Reticular formation

The reticular formation is a set of interconnected
nuclei that are located throughout the brainstem.

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The reticular formation is not anatomically well defined because it
includes neurons located in diverse parts of the brain.

The neurons of the reticular formation make up a complex set of networks
in the core of the brainstem that stretches from the upper part of the midbrain
to the lower part of the medulla oblongata.

The reticular formation includes ascending pathways to the cortex in the ascending
reticular activating system (ARAS) and descending pathways to
the spinal cord via the reticulospinal
tracts of the descending reticular formation.

Neurons of the reticular formation, particularly those of the ascending
reticular activating system, play a crucial role in maintaining behavioural
arousal and consciousness.

The functions of the reticular formation are modulatory and premotor.

The modulatory functions are primarily found in the rostral sector of the reticular formation
and the premotor functions are
localized in the neurons in more caudal regions.

The reticular formation is divided into three columns: 

Raphe Nuclei (median) : are the place of synthesis of the
neurotransmitter serotonin, which plays an important role in
mood regulation.

Gigantocellular Reticular Nuclei (medial zone): are involved in
motor coordination. The parvocellular nuclei regulate exhalation.

Parvocellular reticular nuclei (lateral zone).

The reticular formation is essential for governing some of the basic
functions of higher organisms and is one of the phylogenetically oldest portions of the
brain.

The human reticular formation is composed of almost 100 brain nuclei and contains many projections
into the forebrain, brainstem, and cerebellum, among other region.

It includes the reticular nuclei, reticulothalamic projection fibers,
diffuse thalamo-cortical projections, ascending cholinergic projections, descending non-cholinergic projections, and descending reticulospinal
projections.

The reticular formation also contains two major neural subsystems, the ascending reticular activating system and descending
reticulospinal tracts, which mediate distinct cognitive and physiological
proceses.It has been functionally cleaved both sagittally and coronally.

Traditionally the reticular nuclei are divided into three columns:

·        
In the median column – the raphe
nuclei

·        
In the medial column –
gigantocellular nuclei (because of larger size of the cells)

·        
In the lateral column – parvocellular
nuclei (because of smaller size of the cells)

The original functional differentiation was a division of caudal and rostral. This was based upon the observation
that the lesioning of the rostral reticular formation induces a hypersomnia in the cat brain.

In contrast, lesioning of the more caudal portion of the reticular
formation produces insomnia in cats. This study has led to
the idea that the caudal portion inhibits the rostral portion of the reticular
formation.

Sagittal division reveals more morphological distinctions. The raphe nuclei form a ridge in the middle of
the reticular formation, and, directly to its periphery, there is a division
called the medial reticular formation

The medial RF is large and has long ascending and descending fibers, and
is surrounded by the lateral reticular formation.

The lateral RF is close to the motor nuclei of the cranial nerves, and
mostly mediates their function.

Medial and lateral reticular
formation 

The medial reticular formation and lateral reticular formation are two
columns of neuronal nuclei with ill-defined boundaries that send projections
through the medulla and into the mesencephalon (midbrain).

The nuclei can be differentiated by function, cell type, and projections
of efferent or afferent nerves. Moving caudally from
the rostral midbrain, at the site of the rostral pons and the midbrain, the medial RF becomes less prominent, and the
lateral RF becomes more prominent.

Existing on the sides of the medial reticular formation is its lateral cousin, which is particularly pronounced in the rostral medulla
and caudal pons.

Out from this area spring the cranial nerves, including the very important vagus nerve. The Lateral RF is known for
its ganglions and areas of interneurons around the cranial nerves, which serve to mediate their
characteristic reflexes and functions.

General
functions

The reticular formation consists of more than 100 small neural networks,
with varied functions including the following:

1.  
Somatic motor control – Some motor neurons send their axons to the reticular formation nuclei,
giving rise to the reticulospinal tracts of the spinal cord.

These tracts function in maintaining tone, balance, and
posture—especially during body movements.

The reticular formation also relays eye and ear signals to the
cerebellum so that the cerebellum can integrate visual, auditory, and vestibular stimuli in motor coordination.

Other motor nuclei include gaze centers, which enable the eyes to track
and fixate objects, and central pattern generators, which produce rhythmic signals to the muscles of breathing and
swallowing.

2.  
Cardiovascular control – The reticular formation includes
the cardiac and vasomotor centers of the medulla oblongata.

3.  
Pain modulation – The reticular formation is one
means by which pain signals from the lower body reach the cerebral cortex. It is also the origin of the descending analgesic pathways.

