lactate threshold (LT), followed by separate 10-minute sessions of light-, moderate-, and heavy-intensity aerobic exercise. CBF was estimated using transcranial Doppler ultrasound to measure blood velocity (BV) through the middle cerebral artery and near-infrared spectroscopy to measure deoxygenated hemoglobin (HHb). Executive function was assessed before and after each session using the antisaccade task.
• The results showed that BV increased with increasing exercise intensity, indicating a higher CBF at higher intensities. However, HHb decreased by a similar magnitude across all exercise intensities. Regarding executive function, the study found a comparable reduction in antisaccade reaction time after exercise, regardless of the intensity level.
• These findings suggest that while increasing exercise intensity does lead to higher CBF, as measured by BV, it does not necessarily translate to a greater improvement in post-exercise executive function. The similar decrease in HHb across all intensities might indicate that the brain’s oxygen extraction remains relatively constant, despite changes in CBF.

Question 19

Describe in detail the mechanisms that lead to an aerobic exercise-induced increase in CBF. Is the increase regional or global?

Answer 19

• During aerobic exercise, several mechanisms increase CBF:
• Metabolic Demand: Increased neuronal activity raises the need for oxygen and glucose, promoting vasodilation.
• CO2 Levels: Elevated CO2 from increased respiration causes vasodilation.
• Neurogenic Factors: Activation of the autonomic nervous system increases heart rate and cardiac output.
• Nitric Oxide: Exercise stimulates endothelial nitric oxide production, leading to vasodilation.
  Mechanical Factors: Muscle contractions increase venous return and cardiac output. The increase in CBF can be both regional and global, depending on exercise intensity and type (Giza & Hovda, 2014).

Question 20

What is the average amount of exercise-induced increase in CBF in a young, healthy population?

Answer 20

• In young, healthy individuals, aerobic exercise can increase CBF by approximately 10-30%, depending on the intensity and duration of the activity. This increase ensures adequate oxygen and nutrient delivery to meet the heightened metabolic demands of the brain during exercise (Giza & Hovda, 2014).

Question 21

Describe the mechanisms through which aerobic exercise can lead to an increase in CBF, which would in turn provide a boost in executive function via the dorsolateral prefrontal cortex.

Answer 21

• Aerobic exercise enhances CBF through:
• Increased Cardiac Output: Elevated heart rate and stroke volume boost blood flow to the brain.
• Vasodilation: Elevated CO2 and nitric oxide levels induce vasodilation of cerebral arteries.
• Neurotransmitter Release: Exercise increases norepinephrine and dopamine, improving cognitive function.
  Improved Cerebral Autoregulation: Enhanced ability to maintain stable CBF despite changes in systemic blood pressure. These mechanisms increase oxygen and nutrient delivery to the dorsolateral prefrontal cortex, supporting better executive function performance (Giza & Hovda, 2014).

Question 22

What is the hemo-neural hypothesis (Moore & Cao 2008)? Describe it in detail.

