A. Dopamine Hypothesis
B. Internal Hallucinogens
C. Immune System
A. Eye Movement Abnormalities
B. Event-Related Potentials
IV. Brain Imaging: A new technology
B. Cerebral Blood Flow
Numerous biological factors have been identified as etiologically
important in schizophrenia. New technologies are allowing investigators
to explore areas previously beyond the reach of science. Indeed, a
number of biological factors are now accepted as having a clearly
established relationship to schizophrenia (Schwartz & Africa, 1988).
Nevertheless, it is notoriously difficult to distinguish between
cause and effect in most studies (Holzman, 1987; Schwartz & Africa,
1988). As we have seen, schizophrenia is characterized by impairment in
many areas of functioning. The problem is that as a severe, chronic
disorder (whether physical or mental) progresses, the disorder per se
often becomes secondary to a general collapse of the organism. It
becomes difficult to separate the original specific causal abnormality
amongst all the secondary abnormalities that are a result of the
disorder, but which are now predominant (Holzman, 1987). AIDS is a good
example of this. The original virus becomes secondary to the host of
ensuing problems (infections, etc). The person dies, not because of the
virus per se, but because of the secondary problems that are a result of
the AIDS virus.
Another problem in the search for etiological factors has been the
attempt by investigators to arrive at a "unitary hypothesis" of
schizophrenia, that is, a single explanatory model of the disorder. If
schizophrenia is a heterogeneous disorder, if there are multiple causes
and discrete subtypes (which seems likely), then searching for a single
explanation will be unproductive (Schwartz & Africa, 1988).
A. Dopamine hypothesis
The role of the neurotransmitter dopamine (DA) has been the
predominant focus of research in the biology of schizophrenia for
several decades (Meltzer, 1987).
The core of the DA hypothesis is the idea that there is an
overactivity of DA present in (at least some) schizophrenics.
Some evidence (Meltzer, 1987; Neale & Oltmanns 1980; Schwartz &
1. Phenothiazines: This class of drugs relieves schizophrenic
symptoms, but produces Parkinson's disease-like symptoms
(Parkinson's disease = a mental deterioration occurring in
one's 40's or 50's characterized by uncontrollable and severe
muscle tremors, stiff gait, expressionless face, withdrawal).
Parkinsonism is known to be caused (in part) by low levels of
DA. In addition, the phenothiazine molecule is very similar
in structure to the DA molecule. So, what may be happening is
that phenothiazine fits into DA receptor sites and blocks DA.
This reduced amount of DA getting to the receptors is perhaps
what relieves schizophrenic symptoms.
2. Amphetamines: These drugs can produce symptoms similar to
paranoid schizophrenia, as well as exacerbate already existing
schizophrenic symptoms. Amphetamines apparently release
catecholamines (DA is one of these) and may also prevent their
inactivation (by blocking reuptake and inhibiting MAO). DA in
particular is implicated because phenothiazine is the antidote
for the amphetamine induced symptoms.
3. Levodopa: This chemical is what is known as a "precursor"
of DA, that is, it is a substance which is synthesized into
DA. When levodopa increases, schizophrenic symptoms are
4. Disulfiram: Disulfiram is a chemical which blocks the
conversion of DA to norepinephrine (also a catecholamine).
When this conversion is prevented, schizophrenic symptoms
5. MAO levels: MAO deactivates DA, so if DA activity is
excessive, then MAO levels should be lower than that found in
people without schizophrenia. Numerous studies have been
conducted which examined MAO levels in the blood platelets of
schizophrenics, and decreased levels are frequently found. In
particular, lowered levels are found with schizophrenics who
hallucinate when compared to nonpatients. Nonhallucinating
schizophrenics, however, have higher levels than nonpatients.
Within groups of schizophrenics, patients who are paranoid and
have auditory hallucinations are most clearly associated with
decreased platelet MAO levels.
6. Receptor Site activity: A more recent development is the
idea that there is not necessarily too much DA, but rather
that the DA receptors are over sensitive. There is some
evidence for this: In postmortem examinations of
schizophrenic patients, there appears to be an increased
number of DA receptors (MacKay et al, 1982). More recent
studies have taken advantage of new technologies, permitting
investigators to examine receptor site activity in living
subjects. We will examine this technology (brain imaging) in
a few minutes. A number of recent studies support the
postmortem findings: DA receptor activity is escalated
B. Internal Hallucinogens
With the growing use of psychoactive drugs (eg: LSD &
Mescaline) during the 60's and 70's, it was noted that these drugs
sometimes seem to create experiences very similar to schizophrenic
symptoms. Mescaline was even similar structurally to the
neurotransmitters DA and norepinephrine. This led to the search
for naturally occurring hallucinogenic chemicals in the brain. One
candidate was the chemical adrenochrome, a substance that can be
synthesized from the catecholamines. This was a fascinating
hypothesis, but it never gained much empirical support. Although
adrenochrome was an exciting possibility, no human metabolic
process exists that can synthesize the substance. Its synthesis
from the catecholamines was limited to the lab (Schwartz & Africa,
1988). In addition, the experiences of an LSD or mescaline "trip"
are not exactly like the symptoms seen in schizophrenia.