The nerve fibers in these pathways act in the spinal cord to block the
transmission of some pain signals to the brain.

4.  
Sleep and consciousness – The reticular formation has
projections to the thalamus and cerebral cortex that allow
it to exert some control over which sensory signals reach the cerebrum and come to our conscious attention. It plays a central role in states
of consciousness like alertness and sleep. Injury to the reticular formation can result in irreversible coma.

5.  
Habituation – This is a process in which the brain learns to ignore repetitive, meaningless
stimuli while remaining sensitive to others. A good example of this is a person
who can sleep through loud traffic in a large city, but is awakened promptly
due to the sound of an alarm or crying baby. Reticular formation nuclei that
modulate activity of the cerebral cortex are part of the ascending reticular
activating system.

Major
subsystems

Ascending reticular activating system

Ascending reticular activating
system. Reticular formation labeled near center.

The ascending reticular activating system (ARAS), also known as
the extrathalamic control modulatory system or simply
the reticular activating system (RAS), is a set of
connected nuclei in the brains of vertebrates that is
responsible for regulating wakefulness and sleep-wake transitions. The ARAS is a part of the reticular
formation and is mostly composed of various nuclei in the thalamus and a number of dopaminergic, noradrenergic, serotonergic, histaminergic, and cholinergic brain nuclei.210

Structure of the ARAS

The ARAS is composed of several neuronal circuits connecting the dorsal
part of the posterior midbrain and anterior pons to the cerebral cortex via distinct pathways that
project through the thalamus and hypothalamus.

The ARAS is a collection of different nuclei – more than 20 on each side
in the upper brainstem, the pons, medulla, and posterior hypothalamus. The
nuclei have their own cytoarchitecture and neurochemical identity and act
as neuromodulators.

The neurotransmitters that these neurons release  include acetylcholine, dopamine, norepinephrine, serotonin, and histamine, and glutamate.

They exert cortical influence through direct axonal projections and
indirect projections through thalamic relays.

The thalamic pathway consists primarily of cholinergic neurons in the pontine tegmentum, whereas the hypothalamic
pathway is composed primarily of neurons that release monoamine neurotransmitters, namely dopamine, norepinephrine, serotonin, and histamine.

The orexin neurons of the lateral hypothalamus innervate every component of the ascending reticular activating
system and coordinate activity within the entire system.1415 The most significant components
of the ARAS include

·        
Serotonergic nuclei: Dorsal raphe nucleus and Median raphe nucleus

·        
Dopaminergic nuclei: Ventral tegmental area and substantia nigra pars compacta

·        
Noradrenergic nuclei: Locus coeruleus and related brainstem nuclei

·        
Histaminergic nuclei: Tuberomammillary
nucleus

·        
Cholinergic nuclei: Forebrain cholinergic nuclei and cholinergic nuclei in
the Pontine tegmentum (laterodorsal
tegmental nucleus and Pedunculopontine
nucleus)

·        
Thalamic nuclei: Thalamic reticular nucleus and Intralaminar nucleus,
particularly the Centromedian nucleus

The ARAS consists of evolutionarily ancient areas of the brain, which
are crucial to survival and protected during adverse periods. As a result, the
ARAS still functions during inhibitory periods of hypnosis.17

The ascending reticular activating system which sends neuromodulatory
projections to the cortex – mainly connects to the prefrontal cortex.

There is seen to be low connectivity to the motor areas of the cortex.

Functions of the ARAS

Consciousness

The ascending reticular activating sytem is an important enabling factor
for the state of consciousness.19 The ascending system is seen to
contribute to wakefulness as characterised by cortical and behavioural arousal.5

Regulating sleep-wake transitions

The main function of the ARAS is to modify and potentiate thalamic and
cortical function such that electroencephalogram (EEG) desynchronization ensues.

There are distinct differences in the brain’s electrical activity during
periods of wakefulness and sleep: Low voltage fast burst brain waves (EEG desynchronization) are associated with wakefulness and REM sleep (which are electrophysiologically similar); high voltage slow
waves are found during non-REM sleep.