Answer 22

• The hemo-neural hypothesis, proposed by Moore and Cao (2008), posits that the brain’s blood flow dynamics are intricately linked to neural activity and cognitive functions. This hypothesis suggests that changes in blood flow and blood pressure actively influence neural function and behavior, rather than merely responding to metabolic demands.
• Neurovascular coupling: The hypothesis emphasizes the close relationship between neural activity and cerebral blood flow. When a specific brain region is activated during a cognitive task, there is a corresponding increase in blood flow to that region. This neurovascular coupling ensures that active neurons receive an adequate supply of oxygen and glucose to sustain their increased metabolic demands.
• Hemodynamic influences on neural activity: The hemo-neural hypothesis proposes that changes in blood flow and blood pressure can directly modulate neural activity and cognitive processes. For example, an increase in blood flow may enhance the excitability of neurons, facilitating their firing and communication. Conversely, a decrease in blood flow may suppress neural activity and hinder cognitive performance.
• Bidirectional relationship: The hypothesis suggests that the relationship between hemodynamics and neural activity is bidirectional. While neural activity can trigger changes in blood flow through neurovascular coupling, the hypothesis argues that blood flow dynamics can also shape neural activity and behavior. This implies that the brain’s vasculature not only responds to neural demands but also actively participates in shaping cognitive processes.
• Oxygen and glucose delivery: The hemo-neural hypothesis highlights the importance of efficient oxygen and glucose delivery to the brain. Changes in blood flow and blood pressure can impact the availability of these essential substrates, which are crucial for neural metabolism and function. Inadequate or inconsistent delivery of oxygen and glucose may lead to neural dysfunction and cognitive impairment.
• Removal of metabolic waste: In addition to delivering oxygen and glucose, the brain’s vasculature plays a crucial role in removing metabolic waste products, such as carbon dioxide and lactate. The hemo-neural hypothesis suggests that efficient removal of these waste products is essential for maintaining optimal neural function. Impaired waste removal may lead to the accumulation of neurotoxic substances, which can disrupt neural activity and cognitive processes.
• Implications for cognitive function: The hemo-neural hypothesis has important implications for understanding cognitive function and its relationship to cerebral blood flow. It suggests that individual differences in blood flow dynamics, such as those related to age, cardiovascular health, or lifestyle factors, may contribute to variations in cognitive performance. Furthermore, the hypothesis implies that interventions targeting cerebral blood flow, such as exercise or pharmacological treatments, may have the potential to modulate cognitive function.
• Experimental evidence: Several experimental studies have provided support for the hemo-neural hypothesis. For example, functional neuroimaging studies have demonstrated that changes in blood flow and oxygenation are closely coupled with neural activity during cognitive tasks. Additionally, studies using transcranial Doppler ultrasound have shown that manipulating cerebral blood flow can influence cognitive performance, such as attention and memory.

Question 23

Describe the neurometabolic cascade of concussion (Giza & Hovda 2001, 2014) in extensive detail, providing a step-by-step description of changes, especially in relation to CBF.

Answer 23

• The neurometabolic cascade following a concussion involves several steps:

Step 1: Mechanical disruption
* Rapid acceleration and deceleration of the brain within the skull cause mechanical disruption of neuronal and glial cell membranes.
* This disruption leads to a sudden efflux (outflow) of potassium ions (K+) from the cells and an influx (inflow) of calcium ions (Ca2+) into the cells.
* The ionic imbalance disrupts the normal functioning of neurons and glial cells.

Step 2: Excitotoxicity
* The mechanical disruption also triggers excessive release of glutamate, a neurotransmitter that excites neurons.
* Excessive glutamate further exacerbates the ionic imbalance by allowing more Ca2+ to enter the cells.
* This process, known as excitotoxicity, can lead to cell damage and death.

Step 3: Energy crisis
* To restore the ionic balance, cells activate ionic pumps, which require a significant amount of energy in the form of adenosine triphosphate (ATP).
* The increased demand for ATP depletes the cell’s energy reserves, leading to an energy crisis.
* Despite the reduced CBF, there is a transient increase in glucose metabolism as cells attempt to produce more ATP to restore homeostasis.

Step 4: Anaerobic metabolism and acidosis
* Due to the reduced CBF and increased energy demands, cells shift to anaerobic metabolism, which does not require oxygen.
* Anaerobic metabolism leads to the accumulation of lactate, a byproduct that contributes to acidosis (increased acidity) in the brain.
* Acidosis further impairs cellular function and can exacerbate cell damage.

Step 5: Hypometabolism
* Following the initial period of hypermetabolism, the brain enters a state of reduced metabolic activity.
* Glucose utilization diminishes, and ionic imbalances persist, leading to ongoing cellular dysfunction.
* This hypometabolic state can last for days to weeks following the concussion.

Step 6: Calcium influx and mitochondrial dysfunction
* Persistent influx of Ca2+ into neurons and mitochondria (the cell’s energy producers) leads to mitochondrial dysfunction.
* Impaired mitochondrial function further compromises the cell’s ability to produce ATP and maintain normal functioning.

Step 7: Diffuse axonal injury
* Mechanical forces and biochemical disruptions can cause diffuse axonal injury, where the long, slender projections of neurons (axons) are stretched and damaged.
* Diffuse axonal injury can disrupt communication between neurons and lead to long-term cognitive and functional impairments.