Another, more recently identified substance is
dimethyltryptamine which humans may produce in very small amounts.
Dimethyltryptamine appears to be a short-acting, powerful
psychedelic-like neurotransmitter. The evidence, however, is
still very unclear as to the etiological significance of this
substance (Schwartz & Africa, 1988).
C. Immune System and Season of birth
There is growing research that links schizophrenia to viral
infections and possibly weak immune systems (Meltzer, 1987).
Interestingly, there is a tendency for schizophrenics to be born in
winter and early spring months. It is during these months that
many infectious diseases have peak incidences (Bradbury & Miller,
1985). Thus, one possibility is that schizophrenia is due to some
infectious agent that complicates birth and early development.
There have been various alternative hypotheses advanced which
attempt to account for the seasonality effect (Bradbury & Miller,
1985, for review). Chances are there will be more than one reason
for this effect (Bradbury & Miller, 1985).
A. Eye Movement Abnormalities
An interesting finding is that schizophrenics tend to have a
high rate of eye movement dysfunctions, specifically abnormal
saccadic eye movements.
Some background on normal eye movement: The eye movement
system that we are discussing involves the process by which
a person tracks a moving object, such as a swinging pendulum.
As the pendulum begins to move to the right, the eye is delayed
by about 200 milliseconds before it pursues the object.
However, when the eyes finally begin to move, they are already
lagging behind the object; therefore a rapid eye movement, or
saccade, must occur to put the eyes back on the target. Once
on the target, the saccadic movement stops and the eyes
smoothly pursue the object, until there is another change in
the direction of the object. So, the whole process involves
periods of smooth pursuit periodically corrected by small
saccadic jumps (Holzman, 1987).
But for large numbers of schizophrenics and almost half of their
first-degree relatives, this saccadic movement is not turned off
once the eyes are on target. Instead, their eyes continue to make
small rapid, jerky movements (Holzman, Proctor, Levy, et al. 1974).
This is a very consistent finding; according to a recent review,
"there have been no published reports of failures to replicate"
However, eye tracking dysfunction has also been noted in people
with mood disorders, so the specificity of the dysfunction to
schizophrenia has been questioned. Also questioned is whether the
eye dysfunction is a basic trait of schizophrenia, or simply an
impairment that is a consequence of having schizophrenia or
receiving drug treatment for it.
There is evidence that this dysfunction is specific to
schizophrenia: 45-50% of first-degree relatives of schizophrenics
show eye movement abnormalities that are indistinguishable from
those shown by schizophrenics. Only 10% of the relatives of
nonschizophrenic psychiatric patients show similar dysfunction
(Holzman, 1987). In addition, abnormal eye movements in
schizophrenics appear to be unaffected by drug treatments, nor do
they seem related to stage of illness or the schizophrenic person's
motivation. Indeed, they seem to occur in almost all types of
schizophrenic persons (Holzman, 1987). And the fact that the
abnormalities occur in first-degree relatives as well suggests that
this disorder may be genetically transmitted. Eye movement
dysfunction for other disorders (Mood disorder) appear, instead, to
be a result of drug treatments, such as lithium, which is known to
disrupt normal eye-movement. So, although they may appear the
same, eye-movement abnormalities in schizophrenia are hypothesized
to be a basic trait, while these abnormalities in mood disorder are
hypothesized to be a consequence of treatment (Holzman, 1987).
What this all means remains unclear (Schwartz & Africa, 1988),
there is nothing in these studies that indicate abnormal eye-
movements are causally related to schizophrenia. But it does seem
to suggest that there are certain brain abnormalities that are
quite reliably associated with schizophrenia. The eye movement
impairments (a motor behavior) may be reflecting cortical
dysfunctions, especially in the frontal lobe (Levin, 1984).
B. Event-Related Potentials
When a stimulus is presented to a person, particular low
voltage brain wave patterns will ensue. Event-related potential
(ERP) is the term used to refer to this type of electrical activity
of the brain. These electrical potentials reflect the brain
activity associated with perceptual and cognitive processes - a
useful window into the functioning of the brain.
The earlier research in this area focused on potentials that
occur relatively soon after a stimulus: within 250 milliseconds
following the stimulus. The occurrence of these waves indicates
that the basic physical properties (intensity, etc) have been
registered by the person's nervous system. A number of
abnormalities have been found with schizophrenics (Holzman, 1987):
less variation & higher amplitude compared to normals
diffuse rather than localized (normal's ERPs are highly
localized in the sensorimotor and parietal areas of
in general, there is less activity in the left hemisphere
than in the right
These findings suggest that there is an abnormal amount of sensory
information reaching the schizophrenic's brain - that there is a
failure of inhibitory mechanisms at these early stages of
information processing. Selective attention is impaired.