 Generally speaking, when thalamic
relay neurons are in burstmode the EEG is
synchronized and when they are in tonic mode it is desynchronized.21 Stimulation of the ARAS
produces EEG desynchronization by suppressing slow cortical waves
(0.3–1 Hz), delta waves (1–4 Hz), and spindle wave oscillations (11–14 Hz) and by
promoting gamma band (20 – 40 Hz) oscillations.14

The physiological change from a state of deep sleep to wakefulness is
reversible and mediated by the ARAS. Inhibitory influence from the brain
is active at sleep onset, likely coming from the preoptic area (POA) of the hypothalamus.
During sleep, neurons in the ARAS will have a much lower firing rate;
conversely, they will have a higher activity level during the waking state.23 Therefore, low frequency inputs
(during sleep) from the ARAS to the POA neurons result in an excitatory
influence and higher activity levels (awake) will have inhibitory influence. In
order that the brain may sleep, there must be a reduction in ascending afferent
activity reaching the cortex by suppression of the ARAS.22

Attention

The ARAS also helps mediate transitions from relaxed wakefulness to
periods of high attention.16 There is increased regional
blood flow (presumably indicating an increased measure of neuronal activity) in
the midbrain reticular formation (MRF) and thalamic intralaminar nuclei during
tasks requiring increased alertness and attention.

Clinical significance of the ARAS

Mass lesions in brainstem ARAS nuclei can cause severe
alterations in level of consciousness (e.g., coma).24 Bilateral damage to the
reticular formation of the midbrain may lead to coma or death.25

Direct electrical stimulation of the ARAS produces pain responses in
cats and educes verbal reports of pain in humans.citation needed Additionally, ascending reticular activation
in cats can produce mydriasis,citation needed which can result from prolonged pain. These
results suggest some relationship between ARAS circuits and physiological pain pathways.26

Pathologiesedit

Given the importance of the ARAS for modulating cortical changes,
disorders of the ARAS should result in alterations of sleep-wake cycles and
disturbances in arousal.27 Some pathologies of the ARAS
may be attributed to age, as there appears to be a general decline in
reactivity of the ARAS with advancing years.28 Changes in electrical coupling
have been suggested to account for some changes in ARAS 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.29 Specifically, disruption of the
ARAS has been implicated in the following disorders:

·        
Narcolepsy: Lesions along the PPT/LDT nuclei
are associated with narcolepsy.30 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.14

·        
Schizophrenia: Intractable schizophrenic patients
have a significant increase (> 60%) in the number of PPN neurons27 and dysfunction of NO
signaling involved in modulating cholinergic output of the ARAS.31

·        
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.27

·        
Progressive supranuclear palsy (PSP): Dysfunction of NO signaling has been implicated in the
development of PSP.31

·        
Depression, autism, Alzheimer’s disease, attention deficit disorder: The exact role of the ARAS 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 ARAS.27

·        
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 ARAS begins early in the disease process.30

Developmental influences

There are several potential factors that may adversely influence the
development of the ascending reticular activating system:

·        
Preterm birth:32 Regardless of birth weight or
weeks of gestation, premature birth induces persistent deleterious effects on
pre-attentional (arousal and sleep-wake abnormalities), attentional (reaction
time and sensory gating), and cortical mechanisms throughout development.

·        
Smoking during pregnancy:33 Prenatal exposure to cigarette smoke is
known to produce lasting arousal, attentional and cognitive deficits in humans.
This exposure can induce up-regulation of nicotinic receptors on ?4b2 subunit
on Pedunculopontine nucleus (PPN) cells, resulting in increased tonic activity, resting membrane potential, and hyperpolarization-activated cation current. These major disturbances of the intrinsic membrane properties of PPN
neurons result in increased levels of arousal and sensory gating deficits (demonstrated by a
diminished amount of habituation to repeated auditory stimuli). It is
hypothesized that these physiological changes may intensify attentional
dysregulation later in life.

Descending reticulospinal tractsedit

Spinal cord tracts – reticulospinal
tract labeled in red, near-center at left in figure.

The reticulospinal tracts, also known as the descending or anterior
reticulospinal tracts, are extrapyramidal motor tracts that descend from the reticular formation  in
two tracts to act on the motor neurons supplying the trunk and proximal limb
flexors and extensors. The reticulospinal tracts are involved mainly in
locomotion and postural control, although they do have other functions as well.
The descending reticulospinal tracts are one of four major cortical pathways to
the spinal cord for musculoskeletal activity. The reticulospinal tracts works
with the other three pathways to give a coordinated control of movement, including
delicate manipulations.36 The four pathways can be
grouped into two main system pathways – a medial system and a lateral system.
The medial system includes the reticulospinal pathway and the vestibulospinal
pathway, and this system provides control of posture. The corticospinal and
the rubrospinal tract pathways
belong to the lateral system which provides fine control of movement.

Components of the reticulospinal tractsedit

The tract is divided into two parts, the medial (or pontine) and lateral
(or medullary) reticulospinal tracts (MRST and LRST).

