Brain Research Reviews 31 Ž2000.

106–112
www.elsevier.comrlocaterbres

Interactive report

Schizophrenia: the fundamental questions 1

)
Nancy C. Andreasen
UniÕersity of Iowa Hospitals and Clinics, Mental Health Clinical Research Center, 2911 JPP, 200 Hawkins DriÕe, Iowa City, IA 52242-1057, USA
Accepted 29 September 1999

Abstract

Identifying the correct phentotype of schizophrenia is perhaps the most important goal of modern research in schizophrenia. This
identification is the necessary antecedent of indentifying the pathophysiology and etiology. A working model is proposed, which suggests
that the phenotype should be defined on the basis of abnormalities in neural circuits and a fundamental cognitive process. This type of
unitary model may be more heuristic than early ones that were based on heterogeneous signs and symptoms. q 2000 Elsevier Science
B.V. All rights reserved.

Keywords: Schizophrenia; Neural circuits; Creativity; Cognition; Disease phenotypes

Contents

1. Introduction . ....................................................................... 106

2. The definition of the phenotype ............................................................. 107

3. Clues from epidemiology . ................................................................ 108

4. The etiology and pathophysiology of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

4.1. Hypothesis one: The etiologies are multiple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.2 Hypothesis two: The pathophysiology is an abnormality in the regulation and expression of neurodevelopment . . . . . . . . . . . . . . . . 110
4.3. Hypothesis three: The pathology is a ‘disease of neuronal connectivity’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.4. Hypothesis four: The phenotype is defined by a mental metaprocess rather than by clinical symptoms . . . . . . . . . . . . . . . . . . . . . 110

References .......................................................................... 111

1. Introduction ably, but approximately 2r3 of those who develop

Schizophrenia is one of the most important public health
problems that human society confronts. It is a very com-
mon disorder, affecting 1% of the world population. Peo-
ple who develop schizophrenia experience severe suffer-
ing: approximately 10% commit suicide. The treatments
available in the late 1990s reduce this suffering consider-
)
Tel.: q1-319-356-1553; Fax: q1-319-353-8300; E-mail:
nancy-andreasen@uiowa.edu
1
Published on the World Wide Web on 28 October 1999.
schizophrenia require public assistance from governmental
social security systems within a few years after onset w45x.
The majority of people who develop schizophrenia are
unable to return to work or to school and have relatively
minimal social interactions. The costs to society are counted
in billions of dollars w21x.
This serious mental illness manifests itself in signs and
symptoms that encompass the entire range of human men-
tal activity. Because schizophrenia is a brain disease that
manifests itself in the activities of the mind, it damages a
variety of functions that we regard as specifically human.

