The reticular activating system (RAS) is a complex network of neurons located in the brainstem that regulates states of consciousness such as sleep and wakefulness. It is composed of neurotransmitter systems including cholinergic, adrenergic, serotonergic, and histaminergic neurons. The RAS maintains arousal and attention by transmitting signals from the brainstem to the thalamus and cortex. Disruptions in the RAS can result in disturbances of consciousness and sleep-wake cycles, and have been implicated in disorders such as schizophrenia, PTSD, Parkinson's disease, and Alzheimer's disease.

1. RETICULAR
ACTIVATING SYSTEM
Sneha Arya

2. 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.

3. 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.

4. 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)

5. Introduction
Pathway 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.

6. Introduction

7. Neurotransmitters in RAS
A). Cholinergic system
Cell 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).

8. Neurotransmitters in RAS
B). 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.

9. Neurotransmitters in RAS
C). 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.

10. Neurotransmitters in RAS
D). 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.

11. Reticular Formation

12. Reticular Formation
Fig. 1 -Afferent connections of reticular
formation
Fig. 2 – Efferent connections of reticular
formation

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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

20. Disturbances in the level of consciousness
A). Locked in syndrome.
B). Minimally conscious state.
C). Persistent vegetative state.
D).Chronic Coma.
E). Stupor.
F). Delirium
G).Somnolence
H).Twilight state

21. 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.

22. 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.

23. 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.

24. Disturbances in the level of consciousness
D). 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

25. Disturbances in the level of consciousness
E).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.

26. Disturbances in the level of consciousness
F). 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 .

27. 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.

29. 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.

30. 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.

31. 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.

32. Sleep Disorders
• Insomnia.
• Hypersomnia.
• Narcolepsy and Cataplexy.
• Sleep Apnoea Disorder.
• Nightmare & Night Terror.
• Somnambulism.
• Nocturnal Enuresis.
• Movement Disorders during sleep.

33. Thank you