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Core
The reticular formation is a set of grey matter nuclei (clusters of nerve cell bodies), spread throughout the brainstem, that are functionally linked (see below). The primary function of the reticular formation is to keep the cerebral cortex ‘awake’ by maintaining behavioural arousal (not to be confused with sexual arousal) and consciousness.
Arousal is the state of being awake and is important to cause goal-seeking behaviour (such as looking for food, maintaining mobility and the fight or flight response).
Consciousness is the awareness of both the internal and external environments. The preservation of this requires the reticular formation and cortex to be functioning normally and appropriately connected to each other. In practice, doctors usually assess it from what a patient does, such as opening the eyes, speaking and moving, which is what the scales below record.
Diagram - The Reticular Formation found throughout the Brainstem
SimpleMed original by Dr. Keertana Anne
These functions are carried out by the activation of the ascending reticular activating system (ARAS), which is the pathway connecting the reticular formation to the cerebral cortex. Wake-promoting systems (such as the ARAS) and sleep-promoting neurones inhibit each other, which helps to keep the brain stable in either the awake or the asleep state. Arousal is not all-or-nothing, however: a person can be drowsy, in light sleep or in deep sleep.
The reticular formation functions on a system of inputs and outputs. It receives inputs from the sensory systems and the cortex itself. It sends outputs to three relay sites: the thalamus, the hypothalamus and the basal forebrain (a group of nuclei at the base of the forebrain). These then project onto the cortex (see below). The reticular formation also sends fibres down to the spinal cord, which help to maintain muscle tone.
Diagram - The Reticular Activating System
SimpleMed original by Dr. Keertana Anne
The awake state depends partly on cholinergic fibres (which release acetylcholine) and histaminergic fibres (which release histamine). This helps to explain why drugs that block the action of these chemicals can cause drowsiness. Sedating antihistamines, such as chlorphenamine, are an example, whereas non-drowsy antihistamines are less likely to make a person feel sleepy. Anticholinergic drugs (which block acetylcholine) can also cause drowsiness and, in some people (especially older people), confusion.
Large areas of damage (lesions) to the ARAS itself, or to the connection between the ARAS and the cerebral cortex, can cause a variety of disorders of consciousness. These are explored later on in this article.
Clinical Assessment of Consciousness
There are three primary ways of assessing the conscious state of the brain, and each of them is used in different situations.
Note: ACVPU is a commonly used UK modification of the AVPU scale that includes assessment of new confusion.
The ACVPU scale (Alert, Confused, Voice, Pain, Unresponsive) is used in emergency situations to assess a patient’s response to a variety of stimuli. It is a simple tool used in clinical settings like wards to measure a patient’s conscious level. On observation charts in the UK, a score of anything other than A for Alert prompts review by the medical team.
Alert - the patient is fully awake and shows no evidence of confusion. They will be able to spontaneously open their eyes, speak or move their body.
Confused - the patient is able to respond to you in some way, but is not orientated to place, person or time. This is a new change for the patient, and therefore indicates a potential deterioration in consciousness level.
Responsive to voice - the patient will respond in one of three ways when prompted by a voice. This could be opening the eyes; a verbal response such as a groan; or a slight movement of the limbs.
Responsive to pain - the patient will be able to respond in one of three ways when a painful stimulus is applied. Examples of this include squeezing the fingers or a trapezius squeeze. Central painful stimuli (those applied to the head or trunk, rather than a limb) should be applied carefully to avoid injury.
Unresponsive - the patient is not responsive to any of the above stimuli.
The Glasgow Coma Scale records observed eye, verbal and motor responses. Record the individual components as well as any total, and check for factors that prevent a response from being assessed. A component score does not by itself localise anatomical damage.
Eye Opening
4 Spontaneous eye opening
3 Response to speech
2 Response to pain
1 No eye opening
Verbal Response
5 Orientated to time, place and person
4 Confused speech
3 Inappropriate words
2 Incomprehensible sounds
1 No verbal response
Motor Response
6 Obeys commands
5 Localises to a pressure/pain stimulus
4 Withdraws from pain
3 Abnormal flexion to a pressure/pain stimulus
2 Extensor response to pain
1 No motor response
Diagram - Glasgow Coma Scale responses. Interpret each component with examination findings and factors that interfere with testing.
