Intermittent hypoxia (also known as episodic hypoxia) is an intervention in which a person or animal undergoes alternating periods of normoxia and hypoxia. Normoxia is defined as exposure to

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

levels normally found in

Earth's atmosphere The atmosphere of Earth is composed of a layer of gas mixture that surrounds the Earth's planetary surface (both lands and oceans), known collectively as air, with variable quantities of suspended aerosols and particulates (which create weathe ...

(~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 Altitude sickness, the mildest form being acute mountain sickness (AMS), is a harmful effect of high altitude, caused by rapid exposure to low amounts of oxygen at high elevation. People's bodies can respond to high altitude in different wa ...

. 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 Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenance respiration, the amount of cellul ...

and

walking Walking (also known as ambulation) is one of the main gaits of terrestrial locomotion among legged animals. Walking is typically slower than running and other gaits. Walking is defined as an " inverted pendulum" gait in which the body vaults o ...

, intermittent hypoxia typically works by using long-term facilitation (LTF). LTF, which is synonymous to

long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...

, occurs when there are long-term increases in synaptic strength due to

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

. 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 The carotid body is a small cluster of peripheral chemoreceptor cells and supporting sustentacular cells situated at the bifurcation of each common carotid artery in its tunica externa. The carotid body detects changes in the composition of art ...

, a chemoafferent receptor. The activated carotid body triggers the release of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

that attach to

serotonin receptors 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the Central nervous system, central and peripheral nervous systems ...

on the surface of

motoneurons A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or ...

, 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 biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

pathway then uses downstream molecules such as

TrkB Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recept ...

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

, and

PKA In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...

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 is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of ''individual'' synapses. However this new form ref ...

. 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, nitrogen monooxide, 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 den ...

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, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

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 opti ...

Dosage

An understanding of proper dosage is needed in order to design an effective intermittent hypoxia protocol, particularly due to the

comorbidities In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sickness" ...

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 The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...

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 Fraction of inspired oxygen (''FI''O2), correctly denoted with a capital ''I'', is the molar or volumetric fraction of oxygen in the inhaled gas. Medical patients experiencing difficulty breathing are provided with oxygen-enriched air, which means ...

(''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 The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...

, its downstream effects allow it to also be used as an effective rehabilitative intervention in a number of different

biological system A biological system is a complex Biological network inference, network which connects several biologically relevant entities. Biological organization spans several scales and are determined based different structures depending on what the system is ...

s 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 airway obstruction, obstruction of the respiratory tract#Upper respiratory tract, upper airway lea ...

and

COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...

. The ability to increase muscle activity, specifically for

, has also been demonstrated in both rats and humans after

spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Symptoms of ...

Hippocampal neurogenesis

Hippocampal The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...

has also been demonstrated in rats subjected to intermittent hypoxia. This neurogenesis has shown related

cognitive Cognition is 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, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...

and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

as well as overall increases in spatial cognitive ability. Additionally,

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-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

have shown decreases in blood pressure. Increases in

in rats has also been attributed to this process. Such changes to nitric oxide levels also aid in protection from

myocardial ischemia Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the a ...

and

perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ (anatomy), organ or a tissue (biology), tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion may also refer t ...

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