RETICULAR ACTIVATING SYSTEM

Sneha Arya

Contents:1. Location and structure a. Anatomical components and reticular formation b. Neurotransmitters.

2. Function a. Regulating sleep-wake transitions b. Attention

3. Clinical relevance a. Pain b. Developmental influences c. Pathologies

4. Consciousness. - disorders associated.

5. Sleep. - sleep wake cycle. - disorders associated.

Introduction• The reticular activating system (RAS) is also

known as extra thalamic control modulatory system.

• The reticular activating system (RAS) is a part of the mammalian brain located in the brain stem.

• This is a complex aggregate of neurons with its cell bodies form clusters in the tegmentum of brainstem, the basal forebrain, and the thalamus.

• It is known as reticular because of its diffuse multipolar synapses and interconnection.

Introduction• This reticular formation can be further subdivided

functionally into 3 columns: the raphe (midline), the medial and lateral region. 

1).Median column: ( midbrain and upper pons) : ascending projections towards the cortex ; useful in arousal and attention. 2).Medial column : ( lower pons and medulla) : intrinsic connections for control of eye movements, swallowing and brainstem reflexes. 3). lateral column: (lower pons and medulla) :Descending projections towards the spinal cord for control of muscle tone, respiration and arterial pressure (ANS)

IntroductionPathway of the reticular formation can be described into 2 parts,

the rostral part and the caudal part. 1). ARAS (activating reticular ascending pathway) : The rostral part (vaguely begin at the level of the upper pons and midbrain), contains neuro chemically classified groups of neurons that project to the cerebral cortex either directly or by relay in the thalamus; and it is important in alertness, wakefulness, maintenance of attention and emotional reactions and learning processes. 2). Descending pathway :The caudal part (vaguely the lower pons and medulla) has projection to the spinal cord and is involved in motor function, respiration and regulation of blood pressure.

Introduction

Neurotransmitters in RAS A). Cholinergic systemCell bodies are found in :1). Nucleus basalis of Meynert( NBM, basal forebrain system).2). Pontomesencephalic tegmental neurons. (PMTN). NBM and PMTN activate the cortical neurons via the thalamic neurons.They are active during waking and REM sleep.Functions:1). Arousal.2). Selective attention.3). Learning and memory.4). Neuronal degeneration. (Alzheimer disease).

Neurotransmitters in RASB). Adrenergic system• Cell bodies are found in locus coeruleus in the midbrain.• The adrenergic neurons are active during waking and slow wave sleep

but cease firing during REM sleep.• The neuronal messenger nitric oxide (NO) may also play an important

role in modulating the activity of the noradrenergic neurons in the RAS.

• NO diffusion from dendrites regulates regional blood flow in the thalamus, where NO concentrations are high during waking and REM sleep and significantly lower during slow-wave sleep.

• Furthermore, injections of NO inhibitors have been found to affect the sleep-wake cycle and arousal.

• Hypocretin/orexin neurons of the hypothalamus activate both the adrenergic and cholinergic components of the RAS and may coordinate activity of the entire system.

Neurotransmitters in RASC). Serotonergic system:Cell bodies are found in:1). Caudal raphe nucleus.2). Rostral raphe nucleus.Functions:1). Arousal and selective attention (RAS).2). Sleep.3). Processing sensory information (pain).4). Regulation of muscle tone and segmental spinal reflexes.

Neurotransmitters in RASD). Histaminergic system:Cell bodies found in:1). Posterior lateral hypothalamus.2). Tubero-mamilliary nucleus.Function:1). Maintaining arousal of the forebrain; which is important in sleep wake cycle.

Reticular Formation

Reticular Formation

Fig. 1 -Afferent connections of reticular formation

Fig. 2 – Efferent connections of reticular formation

Reticular Formation Functions• REGULATION OF SLEEP, thus, the

maintenance of the SLEEPING cycle or CIRCADIAN rhythm;

• Filtering of incoming stimuli to discriminate irrelevant background stimuli;

• It’s crucial to maintain the state of CONSCIOUSNESS related to the circadian rhythm – MELATONIN effects on RAS;

• ANS control – respiratory rate, heart rate, GIT activity.

Clinical relevance: Pain• Direct electrical stimulation of the reticular

activating system produces pain responses in cats and educes verbal reports of pain in humans.

• Additionally, ascending reticular activation in cats can produce mydriasis, which can result from prolonged pain.

• These results suggest some relationship between RAS circuits and physiological pain pathways.

Clinical relevance: Pathologies• Given the importance of the RAS for modulating cortical

changes, disorders of the RAS should result in alterations of sleep-wake cycles and disturbances in arousal.

• Changes in electrical coupling have been suggested to account for some changes in RAS activity:

- If coupling were down-regulated, there would be a corresponding decrease in higher-frequency synchronization (gamma band). - Conversely, up-regulated electrical coupling would increase synchronization of fast rhythms that could lead to increased arousal and REM sleep drive.

Clinical relevance:Specifically, disruption of the RAS has been implicated in the following disorders:1. Schizophrenia• Intractable schizophrenic patients have a significant increase (> 60%)

in the number of PPN neurons and dysfunction of NO signaling involved in modulating cholinergic output of the RAS.

2. Post-traumatic stress disorder, Parkinson's disease, REM behavior disorder• Patients with these syndromes exhibit a significant (>50%) decrease

in the number of locus coeruleus (LC) neurons, resulting is increased disinhibition of the PPN.

3. Narcolepsy• There is a significant down-regulation of PPN output and a loss of

orexin peptides, promoting the excessive daytime sleepiness that is characteristic of this disorder.