Step 8: Neuroinflammation and oxidative stress
* The injury triggers inflammatory responses in the brain, with immune cells releasing inflammatory molecules that can further damage neurons.
* Oxidative stress, caused by an imbalance between harmful free radicals and the body’s ability to counteract their effects, also contributes to neuronal damage.

Question 24

What is a transcranial Doppler ultrasound (TCD), and how does it provide a valid proxy for CBF measurement?

Answer 24

• Transcranial Doppler ultrasound (TCD) is a non-invasive diagnostic tool that provides real-time measurement of cerebral blood flow velocity (CBFV) in the major arteries of the brain. This technique is widely used as a reliable proxy for assessing cerebral blood flow (CBF) and brain perfusion.
• How TCD works:
• TCD uses high-frequency sound waves (ultrasound) that are emitted from a transducer placed on the skull.
• The ultrasound waves penetrate the skull and reach the major cerebral arteries, such as the middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA).
• As the sound waves encounter moving blood cells in these arteries, they are reflected back to the transducer with a shifted frequency, known as the Doppler shift.
• The Doppler shift is proportional to the velocity of blood flow in the artery.
• By analyzing the Doppler shift, TCD can estimate the speed and direction of blood flow in real-time.
• Validity as a proxy for CBF measurement:
• Although TCD measures CBFV rather than absolute CBF, changes in CBFV have been shown to correlate well with changes in CBF under most physiological conditions (Giza & Hovda, 2014).
• The relationship between CBFV and CBF is based on the assumption that the diameter of the insonated artery remains constant. In most cases, the large cerebral arteries maintain a relatively constant diameter, making this assumption valid (Bishop et al., 1986; Clyde et al., 1996; Duschek et al., 2018; Rosengarten & Kaps, 2002; Tari et al., 2020).
• Validation studies comparing TCD with other established methods of measuring CBF, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have demonstrated a strong correlation between CBFV and CBF (Dahl et al., 1992; Larsen et al., 1994).

Question 25

What are the pros, cons, strengths, and limitations of TCD?

Answer 25

• Advantages of TCD:
• Non-invasive: TCD does not require any invasive procedures or contrast agents, making it a safe and well-tolerated technique.
• Real-time measurement: TCD provides continuous, real-time monitoring of CBFV, allowing for dynamic assessment of cerebral hemodynamics.
• Bedside availability: TCD is portable and can be performed at the bedside, making it ideal for critically ill patients and in emergency settings.
• Cost-effective: Compared to other imaging modalities, TCD is relatively inexpensive and widely accessible.
• Limitations of TCD:
• Operator-dependent: The accuracy of TCD measurements relies on the skill and experience of the operator in identifying and insonating the target arteries.
• Limited by skull thickness: In some individuals, particularly the elderly or those with thick skull bones, it may be difficult to obtain adequate ultrasound penetration, limiting the ability to measure CBFV.
  Indirect measure of CBF: While CBFV correlates well with CBF in most cases, it is not a direct measure of blood flow. Factors such as changes in vessel diameter or intracranial pressure can affect the relationship between CBFV and CBF.

Question 26

What are alternative tools for measuring CBF aside from TCD? Name the tools and describe their functions.

Answer 26

• Positron Emission Tomography (PET): Uses radiotracers to measure regional CBF by detecting gamma rays emitted from injected tracers.
• Single-Photon Emission Computed Tomography (SPECT): Similar to PET, using different radiotracers to assess regional blood flow.
• Magnetic Resonance Imaging (MRI): Techniques like arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) MRI measure CBF by tracking blood flow and contrast agent dynamics.
• Computed Tomography Perfusion (CTP): Uses iodinated contrast agents and CT imaging to evaluate cerebral perfusion.
  Near-Infrared Spectroscopy (NIRS): Non-invasive technique measuring oxygenation and blood volume, providing indirect estimates of CBF (Giza & Hovda, 2014).

Question 27

What is cerebral blood velocity and how does it differ from cerebral blood flow and why is it measured in cm/s?