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 2 7 - 2
 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
Schizophrenia impairs the ability to think creatively and
imaginatively, to have close social relationships with other
human beings, to use language to express ideas with
clarity, or to experience and express a variety of emotions
such as love and fear. People with schizophrenia are
tormented by intrusive experiences such as hearing voices
or by beliefs that they are being persecuted or injured by
those around them or by alien external forces. No single
sign or symptom defines schizophrenia. It is defined by the
fact that people who suffer from it experience abnormali-
ties in many different kinds of mental activities.
Attempts to understand schizophrenia are shaped by
several fundamental questions, which provide themes for
this Nobel Symposium. Some questions addressed by this
symposium are:
What is the correct basis for identifying the phenotype?
What does epidemiology tell us about its etiologyrpa-
thophysiology?
How many etiologies are there?
This chapter provides a brief introduction to these ques-
tions, which will be amplified in the presentations of the
other participants.
2. The definition of the phenotype
The first of these questions, and perhaps the most
fundamental of all of them, is the definition of the pheno-
type Ži.e., the core or true manifestation of the disease..
The definition of the phenotype in schizophrenia is particu-
larly difficult because patients with this illness suffer from
such a diversity of symptoms. Some mental illnesses, such
as depression, are defined by an abnormality in a single
mental system — i.e. depressed or dysphoric mood in the
case of depression. Schizophrenia, on the other hand, is
characterized by symptoms that reflect multiple mental
processes: hallucinations, or abnormalities in perception;
delusions, or abnormalities in inferential thinking; disorga-
nized speech, or abnormalities in language; disorganized
behavior, or abnormalities in behavioral monitoring and
control. Those four symptoms are the classic ‘positive
symptoms’ of schizophrenia in which normal functions are
distorted or exaggerated. The various ‘negative symptoms’
of schizophrenia are another important aspect of the illness
w6,7,33x. They represent a diminution or absence of mental
functions that are normally present. Alogia Žliterally an
absence of words. is a decrease in the fluency of ideas and
language; affective blunting is a diminution in the ability
to express emotions; avolition is a decrease in the ability to
initiate and pursue goal-directed activity; anhedonia is a
decrease in the ability to seek out and experience pleasur-
able activities, and attentional impairment is a decrease in
the ability to focus attention.
These various symptoms are present in patients suffer-
ing from schizophrenia in patterns that may not overlap at
all. One person with schizophrenia may have hallucina-
107
tions and affective blunting, while another may have delu-
sions and attentional impairment. This non-overlapping
pattern of symptoms raises an obvious question: is there a
core or fundamental theme that unites this diversity of
symptoms and that can provide a more general conceptual-
ization of the phenotype?
This fundamental question raises an even more funda-
mental question: What is the correct basis for defining the
phenotype of schizophrenia? While the answer to this
question seems simple and obvious at first glance, closer
inspection suggests that probing deeply below the surface
may be necessary.
The obvious answer is that the phenotype of
schizophrenia is defined by the criterion-based diagnostic
symptoms that have been developed in the past several
decades. The fourth Diagnostic and Statistical Manual of
the American Psychiatric Association Ž1994. ŽDSM IV. w2x
is perhaps the most widely used, although the definition in
the 10th edition of the International Classification of Dis-
ease Ž1990. ŽICD 10. w68x provides a similar alternative.
Both these criterion-based systems take a purely descrip-
tive approach and define schizophrenia on the basis of
presenting clinical signs and symptoms. Instead of trying
to account for the diversity of symptoms, they emphasize
psychotic symptoms as the defining feature Ži.e., delusions
and hallucinations.. While the criterion-based systems are
clinically useful, in that they have provided a reliable
means for physicians around the world to communicate
with one another, their validity is less well established. By
focusing on only a few of the symptoms with which
patients present, they have identified those that are easy to
operationalize, but this narrow approach has probably sac-
rificed validity for the sake of reliability. If the long-term
goal is to identify the pathophysiology and etiology of
schizophrenia, then the definition of the phenotype must
emphasize a definition that is heuristic for studying mecha-
nisms of illness. With their excessive emphasis on positive
or psychotic symptoms, criterion-based approaches such as
DSM may have distracted investigators away from the
‘real illness’ by over-emphasizing clinical signs and symp-
toms, and perhaps even by over-emphasizing the wrong
ones.
When schizophrenia was delineated at the beginning of
the 20th century by Emil Kraepelin w49x and Eugen Bleuler
w22x, both of these clinician scientists stressed the impor-
tance of defining the illness by attempting to identify a
fundamental ‘morbid process’. Both emphasized that psy-
chotic symptoms, such as delusions and hallucinations, are
not specific to schizophrenia, but occur in many other
illnesses such as mood disorders or dementias. For both
Kraepelin and Bleuler, the most important defining feature
was an impairment in the ability to think in a clear, fluent,
and logical way. The person with schizophrenia suffers
primarily from a fragmenting in cognitive processes. Krae-
pelin highlighted this aspect when he named the illness
‘‘dementia praecox’’, or a serious cognitive illness with an
108 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112

onset at a relatively young age. He saw the diversity of
symptoms as unified by the underlying destruction of
cognitive processes:
‘‘Dementia praecox consists of a series of states, the
common characteristic of which is a peculiar destruc-
tion of internal connections of the psychic
personality . . . . The majority of the clinical pictures are
the expression of a single morbid process, though out-
wardly they often diverge very far from one another.’’
Bleuler highlighted the same concept when he renamed
the illness ‘‘schizophrenia’’. Bleuler’s new name referred
to the ‘fragmenting of the mind’ that he believed to be the
fundamental abnormality. Bleuler emphasized that the per-
son with schizophrenia had lost the capacity to have his
thought processes guided by concepts that were correctly
linked together:
Although the clinicians who originally delineated and
defined schizophrenia emphasized that the disorder was
not defined by clinical symptoms, this perspective has
been lost in DSM IV and ICD 10. Both define schizophre-
nia using a polythetic clustering of symptoms. While use-
ful clinically, the improved reliability of these recent stan-
dardized diagnostic manuals may exact a large price in
terms of validity. Defining schizophrenia as a polythetic
cluster makes the search for mechanisms more difficult,
since it leads to a fragmented model: i.e., hallucinations
are usually explained by one mechanism and negative
symptoms by another. The alternative proposed by Krae-
pelin and Bleuler — that schizophrenia is defined by an
abnormality in a fundamental mental process — makes the
search simpler and more tractable. Consequently, several
recent investigators have proposed ‘cognitive models’ of
schizophrenia w16x.

