Schizophrenia

As schizophrenia is a complex brain disorder, it likely results from the interplay of genetic,
behavioural, developmental and other factors. The exact cause of this group of illnesses is not
known but stress, trauma and viral infection at an early age are factors thought to be involved.

Schizophrenia can run in families and it is likely that the disease has a genetic component – if
one twin of an identical pair has schizophrenia, there is a 46% chance that the other twin will
also suffer from a schizophrenic disorder. It is not known how many genes are involved or how
the genetic predisposition is transmitted. In addition, recent evidence suggests that schizophrenia
may result when neurons  in the brain form inappropriate connections during foetal
development. It may be that an intrauterine starvation or infection causes such inappropriate
connections to form and these may lie dormant until puberty when substantial neuron
reorganisation occurs in the brain. Identification of specific genes involved in the development of
schizophrenia will provide important clues as to what goes wrong in the brains of people with the
disease and this will guide the development of improved treatments.

Stress imposed by life events or family circumstances appears to be an important external event
associated with schizophrenia. The onset of illness is often associated with a distressful period in
life and it may be that stress can trigger the onset of illness in those people with a genetic
predisposition to the disease.

An imbalance in the concentrations of dopaminergic and glutamatergic systems in the brain is

also thought to play a role in the development of schizophrenia. The dopamine hypothesis states
that the behavioural patterns typical of schizophrenia are a result of overactivity of dopamine in
certain regions of the brain. Serotonin is also important in schizophrenia and it may be that the
serotonin system interacts with the dopamine system to modify the way in which it operates. The
serotonin receptors which are important in the treatment of schizophrenia are 5-HT1, 5-HT2 and
5-HT3.

What Happens in the Brain?

The areas of the brain implicated in schizophrenia are the forebrain  , hindbrain  and limbic
system  .

It is thought that schizophrenia may be caused by a disruption in some of the functional circuits
in the brain, rather than a single abnormality in one part of the brain. Although the brain areas
involved in this circuit have not been defined, the frontal lobe, temporal lobe, limbic system,
(specifically the cingulate gyrus  , the amygdala  and the hippocampus  ) and the thalamus 
are thought to be involved. The cerebellum  , which forms part of the hindbrain, also appears to
be affected in people with schizophrenia.

neurotransmitters  are implicated in the development of schizophrenia. The dopamine

hypothesis of schizophrenia postulates that schizophrenia is caused by an overactive dopamine
system in the brain; excessive dopamine and reduced striatal activity can disrupt all aspects of
motor, cognitive and emotional functioning and can result in an acute schizophrenic psychosis.
An excessive dopamine concentration in the brain of people with a schizophrenic disorder was
originally thought to be associated with increased activity of the D2 class of dopamine receptors
in the prefrontal cortex  . Recent studies indicate that reduced numbers of the D1 class of
dopamine receptors may contribute to the rise in dopamine concentration. Other
neurotransmitters, including serotonin, glutamate, gamma aminobutyric acid and acetylcholine
may also be involved in the pathogenesis of schizophrenia. It may be that due to the careful
orchestration between neurotransmitter systems, an imbalance in one neurotransmitter affects
others which are not causally involved in the pathogenesis of disease.

Several structural changes are found in the brains of people with schizophrenia, most of which
occur in the forebrain. Reductions in the volume of grey matter  in the frontal lobe, and
decreased brain volume and activity, have been repeatedly noted among people with a
schizophrenic disorder. The ventricles  are commonly found to be larger than normal, as are the
basal nuclei  , while the hippocampus and amygdala are often smaller. The disease is also
associated with alterations in blood flow to certain areas of the brain.
The Brain
Three cavities, called the primary brain vesicles, form during the early embryonic development
of the brain. These are the forebrain (prosencephalon), the midbrain (mesencephalon), and the
hindbrain (rhombencephalon).