Answer 27

• Cerebral blood velocity (CBV) refers to the speed at which blood travels through the brain’s vasculature, typically measured in centimeters per second (cm/s). This metric is distinct from cerebral blood flow (CBF), which measures the volume of blood passing through a given amount of brain tissue per unit time, usually expressed in milliliters per 100 grams of brain tissue per minute (mL/100g/min).
• Cerebral Blood Velocity (CBV): Measured in cm/s, CBV indicates the speed of blood within the cerebral arteries and veins.
• Cerebral Blood Flow (CBF): Measured in mL/100g/min, CBF quantifies the volume of blood passing through a specific amount of brain tissue in a set time frame.
• Physiological Relevance:
• CBV: Provides information about the dynamic aspects of blood movement, such as how quickly blood is delivered to and moves through brain structures. It is particularly useful in evaluating conditions like stenosis or vasospasm.
• CBF: Offers insights into the overall perfusion of brain tissue, which is crucial for understanding oxygen and nutrient delivery to brain cells. It is particularly important in conditions like stroke, where perfusion deficits can lead to tissue damage.
• CBV: Commonly measured using transcranial Doppler ultrasound, which uses sound waves to assess the speed of blood flow in the major cerebral arteries.
  CBF: Measured using techniques such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI) with arterial spin labeling (ASL).

Question 28

Why is CBV Measured in cm/s?

Answer 28

· The measurement of CBV in cm/s is due to its focus on the speed of blood flow. Using cm/s allows clinicians and researchers to assess the dynamic aspects of blood movement, such as the rate of delivery to brain tissues and the potential impact of vascular abnormalities on blood speed. This unit is particularly useful for detecting changes in flow speed that may indicate pathological conditions like stenosis, where blood flow is restricted and velocity can change significantly.
In summary, while both CBV and CBF are critical for understanding cerebral hemodynamics, they offer different types of information: CBV provides data on the speed of blood flow, which can help diagnose and monitor vascular conditions, whereas CBF provides data on the volume of blood flow, which is essential for assessing overall brain perfusion and metabolic health.

Question 29

Is TCD a valid proxy for measuring CBF, and why?

Answer 29

· Transcranial Doppler (TCD) ultrasound is commonly used to measure cerebral blood velocity (CBV) in the major cerebral arteries. While it provides valuable information about the speed of blood flow, its use as a direct proxy for cerebral blood flow (CBF) is limited due to several reasons.
· TCD: Measures the velocity of blood flow (cm/s) in large cerebral arteries like the middle cerebral artery (MCA). It does not directly measure the volume of blood flowing through brain tissue.
· CBF: Refers to the volume of blood passing through a given amount of brain tissue per unit time (mL/100g/min), reflecting tissue perfusion.
· Assumptions: To use TCD as a proxy for CBF, it is often assumed that the diameter of the blood vessel remains constant. This assumption allows for the inference that changes in blood velocity directly relate to changes in blood flow volume. However, this is not always the case because:
· Blood vessel diameter can vary due to vasodilation or vasoconstriction.
· Blood velocity changes may not uniformly reflect changes in blood flow across different regions of the brain.
· Limitations: TCD is limited to assessing large vessels and cannot measure flow in smaller arterioles and capillaries, which are crucial for determining overall CBF.
· Utility: TCD is valuable in certain clinical situations, such as detecting vasospasm following subarachnoid hemorrhage, assessing collateral blood flow in stroke, and monitoring cerebral autoregulation. These uses rely on the relative changes in blood velocity rather than absolute CBF values.
· Research: In research, TCD can be used to study dynamic changes in blood flow velocity in response to various stimuli or conditions, providing insights into cerebral hemodynamics.
· For a comprehensive assessment of CBF, TCD is often used in conjunction with other imaging modalities that directly measure CBF, such as:
· Positron Emission Tomography (PET): Provides high-resolution images of blood flow and metabolism.
· Single-Photon Emission Computed Tomography (SPECT): Offers functional imaging of blood flow.
· Magnetic Resonance Imaging (MRI): Techniques like arterial spin labeling (ASL) directly measure CBF.
TCD provides valuable information about cerebral hemodynamics by measuring blood flow velocity, but it has limitations as a direct proxy for CBF. Changes in velocity measured by TCD can infer changes in flow under certain conditions, but it is not a direct measure of CBF. For accurate and comprehensive assessment of CBF, TCD should be complemented with other imaging modalities that can measure blood volume and flow distribution across different brain regions.

Question 30

What is the average CBF via MCAV values at baseline and during exercise for healthy young adults?