SimpleMed original by Dr. Keertana Anne
Patients are given an overall score and also a breakdown of the individual components, for example GCS 11 = E3 V4 M4. A score of 15 is the highest possible, and 3 is the lowest (because for each category, no response results in a score of 1). The Glasgow Coma Scale is only used in living patients and does not apply to brain death.
GCS 15 means that the best observed responses score E4, V5 and M6. It does not prove that every neurological structure or function is normal. Interpret the responses alongside the history and examination, accounting for sedation, communication difficulties and other factors that could affect the response. A non-testable component should be documented rather than assumed to score 1.
The Electroencephalogram (EEG)
The EEG is a test used to measure the electrical activity in the brain. It works by placing electrodes a few centimetres apart on the scalp. Each electrode records the combined electrical activity of large numbers of neurones in the cortex beneath it. The EEG has a high temporal resolution, meaning that it is good at timing events, down to milliseconds. It has a low spatial resolution, meaning that it is poor at showing exactly where in the brain the activity comes from, because the electrodes are widely spaced on the scalp (see below).
Diagram - An EEG Recording Cap
Licensed under Creative Commons, Source.
The EEG can detect neuronal synchrony (many neurones firing together in a regular rhythm). Synchrony occurs normally in sleep, when wake-promoting systems are inhibited and the EEG shows large, slow waves. It also occurs in epilepsy, where abnormal excessive or synchronous activity of neurones causes seizures. EEG patterns can also be affected by changes in conscious states such as a coma or brain death.
Sleep is a physiological, recurring process that the human body undergoes and is considered a partially unconscious state of the mind. During the process, the mind and body are both unable to react to stimuli in a way they would normally do if awake, however the brain itself remains very active. The functions of sleep are mostly unknown, but some theories are that sleep has a role in memory consolidation, clearance of extracellular debris (waste material outside cells), and ‘resetting’ of the CNS (central nervous system).
It can be classified into two categories - Rapid Eye Movement (REM) and non-Rapid Eye Movement (non-REM) and the body cycles through these two stages while asleep (see below).
During REM sleep, the EEG pattern is similar to that of an awake person, and the sleeper is able to dream. Muscle tone is greatly reduced (atonia) because lower motor neurones (the nerve cells that carry signals from the spinal cord to the muscles) are inhibited. Some functions are preserved, such as penile erection.
Non-REM sleep is classified as N1, N2 and N3; N3 is slow-wave sleep and combines the older stages 3 and 4. Non-REM sleep generally retains muscle tone. Sleep stages reflect changing activity across sleep–wake networks rather than a simple on/off switch in the arousal system.
Diagram - Historical hypnogram (a graph of sleep stages across the night) using stages 1–4. Current terminology is N1 and N2, with the older stages 3 and 4 combined as N3. This figure illustrates transitions through the night rather than current scoring labels.
Licensed under Creative Commons, Source.
Sleep cycles between non-REM stages N1, N2 and N3 and REM sleep. Deep N3 sleep has prominent high-amplitude (tall) slow waves, reflecting more synchronous cortical activity, whereas REM has low-amplitude (small) activity made up of a mixture of wave speeds (mixed-frequency).
Diagram - Schematic EEG patterns in wakefulness, REM and non-REM stages N1, N2 and N3. Sleep spindles and K-complexes characterise N2; prominent slow waves characterise N3.
SimpleMed original by Dr. Keertana Anne
Awake - characterised by low-amplitude, fast activity. Beta waves (small, fast waves of around 13 to 30 cycles per second, or Hz) are prominent in the awake brain. In relaxed wakefulness, slower alpha waves dominate the recording over the back of the head, and they are suppressed when the eyes open.
N1 sleep - light sleep, with reduced alpha activity (the slower waves of relaxed wakefulness) and low-amplitude (small) activity of mixed speeds, often predominantly theta (slower than alpha).
N2 sleep - characterised by sleep spindles (short bursts of fast activity) and K-complexes (large single waves) against the background EEG. These events help distinguish N2 from N1; N3 is identified by prominent slow-wave activity.
N3 sleep - deep non-REM sleep characterised by prominent high-amplitude slow waves. It combines the older stages 3 and 4.
REM sleep - low-amplitude mixed-frequency EEG activity, which can include sawtooth waves (waves with a jagged, saw-like shape), alongside rapid eye movements and low muscle tone. It resembles wakefulness but is not defined by beta waves alone.