·        
The MRST is responsible for exciting
anti-gravity, extensor muscles. The fibers of this tract arise from the caudal pontine reticular nucleus and the oral pontine reticular nucleus and project to the lamina VII and lamina VIII of the spinal cord
(BrainInfo)

·        
The LRST is responsible for
inhibiting excitatory axial extensor muscles of movement. The fibers of this
tract arise from the medullary reticular formation, mostly from the gigantocellular
nucleus, and descend the length of the spinal cord in the anterior
part of the lateral column. The tract terminates in lamina VII mostly with some
fibers terminating in lamina IX of the spinal cord.

The ascending sensory tract conveying information in the opposite
direction is known as the spinoreticular tract.

Functions of the reticulospinal tractsedit

1.  
Integrates information from the motor
systems to coordinate automatic movements of locomotion and posture

2.  
Facilitates and inhibits voluntary
movement; influences muscle tone

3.  
Mediates autonomic functions

4.  
Modulates pain impulses

5.  
Influences blood flow to lateral geniculate nucleus of the thalamus.

Clinical significance of the
reticulospinal tractsedit

The reticulospinal tracts are mostly inhibited by the corticospinal tract;
if damage occurs at the level of or below the red nucleus (e.g. to the superior colliculus), it is called decerebration, and causes decerebrate
rigidity: an unopposed extension of the head and limbs. The reticulospinal
tracts also provide a pathway by which the hypothalamus can control sympathetic
thoracolumbar outflow and parasympathetic sacral outflow.

Historyedit

The term “reticular formation” was coined in the late 19th
century by Otto Deiters, coinciding with Ramon y Cajal’s neuron doctrine. Allan Hobson states in his book The
Reticular Formation Revisited that the name is an etymological vestige
from the fallen era of the aggregate field theory in the neural sciences. The term “reticulum” means “netlike
structure,” which is what the reticular formation resembles at first
glance. It has been described as being either too complex to study or an
undifferentiated part of the brain with no organization at all. Eric Kandel describes the reticular
formation as being organized in a similar manner to the intermediate gray
matter of the spinal cord. This chaotic, loose, and intricate form of
organization is what has turned off many researchers from looking farther into
this particular area of the brain.citation needed The cells lack clear ganglionic boundaries,
but do have clear functional organizations and distinct cell types. The term
“reticular formation” is seldom used anymore except to speak in
generalities. Modern scientists usually refer to the individual nuclei that
comprise the reticular formation

Moruzzi and Magoun first
investigated the neural components regulating the brain’s sleep-wake mechanisms
in 1949. Physiologists had proposed that some structure deep within the brain
controlled mental wakefulness and alertness.20 It had been thought that
wakefulness depended only on the direct reception of afferent (sensory) stimuli at the cerebral cortex.

The direct electrical stimulation of the brain could simulate
electrocortical relays. Magoun used this principle to demonstrate, on two
separate areas of the brainstem of a cat, how to produce wakefulness from
sleep. First the ascending somatic and auditory paths; second, a series of “ascending relays from the
reticular formation of the lower brain stem through the midbrain tegmentum, subthalamus and hypothalamus to the internal capsule.The latter was of particular
interest, as this series of relays did not correspond to any known anatomical
pathways for the wakefulness signal transduction and was coined the ascending
reticular activating system (ARAS).

Next, the significance of this newly identified relay system was
evaluated by placing lesions in the medial and lateral portions of the front of the midbrain. Cats with mesancephalic
interruptions to the ARAS entered into a deep sleep and displayed corresponding
brain waves. In alternative fashion, cats with similarly placed interruptions
to ascending auditory and somatic pathways exhibited normal sleeping and
wakefulness, and could be awakened with somatic stimuli. Because these external
stimuli would be blocked by the interruptions, this indicated that the
ascending transmission must travel through the newly discovered ARAS.

Finally, Magoun recorded potentials within the medial portion of the
brain stem and discovered that auditory stimuli directly fired portions of the
reticular activating system. Furthermore, single-shock stimulation of the sciatic nerve also activated the medial
reticular formation, hypothalamus, and thalamus. Excitation of the ARAS did not
depend on further signal propagation through the cerebellar circuits, as the
same results were obtained following decerebellation and decortication. The
researchers proposed that a column of cells surrounding the midbrain reticular
formation received input from all the ascending tracts of the brain stem and
relayed these afferents to the cortex and therefore regulated wakefulness.

 

Reticular formation

Axial section of the pons, at its upper part.

Section of the medulla oblongata at about the middle of the olive. (Formatio reticularis grisea
and formatio reticularis alba labeled at left.)

 

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