Answer 30

· Cerebral blood flow (CBF) through the middle cerebral artery (MCA) is often estimated using transcranial Doppler (TCD) ultrasound to measure the middle cerebral artery blood velocity (MCAv). The average MCAv values at baseline and during exercise can vary depending on the study and the specific conditions. However, some general values for healthy young adults can be provided based on existing literature.
· For healthy young adults at rest, the average MCAv values typically range between:
· MCAv: 50-70 cm/s
· During moderate to intense exercise, there is usually an increase in MCAv due to increased cardiac output and cerebral autoregulation mechanisms. The average MCAv values during exercise can vary, but a common range reported in studies is:
· MCAv during moderate exercise: Approximately 60-80 cm/s
· MCAv during intense exercise: Can reach values above 80 cm/s, sometimes up to 100 cm/s or more depending on the intensity of the exercise and the individual’s fitness level.
· Several factors can influence the changes in MCAv during exercise, including:
· Exercise Intensity: Higher intensity exercise typically leads to greater increases in MCAv.
· Fitness Level: More physically fit individuals may exhibit different patterns of MCAv response to exercise compared to less fit individuals.
· Age and Sex: These factors can also influence baseline and exercise MCAv values.
· Ainslie et al. (2008): This study reported that young, healthy adults had an average MCAv of approximately 55-60 cm/s at rest and observed increases of around 20-30% during moderate to high-intensity exercise.
· Willie et al. (2011): Found that during incremental exercise to exhaustion, MCAv increased progressively, reaching peak values around 80-100 cm/s.
While baseline MCAv values in healthy young adults typically range from 50-70 cm/s, during moderate to intense exercise, these values can increase significantly, often ranging from 60-100 cm/s or more. The specific values can vary based on individual differences and the exact conditions of the exercise protocol. These measurements are crucial for understanding the cerebral hemodynamic responses to physical activity and ensuring appropriate cerebral perfusion during increased physical demands.

Question 31

What percentage increase from baseline do healthy adults see in MCAV during moderate intensity exercise?

Answer 31

· During moderate-intensity exercise, healthy adults typically see an increase in middle cerebral artery blood velocity (MCAv). The percentage increase can vary depending on the study, the specific population, and the exact intensity of the exercise. However, a general range can be provided based on existing literature.
· General Range: Studies have shown that MCAv can increase by approximately 10-30% from baseline during moderate-intensity exercise.
· Ainslie et al. (2008): This study observed that MCAv increased by around 20-30% during moderate to high-intensity exercise in young, healthy adults .
· Ainslie, P. N., et al. (2008). Regulation of cerebral blood flow during exercise: A review. Progress in Neurobiology, 82(3), 237-259.
· Ide et al. (2003): Found that moderate exercise induced an increase in MCAv of approximately 10-20% in healthy young adults .
· Ide, K., et al. (2003). Middle cerebral artery blood velocity during exercise in the heat with and without thigh compression. Acta Physiologica Scandinavica, 177(3), 233-239.
· Several factors can influence the magnitude of the increase in MCAv during exercise:
· Exercise Intensity: As the intensity of exercise increases, the percentage increase in MCAv tends to be higher.
· Fitness Level: More physically fit individuals may have different baseline and exercise responses compared to less fit individuals.
· Measurement Techniques: Differences in TCD methodologies and protocols can affect reported values.
· Individual Variability: Age, sex, and baseline cardiovascular health can contribute to variations in response.
· Healthy adults typically experience a 10-30% increase in MCAv from baseline during moderate-intensity exercise.
This increase is a result of enhanced cardiac output and cerebral autoregulatory mechanisms that ensure adequate cerebral perfusion during physical activity. The specific percentage increase can vary based on several factors, including the intensity of the exercise, individual fitness levels, and study methodologies.

Question 32

What is the function of the circle of willis and where is it

Answer 32

Location: At the base of the brain, in the interpeduncular fossa.

Function: Provides an anastomotic connection between the anterior and posterior cerebral blood circulations, ensuring consistent blood supply to the brain.

Question 33

Is there a difference in cerebral blood velocity (CBV) in the right and left middle cerebral arteries (MCAs) when measured using transcranial Doppler (TCD)?

