Lecture 14
      
                               Schizophrenia: Etiology
                                 Biological Factors
      
      
      Lecture Outline
      
      I.   Introduction
      II.  Biochemistry
           A. Dopamine Hypothesis
           B. Internal Hallucinogens
           C. Immune System   
      III. Psychophysiology
           A. Eye Movement Abnormalities
           B. Event-Related Potentials
      IV.  Brain Imaging: A new technology
           A. Hypofrontality
           B. Cerebral Blood Flow
      V.   Genetics
      VI.  Conclusions
      
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      I. Introduction
      
           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).
      
      II. Biochemistry
      
      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 &
      Africa, 1988):
      
      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
      exacerbated.
      
      4. Disulfiram:  Disulfiram is a chemical which blocks the
      conversion of DA to norepinephrine (also a catecholamine). 
      When this conversion is prevented, schizophrenic symptoms
      worsen. 
      
      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
      (Holzman, 1987).
      
      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).
      
      III. Psychophysiology
      
           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" (Holzman, 1987). 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 the brain. 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 processing. 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 findings. A. Hypofrontality 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). V. Genetics 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. VI. Conclusion 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 schizophrenia.