More recent work has focused on ERPs that occur later - after
250 ms following the stimulus onset. Of particular interest has
been a positive wave that occurs at 300ms, referred to as the P300.
P300 waves reflect the cognitive work done on the stimulus by the
person, and not merely the registration of the physical aspects of
the stimulus. P300 waves are enhanced by stimuli that are
unexpected, task relevant, attended to, and consciously apprehended
(Holzman, 1987) (see Figure 14-1). schizophrenics, however, have
P300s that are smaller (attenuated) in amplitude than normals.
This is a quite consistent finding (Buchsbaum & Haier, 1987;
Holzman, 1987). What this suggests is that schizophrenic persons
have trouble extracting information from the stimulus.
In sum, schizophrenia is characterized by impairments both at
the stimulus input end of things, and also during cognitive
Unfortunately, the specificity of these findings to
schizophrenia is still in question. Very few studies have actually
compared schizophrenics with persons with other mental disorders.
P300 attenuation is certainly not limited to schizophrenia: it
occurs in depression, old age, infantile autism, when fatigued, and
with certain drugs as well (Holzman, 1987). Like eye movement
abnormalities, early ERP abnormalities occur in unaffected
relatives, suggesting that there is a genetic component (Holzman,
1987). Both the eye-movement and ERP abnormalities suggest a basic
attentional/ cognitive processing deficit.
IV. Brain Imaging: A new technology
A group of related new technologies has made it possible to study
the structure and processes (metabolism, blood flow, electrical
activity, chemistry) of the living brain (Buchsbaum & Haier, 1987).
These technologies are collectively know as brain imaging. A complete
description of the processes involved in brain imaging is beyond the
scope of this lecture; however, a brief introduction follows.
There are a number of types of imaging. They include X-ray
computed tomography (CT), developed in the early 70's, positron emission
tomography (PET), and magnetic resonance imaging (MRI - also known as
NMR for nuclear magnetic resonance). Each technology produces an image
of the functioning brain on a computer screen. Computer graphics and
colors are used to identify different structures and processes. These
images are constructed by the computer using information acquired from
numerous electrodes or probes placed on the scalp or from rings of
crystals or antennas placed around the head. Direct readings of brain
processes and structures are taken, or low-level radioactive versions of
naturally occurring substances are released in the brain and then
tracked, allowing the researcher to infer the structures and processes
that are present. The end result is a grid of readings, like depth
soundings a ship might make in a bay, representing the topography and
function of the area being imaged. These readings are translated by a
computer into a visual representation of the brain.
Each type of brain imaging has made special contributions: CT and
MRI to the production of anatomical images, PET to images of brain
function measured in terms of chemistry, metabolism and blood-flow. But
above all, brain imaging replaces the need for more dangerous,
unpleasant, and difficult to perform procedures. The importance of this
work was recognized when A. M. Cormack and G. N. Hounsfield won the
Nobel prize in the 1970's for their development of X-ray CT technology
(Gregory, 1987). All of the methods for brain imaging are still under
active development (Buchsbaum & Haier, 1987). Nonetheless,
schizophrenia research has already led to a number of interesting
The ratio of frontal lobe metabolic activity to whole-surface
brain metabolic activity seems to be reduced in schizophrenia
(Buchsbaum & Haier, 1987). For example, frontal lobe protein
synthesis has been found to be attenuated. There is some evidence
that reduced frontal lobe activity may also occur in persons with
bipolar mood disorders (Buchsbaum & Haier, 1987), so the
specificity of hypofrontality is not certain. However,
hypofrontality is a quite consistent finding in schizophrenia
research. Although not confirmed, frontal atrophy does seem to
characterize schizophrenic patients.
B. Cerebral Blood Flow
Reduction in blood flow is a general finding of brain imaging
research. The reduction, however, does not seem to be a
characteristic of the whole brain, as seen in certain organic
disorders, but rather of specifically located brain regions,
especially the frontal cortex (Buchsbaum & Haier, 1987).
The rate of schizophrenia in the general population is less than
one percent. Relatives of schizophrenics are at a significantly higher
risk for schizophrenia. Eg: Children of a schizophrenic parent: 9-16%
Children of 2 affected parents: 40-68%
Identical twins (concordance rate): 50-60%
(but some report figures as high as
high as 86%)
However, if schizophrenia was purely a genetically transmitted disorder,
than the numbers for identical twins should be 100%. They never are, so
there must be other causes as well.
Nevertheless, twin studies and adoption studies consistently
indicate a genetic component to schizophrenia (Gottesman, Mcguffin &
Farmer, 1987). Your text reviews some of these studies - I will let you
review them on your own. These studies establish two things very
firmly: that genes do have some role in at least some types of
schizophrenia, and that genes are not the whole story in schizophrenia.
Today we have examined some of the biological and genetic factors
involved in schizophrenia. Perhaps more than any other psychological
disorder, schizophrenia has clear, established biological abnormalities
associated with its etiology. The continuing development of brain
imaging technologies promises new advances in the study of