Answer 33

Yes, there can be a difference in cerebral blood velocity (CBV) in the right and left middle cerebral arteries (MCAs) when measured using transcranial Doppler (TCD).

Some key points:

1. Anatomical variations:
   
   • The circle of Willis may not be completely symmetrical, leading to slight differences in the blood flow dynamics between the right and left MCAs.
2. Physiological factors:
   
   • Differences in vascular tone, autoregulation, and metabolic activity between the two cerebral hemispheres can result in asymmetric CBV.
3. Pathological conditions:
   
   • Unilateral cerebrovascular diseases, such as stenosis or occlusion, can cause reduced CBV in the affected MCA compared to the contralateral side.
4. Measurement accuracy:
   
   • Slight differences in the angle and position of the TCD probe between the right and left sides can contribute to minor asymmetries in the measured CBV values.

In general, a difference of up to 20% in CBV between the right and left MCAs is considered within the normal range. Larger differences may indicate the presence of a unilateral cerebrovascular pathology and should be further investigated.

Question 34

How do you know you;re measuring the CBV through MCA instead of PCA or ACA with TCD? Do the sound waves differ?

Answer 34

You make a good point. Determining which cerebral artery is being measured with transcranial Doppler (TCD) can be challenging, as the sound waves do not necessarily differ between the major cerebral arteries.

Here are some key ways to identify the specific artery being measured with TCD:

1. Depth of insonation:
   
   • MCA is typically detected at a depth of 45-55 mm.
   • ACA is detected at a depth of 60-70 mm.
   • PCA is detected at a depth of 60-70 mm, posterior to the MCA.
2. Flow direction:
   
   • MCA flow is typically away from the probe.
   • ACA flow is towards the probe.
   • PCA flow is away from the probe.
3. Velocity profile:
   
   • MCA has a typical “windsock” shaped velocity waveform.
   • ACA has a more rounded, less pulsatile waveform.
   • PCA has a less pulsatile waveform compared to the MCA.
4. Anatomical landmarks:
   
   • The MCA is the largest branch of the internal carotid artery.
   • The ACA is the first branch of the internal carotid artery, anterior to the MCA.
   • The PCA is a branch of the basilar artery, posterior to the MCA.

Careful probe positioning and utilization of these identifying characteristics are crucial to ensure the correct cerebral artery is being insonated and measured with TCD. Verifying the results with other imaging modalities can also help confirm the vessel being assessed.

Question 35

What does temporal resolution mean in the context of TCD and eyetracker?

Answer 35

Temporal resolution in Transcranial Doppler (TCD) and eye tracking:

TCD: Refers to the sampling rate (50-200 Hz) for measuring cerebral blood flow velocity, enabling analysis of dynamic changes.

Eye tracking: Refers to the frequency (30 Hz to 2000 Hz+) at which eye position is sampled, allowing capture of rapid eye movements critical for studying visual attention and cognition.

Higher temporal resolution provides more detailed data but requires greater resources. The appropriate resolution depends on the specific application and requirements.

Question 36

How can changes in the pressor response influence the cognitive benefits of exercise?

Answer 36

· The pressor response, characterized by an increase in blood pressure during exercise, is an important physiological mechanism that may contribute to the executive function (EF) benefits observed following acute bouts of exercise.

• The pressor response involves a coordinated increase in sympathetic nervous system activity, leading to peripheral vasoconstriction and an elevation in both systolic and diastolic blood pressure. This increase in perfusion pressure has been shown to enhance cerebral perfusion and oxygenation, even in the absence of changes in global CBF (Washio & Ogoh, 2023). Importantly, the prefrontal cortex, which is a critical neural substrate for EF, is highly sensitive to changes in cerebral perfusion and oxygenation.
• By increasing cerebral perfusion pressure, the pressor response may facilitate the delivery of oxygen and metabolic substrates to prefrontal regions, enhancing their neural efficiency and information processing capabilities. This improved neural functioning within EF-related networks could then manifest as the behavioral improvements in tasks like the antisaccade that are commonly observed following acute exercise.
• Furthermore, the magnitude of the pressor response may interact with individual differences in factors like fitness level, age, and concussion history to modulate the extent of postexercise EF benefits. For example, individuals with higher fitness levels tend to exhibit a more pronounced pressor response during exercise, which could contribute to the larger EF improvements sometimes observed in this population (Dupuy et al., 2015).