During subsequent development, the three primary brain vesicles develop into five secondary
brain vesicles. The names of these vesicles and the major adult structures that develop from the
vesicles follow (see Table 1 ):

 The telencephalon generates the cerebrum (which contains the cerebral cortex, white
matter, and basal ganglia).
 The diencephalon generates the thalamus, hypothalamus, and pineal gland.
 The mesencephalon generates the midbrain portion of the brain stem.
 The metencephalon generates the pons portion of the brain stem and the cerebellum.
 The myelencephalon generates the medulla oblongata portion of the brain stem

TABLE 1 The Vesicles and Their Components

Important Components or
Primary Vesicles Secondary Vesicles Adult Structure Features
prosencephalon telencephacerebrum cerebral (cerebral cerebral cortex (gray matter):
(forebrain) hemispheres) motor areas, sensory areas,
association areas
prosencephalon telencephacerebrum cerebral (cerebral cerebral white matter:
(forebrain) hemispheres) association fibers, commisural
fibers, projection fibers
prosencephalon telencephacerebrum cerebral (cerebral basal ganglia (gray matter):
(forebrain) hemispheres) caudate nucleus & amygdala,
putamen, globus pallidus
prosencephalon diencephalon diencephalon thalamus: relays sensory
information
prosencephalon diencephalon diencephalon hypothalamus: maintains body
(forebrain) homeostasis
prosencephalon diencephalon diencephalon mammillary bodies: relays
(forebrain) sensations of smells to cerebrum
prosencephalon diencephalon diencephalon optic chiasma: crossover of optic
(forebrain) nerves
prosencephalon diencephalon diencephalon infundibulum: stalk of pituitary
(forebrain) gland
prosencephalon diencephalon diencephalon pituitary gland: source of
 Important Components or
Primary Vesicles Secondary Vesicles Adult Structure Features
(forebrain) hormones
prosencephalon diencephalon diencephalon epithalamus: pineal gland
(forebrain)
mesencephalon mesencephalon brain stem midbrain: cerebral peduncles,
(midbrain) sup. cerebellar peduncles,
corpora quadrigemina, superior
colliculi
rhombencephalon metencephalon brain stem pons: middle cerebellar
(hindbrain) peduncles, pneumotaxic area,
apneustic area
rhombencephalon metencephalon cerebellum sup. cerebellar peduncles,
(hindbrain) middle cerebellar peduncles,
inferior cerebellar peduncles
rhombencephalon myelencephalon brain stem medulla oblongata: pyramids,
(hindbrain) cardiovascular center,
respiratory center

 .

A second method for classifying brain regions is by their organization in the adult brain. The
following four divisions are recognized (see Figure 1 ).
 Figure The four divisions of the adult brain.
1

 The cerebrum consists of two cerebral hemispheres connected by a bundle of nerve

fibers, the corpus callosum. The largest and most visible part of the brain, the cerebrum,
appears as folded ridges and grooves, called convolutions. The following terms are used
to describe the convolutions:
o A gyrus (plural, gyri) is an elevated ridge among the convolutions.
 o A sulcus (plural, sulci) is a shallow groove among the convolutions.
o A fissure is a deep groove among the convolutions.

The deeper fissures divide the cerebrum into five lobes (most named after bordering skull
bones)—the frontal lobe, the parietal love, the temporal lobe, the occipital lobe, and the
insula. All but the insula are visible from the outside surface of the brain.

A cross section of the cerebrum shows three distinct layers of nervous tissue:

o The cerebral cortex is a thin outer layer of gray matter. Such activities as speech,
evaluation of stimuli, conscious thinking, and control of skeletal muscles occur
here. These activities are grouped into motor areas, sensory areas, and association
areas.
o The cerebral white matter underlies the cerebral cortex. It contains mostly
myelinated axons that connect cerebral hemispheres (association fibers), connect
gyri within hemispheres (commissural fibers), or connect the cerebrum to the
spinal cord (projection fibers). The corpus callosum is a major assemblage of
association fibers that forms a nerve tract that connects the two cerebral
hemispheres.
o Basal ganglia (basal nuclei) are several pockets of gray matter located deep inside
the cerebral white matter. The major regions in the basal ganglia—the caudate
nuclei, the putamen, and the globus pallidus—are involved in relaying and
modifying nerve impulses passing from the cerebral cortex to the spinal cord.
Arm swinging while walking, for example, is controlled here.
 The diencephalon connects the cerebrum to the brain stem. It consists of the following
major regions:
o The thalamus is a relay station for sensory nerve impulses traveling from the
spinal cord to the cerebrum. Some nerve impulses are sorted and grouped here
before being transmitted to the cerebrum. Certain sensations, such as pain,
pressure, and temperature, are evaluated here also.
o The epithalamus contains the pineal gland. The pineal gland secretes melatonin,
a hormone that helps regulate the biological clock (sleep-wake cycles).
o The hypothalamus regulates numerous important body activities. It controls the
autonomic nervous system and regulates emotion, behavior, hunger, thirst, body
temperature, and the biological clock. It also produces two hormones (ADH and
oxytocin) and various releasing hormones that control hormone production in the
anterior pituitary gland.

The following structures are either included or associated with the hypothalamus.

o The mammillary bodies relay sensations of smell.

o The infundibulum connects the pituitary gland to the hypothalamus.
o The optic chiasma passes between the hypothalamus and the pituitary gland.
Here, portions of the optic nerve from each eye cross over to the cerebral
hemisphere on the opposite side of the brain.
 The brain stem connects the diencephalon to the spinal cord. The brain stem resembles
the spinal cord in that both consist of white matter fiber tracts surrounding a core of gray
matter. The brain stem consists of the following four regions, all of which provide
connections between various parts of the brain and between the brain and the spinal cord.
(Some prominent structures are illustrated in Figure 2 ).

Figure Prominent structures of the brain stem.

2

o The midbrain is the uppermost part of the brain stem.

o The pons is the bulging region in the middle of the brain stem.
o The medulla oblongata (medulla) is the lower portion of the brain stem that
merges with the spinal cord at the foramen magnum.
o The reticular formation consists of small clusters of gray matter interspersed
within the white matter of the brain stem and certain regions of the spinal cord,
diencephalon, and cerebellum. The reticular activation system (RAS), one
component of the reticular formation, is responsible for maintaining wakefulness
and alertness and for filtering out unimportant sensory information. Other
components of the reticular formation are responsible for maintaining muscle tone
and regulating visceral motor muscles.
 The cerebellum consists of a central region, the vermis, and two winglike lobes, the
cerebellar hemispheres. Like that of the cerebrum, the surface of the cerebellum is
convoluted, but the gyri, called folia, are parallel and give a pleated appearance. The
cerebellum evaluates and coordinates motor movements by comparing actual skeletal
movements to the movement that was intended.
The limbic system is a network of neurons that extends over a wide range of areas of the brain.
The limbic system imposes an emotional aspect to behaviors, experiences, and memories.
Emotions such as pleasure, fear, anger, sorrow, and affection are imparted to events and
experiences. The limbic system accomplishes this by a system of fiber tracts (white matter) and
gray matter that pervades the diencephalon and encircles the inside border of the cerebrum. The
following components are included:

 The hippocampus (located in the cerebral hemisphere)

 The denate gyrus (located in cerebral hemisphere)
 The amygdala (amygdaloid body) (an almond-shaped body associated with the caudate
nucleus of the basal ganglia)
 The mammillary bodies (in the hypothalamus)
 The anterior thalamic nuclei (in the thalamus)
 The fornix (a bundle of fiber tracts that links components of the limbic system)

Neurotransmitters

Many studies have investigated the possible role of brain neurotransmitters in the development
of schizophrenia. Most of these studies have focused on the neurotransmitter called dopamine.
The "dopamine theory of schizophrenia" states that schizophrenia is caused by an overactive
dopamine system in the brain. There is strong evidence that supports the dopamine theory, but
there are also some data that do not support it:

Evidence FOR the Dopamine Theory of Schizophrenia:

1. Drugs that block dopamine reduce schizophrenic symptoms.

2. Drugs that block dopamine have side effects similar to Parkinson's disease.
Parkinson's disease is caused by a lack of dopamine in a parts of the brain called the basal
ganglia.
3. The best drugs to treat schizophrenia resemble dopamine and completely block dopamine
receptors.
4. High doses of amphetamines cause schizophrenic-like symptoms in a disorder called
"amphetamine psychosis." Amphetamine psychosis is a model for schizophrenia because
drugs that block amphetamine psychosis also reduce schizophrenic symptoms.
Amphetamines also make the symptoms of schizophrenia worse.
5. Children at risk for schizophrenia may have brain wave patterns similar to adults with
schizophrenia. These abnormal brain wave patterns in children can be reduced by drugs
that block dopamine receptors.

Evidence AGAINST the Dopamine Theory of Schizophrenia:

1. Amphetamines do more than increase dopamine levels. They also alter other neurotransmitter
levels.
2. Drugs that block dopamine receptors act on receptors quickly. However, these drugs
sometimes take many days to change the behavior of people with schizophrenia.
3. The effects of dopamine blockers may be indirect. These drugs may influence other systems
that have more impact on the schizophrenic symptoms.
4. New drugs for schizophrenia, for example, clozapine, block receptors for both serotonin and
dopamine.
5. There are approximately 50 neurotransmitters identified. There are billions of nerve cells
located in the brain, which do not directly touch each other. Nerve cells communicate
messages by secreting neurotransmitters. Neurotransmitters can excite or inhibit neurons
(nerve cells). Some common neurotransmitters are acetylcholine, norepinephrine, dopamine,
serotonin and gamma aminobutyric acid (GABA). Acetylcholine and norepinephrine are
excitatory neurotransmitters while dopamine, serotonin, and GABA are inhibitory. Each
neurotransmitter can directly or indirectly influence neurons in a specific portion of the brain,
thereby affecting behavior.
Mechanism of impulse transmission
6. A nerve impulse travels through a nerve in a long, slender cellular structure called an axon,
and it eventually reaches a structure called the presynaptic membrane, which contains
neurotransmitters to be released in a free space called the synaptic cleft. Freely flowing
neurotransmitter molecules are picked up by receptors (structures that appear on cellular
surfaces that pick up molecules that fit into them like a "lock and key") located
7. Neurotransmitters are chemicals that transmit messages from one nerve cell (neuron)
to another. The nerve impulse travels from the first nerve cell through the axon—a
single smooth body arising from the nerve cell— to the axon terminal and the synaptic
knobs. Each synaptic knob communicates with a dendrite or cell body of another
neuron, and the synaptic knobs contain neurovesicles that store and release
neurotransmitters. The synapse lies between the synaptic knob and the next cell. For
the impulse to continue traveling across the synapse to reach the next cell, the synaptic
knobs release the neurotransmitter into that space, and the next nerve cell is stimulated
to pick up the impulse and continue it.
8. in a structure called the postsynaptic membrane of another nearby neuron. Once the
neurotransmitter is picked up by receptors in the postsynaptic membrane, the molecule is
internalized in the neuron and the impulse continues. This process of nerve cell
communication is extremely rapid.
9. Once the neurotransmitter is released from the neurotransmitter vesicles of the presynaptic
membrane, the normal movement of molecules should be directed to receptor sites located on
the postsynaptic membrane. However, in certain disease states, the flow of the
neurotransmitter is defective. For example, in depression, the flow of the inhibitory
neurotransmitter serotonin is defective, and molecules flow back to their originating site (the
presynaptic membrane) instead of to receptors on the postsynaptic membrane that will
transmit the impulse to a nearby neuron.
10. The mechanism of action and localization of neurotransmitters in the brain has provided
valuable information concerning the cause of many mental disorders, including clinical
depression and chemical dependency, and in researching medications that allow normal flow
and movement of neurotransmitter molecules.