Insomnia - a condition involving difficulty getting to sleep or staying asleep. It has many causes, including stress, anxiety or depression, noise, a room that is too hot or cold, and alcohol, caffeine or nicotine. It often occurs alongside other conditions, including mental health conditions such as anxiety and depression.
Narcolepsy - a rare condition presenting with difficulty regulating sleep-wake cycles, resulting in a person being overcome by sleep at inappropriate times. Many people with narcolepsy also have cataplexy, a sudden loss of muscle strength that can cause a fall and may be triggered by emotions such as anger, sadness or laughter.
Sleep Apnoea - a common condition in which the airway repeatedly narrows or closes during sleep, causing frequent waking. This entry describes obstructive sleep apnoea (OSA), the most common type. Risk factors include increasing age, male sex, obesity (excess neck fat can compress the airway), alcohol and smoking. It causes excessive daytime sleepiness. CPAP (continuous positive airway pressure) is the first-line treatment for moderate to severe OSA: a machine gently pumps air through a mask to keep the airway open. Lifestyle changes such as weight loss, stopping smoking and drinking less alcohol can sometimes be enough on their own.
Disorders of consciousness involve impaired wakefulness, awareness or both. They can follow dysfunction of cerebral hemispheric or arousal networks. Locked-in syndrome is discussed here as an important differential diagnosis, because severe motor impairment can conceal preserved consciousness.
Brain injuries can be categorised into three mechanisms of injury:
- Traumatic, for example as a result of a car accident
- Non-traumatic, caused by acute health conditions such as a stroke or infections
- Progressive brain damage, caused by conditions that gradually worsen over time, such as Alzheimer’s disease or brain tumours. A gradual decline in consciousness from progressive brain damage, usually near the end of life (terminal decline of consciousness), is recognised separately from the prolonged disorders of consciousness that follow sudden-onset brain injury.
The states described below differ in wakefulness, awareness and the ability to demonstrate a response. They are not a single severity ladder, and locked-in syndrome must be distinguished from the other conditions, in which consciousness is impaired. Coma, the vegetative state and the minimally conscious state usually follow sudden-onset brain injury, which may be traumatic or non-traumatic. A disorder of consciousness is called prolonged once it has continued for at least 4 weeks after a sudden-onset brain injury.
Locked-in syndrome: Awareness is preserved despite severe paralysis and inability to speak. Classic cases involve ventral pontine motor pathways with sparing of arousal networks. Vertical eye movements or blinking may permit purposeful communication, so lack of limb movement must not be mistaken for lack of consciousness.
Minimally conscious state: Limited but demonstrable awareness is shown by inconsistent yet reproducible purposeful responses. Two subtypes are described: MCS-minus, with non-reflex behaviours such as visual pursuit or localising a painful stimulus, and MCS-plus, which also shows some language-related behaviour, such as following simple commands, intelligible speech or intentional communication, still inconsistently. Diagnosis requires careful repeated assessment; one isolated movement is insufficient. Reliable functional communication or functional object use indicates emergence from this state.
Vegetative state (unresponsive wakefulness syndrome): Wakefulness, including eye opening and sleep–wake cycles, is present without behavioural evidence of awareness. Reflex and spontaneous movements can occur. Serial assessment is needed to distinguish these from purposeful responses.
Coma: Wakefulness and awareness are absent: the patient cannot be awakened and does not initiate purposeful responses. Reflex responses may remain. Coma can result from bilateral cerebral hemispheric dysfunction or dysfunction of the arousal system; combined cortical and brainstem structural damage is not required. Sedative or anaesthetic drugs can also produce profound unresponsiveness.
Brain death: In the UK this is diagnosed using neurological criteria (also called brainstem death). It means permanent loss of the capacity for consciousness together with permanent loss of the capacity to breathe, because brainstem function has permanently ceased. There is no statutory definition of death in the UK, but the courts recognise brainstem death as legal death. Two doctors perform a full set of clinical tests, including an apnoea test (a test of whether the patient makes any effort to breathe), once the necessary preconditions for testing are met. The tests are repeated on a second occasion. Diagnosis is based on strict clinical criteria rather than EEG findings.
Edited by: Dr. Maddie Swannack
Reviewed by: Adrian Judge and Dr. Marcus Judge
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