Conversely, concussive injuries have been associated with dysregulation of autonomic control and attenuated pressor responses (Gall et al., 2004). This impairment in the exercise-induced increase in blood pressure may partially explain the reduced or delayed EF benefits sometimes reported in individuals recovering from a sport-related concussion.

Question 37

Why did you decide that CBF is the candidate mechanism for a postexercise EF benefit over all the other possibilities?

Answer 37

• Hippocampal neurogenesis: Research on chronic bouts of exercise has reported that hippocampal neurogenesis is a primary moderator associated with an EF benefit.
• For instance, van Praag et al. (2005) found that mice provided ad libitum access to exercise over 45 days exhibited improved memory and spatial learning (via the Morris water maze task) compared to sedentary controls and that enhanced memory performance was associated with hippocampal neurogenesis.
• In humans, Erickson et al. (2011) employed fMRI to evaluate hippocampal volume changes in older adults who completed a year-long exercise program (i.e., walking three times weekly at 60-75% of HR reserve) and an age-matched sedentary control group. At 12 months, results demonstrated that the exercise group exhibited a 2% increase in hippocampal volume, whereas over the same duration, a 1.4% reduction in hippocampal volume was observed in the sedentary controls.
• Therefore, compelling evidence suggests that chronic exercise promotes neurogenesis, prevents neural death, and supports improved EF. Although chronic exercise supports hippocampal neurogenesis, it is unlikely that such a change would support improved EF following a single bout of exercise (Ming & Song, 2011).
• As such, it has been proposed that a single bout of exercise improves EF via (1) increased biomolecule concentrations (e.g., brain-derived neurotrophic factor (BDNF) and catecholamines) (for review, see Knaepen et al., 2010; Zouhal et al., 2008) (2) increased resting state functional connectivity (Schmitt et al., 2019), and (3) increased CBF (Tari et al., 2020), that improve the efficiency and effectiveness of EF networks.
• BDNF is a neuroprotective hormone that aids neuronal and glial survival and growth, modulates neurotransmitter levels/binding, and promotes neuronal plasticity (Bathina & Das, 2015).
• Hwang et al. (2016) investigated the impact that 20-min of high-intensity aerobic exercise (i.e., 85-90% of VO2max) had on Stroop task performance and serum BDNF. Results showed the expected postexercise reduction in Stroop task RTs, which was linked to increased serum BDNF levels.
• In contrast, Ferris et al. (2007) had participants perform the Stroop task prior to and following 30-min of aerobic exercise at 10% above the ventilatory threshold (i.e., the point when ventilation increases faster than the rate of VO2 consumption demand). Results showed that although Stroop task performance improved postexercise, the magnitude of the benefit was not related to serum BDNF levels.
• Thus, BDNF’s role in exerting a postexercise EF benefit remains equivocal. Indeed, it could be that individual differences in resting BDNF levels (Casey et al., 2009; Lommatzsch et al., 2005) and the genetic predisposition for BDNF release in response to exercise (Chen et al., 2008) contribute to these equivocal findings and support the need for further investigation.
• Catecholamines are monoamine derivatives foundational to the production of epinephrine and norepinephrine and have been linked to improved EF.
• A meta-analysis by McMorris et al. (2011) states that an acute bout of moderate-intensity exercise (i.e., 50-75% VO2max) improves working memory when compared to light- or heavy-intensity exercise and that this improvement is linked to increased catecholamine metabolite concentrations in the brain (i.e., increased norepinephrine and dopamine).
• In contrast, Ando et al. (2022) had participants complete a single bout of aerobic and resistance exercise for 30-min (53-58% of HRmax) and observed that a postexercise inhibitory control benefit was not linked to a pre- to postexercise change in catecholamine levels.
• Taken together, the literature does not demonstrate that changes in catecholamines are the sole mechanism by which postexercise EF is influenced.
• Connectivity: Another proposed mechanism modulating postexercise EF benefits is increased functional connectivity in DLPFC networks (Verburgh et al., 2014). Functional connectivity measures how brain regions interact and is quantified via non-invasive imaging (i.e., fMRI).
• Schmitt et al. (2019) had participants complete 30-min single bouts of aerobic exercise at low- (i.e., 35% below lactate threshold) and high-intensities (i.e., 20% above lactate threshold) and showed improved connectivity within DLPFC regions for both intensities.
• In contrast, Voss et al. (2020) showed that a 20-min single bout of moderate-intensity exercise (i.e., 65% of HRmax) improved n-back task performance but did not alter functional connectivity with frontoparietal EF networks. Accordingly, it is unclear whether enhanced functional connectivity is a primary moderator of a postexercise EF benefit.
• CBF: An exercise-mediated increase in CBF is the fourth candidate mechanism related to a postexercise EF benefit. Exercise rapidly increases CO2 (a by-product of cellular metabolism), HR, and systolic blood pressure, facilitating a systemic increase in perfusion (Smith & Ainslie, 2017).
• Byun et al. (2014) demonstrated that a 10-min single bout of light-intensity exercise (30% VO2peak) improved Stroop task performance and was a result linked to increased cerebral oxygenation in the DLPFC as assessed via fNIRS.
• As well, Tari et al. (2020) investigated the relationship between CBF and EF by comparing separate conditions requiring: (1) 10-min of moderate- to heavy-intensity aerobic exercise (wattage determined via participant-specific incremental ramp test to volitional exhaustion) and (2) 10-min of hypercapnia (5% CO2: higher-than-atmospheric concentration of CO2). The hypercapnic condition was used because it increases CBF independent of the metabolic costs of exercise via chemoreceptor reflex-induced vasodilation (O’regan & Majcherczyk, 1982). Results showed that exercise and hypercapnic conditions provided an equivalent magnitude postexercise EF reduction in antisaccade RTs.
• In turn, disease states (e.g., cognitive decline) and age-related impairments to EF have been linked to cerebral hypoperfusion.
  For example, Bertsch et al. (2009) demonstrated that healthy young adults show increased resting-state CBF and improved cognitive performance compared to a healthy cohort of older adults (> 55 years of age). As such, the bidirectional relationship between CBF and EF suggests that CBF provides a strong candidate mechanism for a single-bout postexercise EF benefit.