3. Clues from epidemiology

‘‘Of the thousands of associative threads that guide our
thinking, this disease seems to interrupt, quite haphaz-
ardly, sometimes single threads, sometimes a whole
group, and sometimes whole segments of them.’’
Thus the ‘founding fathers’ of schizophrenia believed
that they had identified a disease that had many different
kinds of symptomatic manifestations at the clinical level,
but that was in fact defined by an abnormality in a more
basic mental process. Their thinking, reshaped in 21st
century terms, would be expressed by a ‘working model’
similar to that shown below. Schizophrenia is a disease
that is characterized by multiple different symptoms when
assessed at the clinical level Že.g., hallucinations, avolition.
and multiple disturbances in cognitive processes when
assessed at the systems level Že.g., memory, language..
However, schizophrenia is ultimately a disease of the mind
that is characterized by a ‘disturbance in thinking’ — an
abnormality in a fundamental cognitive process.
As we search for ‘the holy grail’ — the etiology and
pathophysiology of schizophrenia — we can be guided by
some simple and very consistent observations concerning
the epidemiology of the disorder w21x. These include the
following:
1. Schizophrenia has a similar clinical presentation and a
similar prevalence throughout the world — a lifetime
prevalence of approximately 1%. Because schizophre-
nia is at present a lifetime disorder, the lifetime preva-
lence and the point prevalence are essentially the same.
2. Schizophrenia has been present for centuries, as in-
ferred from literary descriptions.
3. ‘Classic’ cases begin in young adult life.
4. Males are more frequently and severely affected.
5. The illness tends to run in families.
6. Despite the fact that the majority of people with
schizophrenia do not marry or have children, the dis-
ease persists in the human population.

Working Model
Etiology: Multiple convergent factors such as
DNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological Experiences

Pathophysiology: Brain development from conception to early adulthood

Že.g., neuron formation, migration, synaptogenesis, pruning, apoptosis, activity dependent changes.

Anatomic and functional disruption in neuronal connectivity and communication

Impairment in a fundamental cognitive process

Impairment in one or more second-order cognitive processes Že.g., attention, memory, language, emotion.

Symptoms of schizophrenia Že.g., hallucinations, delusions, negative symptoms, disorganized speech.

