Intermittent Hypoxia
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Intermittent hypoxia (also known as episodic hypoxia) is an intervention in which a person or animal undergoes alternating periods of normoxia and
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
. Normoxia is defined as exposure to oxygen levels normally found in Earth's atmosphere (~21% O2) and hypoxia as any oxygen levels lower than those of normoxia. Normally, exposure to hypoxia is negatively associated to physiological changes to the body, such as altitude sickness. However, when used in moderation, intermittent hypoxia may be used clinically as a means to alleviate various pathological conditions.


General Mechanisms

When used as a rehabilitative intervention, particularly for respiration and walking, intermittent hypoxia typically works by using long-term facilitation (LTF). LTF, which is synonymous to long-term potentiation, occurs when there are long-term increases in synaptic strength due to synaptic plasticity. In the case of intermittent hypoxia, these increases in synaptic strength result in increased motor output. Reduced partial pressures of oxygen in the arteries due to intermittent hypoxia are sensed by and stimulate the carotid body, a chemoafferent receptor. The activated carotid body triggers the release of
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
that attach to serotonin receptors on the surface of motoneurons, such as the phrenic motoneuron in the case of respiratory recovery. This
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathway then uses downstream molecules such as TrkB, BDNF, and
PKA PKA may refer to: * Professionally known as: ** Pen name ** Stage persona * p''K''a, the symbol for the acid dissociation constant at logarithmic scale * Protein kinase A, a class of cAMP-dependent enzymes * Pi Kappa Alpha, the North-American so ...
to increase the synaptic output of the involved motor neuron which in turn increases the motor output of the involved muscles and, thus, decreases functional impairment. As the amount of intermittent hypoxia changes the amount of serotonin release and, as a result, the amount of LTF, this process exhibits metaplasticity. Metaplasticity occurs when the LTF is itself plastic or variable. Intermittent hypoxia-induced LTF has also been demonstrated in carotid denervated rats, suggesting that synaptic plasticity due to intermittent hypoxia also works through other mechanisms outside of carotid chemoafferents. Aside from this, intermittent hypoxia also alters overall
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
production, concentration, and gene expression, which occurs due to cardiovascular adaptations to hypoxia. This mechanism is relevant when used as a means to decrease
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
or increase
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...


Dosage

An understanding of proper dosage is needed in order to design an effective intermittent hypoxia protocol, particularly due to the comorbidities associated with hypoxia. For example, intermittent hypoxia has been shown to induce LTF in rats while continuous hypoxia does not. And acute IH shows no evidence of the hippocampal cell death found in rats while chronic intermittent hypoxia exposure does Though intermittent hypoxia has been used for various therapeutic applications across a number of physiological system, there is a general consensus in what can be considered a safe and beneficial amount of intermittent hypoxia. Such a protocol would involve a fraction of inspired oxygen (''Fi''O2) ranging between 0.09 – 0.16 with 3 – 15 episodes per day with comorbidities found in the range of a ''Fi''O2 of 0.03 – 0.08 and 48 – 2400 episodes per day.


Pathological and beneficial effects


Therapeutic applications

Though intermittent hypoxia is initially involved with only the respiratory system, its downstream effects allow it to also be used as an effective rehabilitative intervention in a number of different biological systems in both animals and humans.


LTF

For the respiratory system, the LTF facilitated by intermittent hypoxia aids in increasing phrenic motor nerve output. This has been shown to help people with
obstructive sleep apnea Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. These episod ...
and COPD. The ability to increase muscle activity, specifically for walking, has also been demonstrated in both rats and humans after spinal cord injury.


Hippocampal neurogenesis

Hippocampal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
has also been demonstrated in rats subjected to intermittent hypoxia. This neurogenesis has shown related
cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
improvements such as enhanced
learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...
and memory as well as overall increases in spatial cognitive ability. Additionally,
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
-like effects are exhibited in rats undergoing such treatment.


Nitric oxide production

Nitric oxide level changes due to intermittent hypoxia also provide potential benefits. People with
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
have shown decreases in blood pressure. Increases in
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
in rats has also been attributed to this process. Such changes to nitric oxide levels also aid in protection from myocardial ischemia and
perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...
.


See also

*
Hypoxia (medical) Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either '' generalized'', affecting the whole body, or ''local'', affecting a region of the bo ...
*
Hypoxia (disambiguation) Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the t ...
* Intermittent hypoxic training


References

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