Question 38

Give me a brief play by play of the neurometabolic cascade

Answer 38

• Immediate Cellular Consequences (0-10 minutes):
• • Abrupt efflux of potassium (K+)
• • Sudden release of glutamate
• • Influx of calcium
• • Increased activity of ion pumps to restore homeostasis, requiring more ATP and glucose metabolism
• Neurometabolic Cascade:
• • Hypermetabolism (0-30 minutes):
• • Glucose levels increase
• • Cerebral blood flow decreases
• • Hypometabolism (30 minutes - 10 days):
• • Glucose levels fall below normal
• • Cerebral blood flow gradually returns to normal
• Persistent Cellular Disruptions:
• • Calcium levels remain elevated for 2-3 days before rapidly declining
• • K+ levels return to normal within ~30 minutes
• • Glutamate returns to baseline within ~10 minutes
• Functional Impairments:
• • The rapid cellular changes and subsequent hypometabolic phase contribute to:
• • Functional impairments
• • Cognitive deficits
• Motor and sensory impairments

Question 39

What are the major differences between the old and new neurometabolic cascade model by Giza and Hovda 2001 versus 2014

Answer 39

Old Model (2001):

Focused on the acute phase changes in the first hour post-injury, including the spike in glutamate, potassium, and glucose, followed by the prolonged hypometabolic phase.
Described the acute energy crisis and the mismatch between cerebral blood flow and metabolic demand.

New Model (2014):

Provides a more comprehensive overview of the neurometabolic changes across the complete timeline of concussion recovery.

Incorporates additional mechanisms and pathways involved in the neurometabolic cascade, including:

Immediate disruption of the blood-brain barrier and cerebrovascular function.
Delayed metabolic depression and mitochondrial dysfunction.

Impairment of neurotransmitter systems (e.g., dopamine, serotonin).
Activation of inflammatory pathways and oxidative stress.
Alterations in gene expression and protein synthesis.

Emphasizes the dynamic and heterogeneous nature of the neurometabolic response, with variations depending on injury severity and individual factors.

Highlights the potential for prolonged metabolic, structural, and functional impairments that can lead to persistent post-concussive symptoms.