Clinical relevance:4. Progressive supranuclear palsy (PSP)• Dysfunction of NO signaling has been implicated in the development

of PSP.5. Depression, autism, Alzheimer's disease, attention deficit disorder• The exact role of the RAS in each of these disorders has not yet been

identified. However, it is expected that in any neurological or psychiatric disease that manifests disturbances in arousal and sleep-wake cycle regulation, there will be a corresponding dysregulation of some elements of the RAS.

6. Parkinson's disease• REM sleep disturbances are common in Parkinson's. It is mainly a

dopaminergic disease, but cholinergic nuclei are depleted as well. Degeneration in the RAS begins early in the disease process.

Consciousness• Consciousness is defined as the state of awareness

of self and the environment.• The consciousness system has two principal

functions:1) Maintenance of waking state (arousal or level of consciousness)2) Content of experience (awareness or content of consciousness).

• Clinical significance: Consciousness tells us about a patient’s alertness, awareness and attention.

Glasgow Coma Scale

• Conscious: normal, attentive; oriented to self, place, and mind• Confused: impaired or slowed thinking; disoriented• Delirious: disoriented, restless, clear deficit in attention;

possible incidence of hallucinations and delusions• Somnolent: excessive drowsiness; little response to external

stimuli• Obtunded: decreased alertness, slowed motor responses;

sleepiness• Stuporous: conscious but sleep-like state associated with little

or no activity; only responsiveness is in reaction to pain• Comatose: no response to stimuli, cannot be aroused; no gag

reflex or pupil response to light

Disturbances in the level of consciousness

A). Locked in syndrome.B). Minimally conscious state.C). Persistent vegetative state.D).Chronic Coma.E). Stupor.F). DeliriumG).SomnolenceH).Twilight state

Disturbances in the level of consciousness

A). Locked-in syndrome is a condition in which a patient is aware and awake but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for the eyes.

Total locked-in syndrome is a version of locked-in syndrome where the eyes are paralyzed as well.

Disturbances in the level of consciousness B). Minimally conscious state• the patient has intermittent periods of awareness and

wakefulness and displays some meaningful behaviour.

C). Persistent vegetative state• the patient has sleep-wake cycles, but lacks awareness

and only displays reflexive and non-purposeful behaviour. After four weeks in a vegetative state (VS), the patient is classified as in a persistent vegetative state. This diagnosis is classified as a permanent vegetative state (PVS) after approximately 1 year of being in a vegetative state.

Disturbances in the level of consciousness C). Chronic coma• the patient lacks awareness and sleep-wake cycles and

only displays reflexive behaviour.

• In medicine, a coma is a state of unconsciousness, lasting more than six hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light, sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions.

• Although a coma patient may appear to be awake, they are unable to consciously feel, speak, hear, or move.

Disturbances in the level of consciousnessD). Stupor• Derived from latin word which means insensible.• It is a state of diminished consciousness in which

the patient remains mute and still although the eyes are open and may follow external objects/respond to base stimuli such as pain.

• Commonly seen in toxic states severe hypothermia, neoplasms of brain, vitamin D deficiency, etc

• Psychiatry schizophrenia(catatonia), severe clinical depression

Disturbances in the level of consciousnessE).Delirium• It is defined as transient reversible altered state of

consciousness commonly associated with hallucinations, delusions, disordered speech, confusion and autonomic dysfunction.

• The level of consciousness may be consistently diminished or may fluctuate.

• Medical conditions- hyponatremia, traumatic head injury, severe hyperthermia, dehydration.

Disturbances in the level of consciousnessF). Somnolence

• Pathological sleepiness or drowsiness from which one can be aroused to a normal state of consciousness.

• In psychiatry most commonly seen in- - insomnia . - Use of psychotropics .

Disturbances in the level of consciousness

G). Twilight state• a state of clouded awareness wherein the person is

transiently not aware of their current environment, experiences fleeting auditory or visual hallucinations, and reacts to them by engaging in irrational acts, like public nudity, fleeing, or committing acts of violence.

• It is commonly seen in dissociative disorders, ganser’s syndrome, LSD abusers.

CYCLE BETWEEN SLEEP & WAKEFULNESS

• There’s yet no explanation for the reciprocal operation of the sleep-wakefulness cycle;

• But some suggest that when the sleep centers are NOT activated, the mesencephalic & upper pontile RAS are released from inhibition, which allows the RAS to become spontaneously active;

• This will excite PNS & Cerebral Cortex, both of which send POSITIVE FEEDBACK to the same reticular activating nuclei to activate them still further;

• So, once wakefulness starts it has a natural tendency to sustain itself;

• After a few hours, the brain & even neurons themselves become fatigued & the positive feedback fades & sleep- promoting centers take over.

REM Sleep

• Active dreaming & active bodily muscle movements.

• Arousal is difficult by sensory stimuli ; whereas spontaneous awakening is easy.

• Muscle tone is exceedingly depressed – strong inhibition of the spinal muscle control areas.

• Heart rate & respiratory rate become irregular.

• Irregular muscle movements occur.

• Brain is ↑ active & brain waves are similar to those of wakefulness.

NREM Sleep• Brain activity lesser than being awake by 30%.

• Muscle tone and body temperature is maintained.• Respiration is regular.

• Decreased heart rate and BP.

• Increased GIT motility.

• Spontaneous arousal is difficult ; by external stimulus is easy.

• Not often associated with dreams.

Sleep Disorders• Insomnia.

• Hypersomnia.

• Narcolepsy and Cataplexy.

• Sleep Apnoea Disorder.

• Nightmare & Night Terror.

• Somnambulism.

• Nocturnal Enuresis.

• Movement Disorders during sleep.

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