 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
The existence of schizophrenia is not defined by geog-
raphy. Unlike some illnesses Že.g., multiple sclerosis.,
prevalence rates are the same throughout the world. The
similar clinical presentation and lifetime prevalence has
been documented in several international studies. The
largest and most influential of these has been the WHO
International Collaborative Study w60x. Conducted in multi-
ple countries with different cultures and different levels of
industrialization, it documented that the rate of schizophre-
nia varied slightly but that most countries had similar rates
in the expected range.
Although it has sometimes been suggested that
schizophrenia could be ‘a disease of civilization’, this
seems unlikely. Although schizophrenia was only demar-
cated as a specific diagnostic entity at the end of the 19th
century, earlier accounts appear in literature. Many charac-
ters ‘become mad’ in classical tragedy, although the pat-
terns of illness do not map precisely on the modern
conceptions of schizophrenia — a fact probably due to
both literary license and to the fact that the nosology of
mental illness was not highly refined at that time. By the
era of Elizabethan drama, however, we have portrayals of
schizophrenia that closely resemble the modern concept
w5x. The madness of Ophelia in Hamlet is quite similar to
modern schizophrenia, and the portrayal of ‘Poor Tom’,
son of Gloucester pretending to be a ‘Bedlam beggar’
escaped from the large Bethlehem Hospital where mental
patients were housed, is a near-perfect portrayal of both
hallucinations and disorganized speech:
Who gives anything to Poor Tom? Whom the foul fiend
hath led through fire and through flame . . . ? Tom’s
a-cold,,— O, do de, do de, do de . . . Do poor Tom some
charity, whom the foul fiend vexes. There I could have
him now, — and there, and there again, and there.King
Lear III.iv.51
‘Classic’ schizophrenia usually has its onset in the late
teens or early twenties, and it occurs more often in males
and affects them more severely than females. These obser-
vations may contain important clues about pathophysiol-
ogy and etiology. The age of onset is too late for the
mechanism to be simply one of fetal or early childhood
brain development. Whatever the factors are that lead to
this illness, their effects must be cumulative, or must
require a ‘releasing phenomenon’, or both. Because human
brain development is an ongoing process that continues
into early adulthood, the age of onset suggests that the
development of schizophrenia must be influenced by
molecular mechanisms involved in the regulation of brain
maturation and that adolescence is a critical period during
which these mechanisms exert their influence. The male
predominance — a clue that is rarely pursued — suggests
that at least one molecular influence may be x-linked.
Schizophrenia is also familial. It clearly has a genetic
component, although it does not appear to be a purely
109
genetic disease, as Huntington’s disease, Tay Sachs dis-
ease, or cystic fibrosis are. Solid and well-designed stud-
ies, conducted since early in this century, have shown that
the disease tends to run in families w52x. As compared with
the population prevalence of approximately 1%, the preva-
lence among siblings and parents is increased approxi-
mately tenfold to around 10%. The prevalence in the
adopted offspring of schizophrenic mothers, reared by
‘normal mothers’, is also around 10%, indicating that the
familiality of the disorder cannot be explained by the
family environment or the stress of living with a
schizophrenic family member. Twin studies have shown a
concordance rate of approximately 40% in monozygotic
twins, as compared to a 10% concordance in dizygotic
twins. Thus schizophrenia cannot be due only to genetic
factors. Further, it does not follow classical Mendelian
patterns of inheritance. In fact, schizophrenia often co-ex-
ists in familial pedigrees with other psychotic illnesses,
such as severe mood disorders. Nor do symptoms breed
true within families. Thus, as a genetic disorder,
schizophrenia is ‘complex’, much as hypertension or can-
cer are. It probably cannot be explained by a single gene,
or by genetic factors alone.
The fact that schizophrenia persists in the human popu-
lation despite the fact that the majority of people who
develop it do not marry or procreate is fascinating. This
observation should perhaps be coupled with another that
has been less frequently noted and has not yet been
systematically investigated: a substantial number of highly
creative individuals have family members who are in the
schizophrenia spectrum. The association between manic-
depressive illness and creativity is well-established, but
most of this work has focused on literary or artistic
creativity w4,9,47x. In the case of schizophrenia, there may
be a link with scientific creativity instead, although the
evidence at present is only anecdotal. However, an impres-
sive number of Nobel Laureates have an association with
schizophrenia. Bertrand Russell had a son and granddaugh-
ter who suffered from schizophrenia, as well as an aunt
and uncle who probably also suffered from this illness
when it was simply called ‘insanity’ w53x. Albert Einstein
had a son by his first wife who developed schizophrenia
w27x. John Nash, a recent Nobel laureate in economics,
developed schizophrenia himself in his early 30s and also
has a son who suffers from schizophrenia w55x. James
Joyce was emotionally aloof and cold and became increas-
ingly disorganized artistically; his daughter Lucia suffered
from hebephrenic schizophrenia w3x. Isaac Newton was a
solitary, chronically suspicious, and socially aloof man
who had a variety of unusual interests and beliefs; he
would probably be called schizotypal using modern
nomenclature; however, he also had a psychotic break at
age 40 w66x.
Coupled with the persistence of schizophrenia through-
out history despite decreased fertility and procreation, this
modest association between schizophrenia and ‘genius’
110 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
suggests that, perhaps like sickle cell anemia, a predisposi-
tion to schizophrenia may convey a biological advantage.
4. The etiology and pathophysiology of schizophrenia
We can formulate several hypotheses about the illness,
based on its epidemiology, although these are necessarily
speculative. These hypotheses provide a structure on which
‘the search for the holy grail’ may be based.
4.1. Hypothesis one: The etiologies are multiple
Because the prevalence appears to be distributed fairly
evenly throughout space and time, the etiology of
schizophrenia is not linked to a particular place or to a
particular time in history. This suggests, but does not
require, that the etiologies are probably multiple. This
concept is portrayed in the Working Model. Most cases
probably occur as a consequence of multiple hits, much
like cancer — an accumulation of genetic and non-genetic
influences ranging from genes coded within DNA to expo-
sure to toxins or drugs Že.g., radiation, amphetamines.,
viruses and other pathogens, injuries to the brain occurring
at the time of birth or later, nutrition, or psychological
experiences that produce somatic effects such as exposure
to stress. Conceivably, some forms in some individuals
could be due to a single ‘necessary and sufficient’ factor.
More likely Žand more daunting in terms of identifying
etiologies of schizophrenia. is the possibility that the phe-
notype of schizophrenia is produced by the influence of
multiple factors that lead to a final common pathway in the
brain. That is, the schizophrenia of ‘poor Tom’ and of the
last patient that I saw in Iowa could be caused by a
different and even non-overlapping constellation of factors
that produce a similar brain injury, hypothesized in the
Working Model to be an abnormality in neural connectiv-
ity that occurs as the brain develops and modifies itself in
response to a variety of internal and external influences.
4.2. Hypothesis two: The pathophysiology is an abnormal-
ity in the regulation and expression of neurodeÕelopment
Schizophrenia differs from the classical dementias in
that there is no visible neuropathological marker such as
plaques, tangles, or Lewy bodies. Importantly, the gliosis
that is seen as a marker of neuronal death in neurodegener-
ative diseases is not present in schizophrenia w59x. This
suggests that the pathophysiology and etiology must be
related to a maturational or developmental brain process
Že.g., neurite formation, synaptogenesis, neuronal pruning,
apoptosis. w8,23,34,35,48,54,64,65,69 x. This sets the time
period for the etiology of schizophrenia as some time
between the beginning of neuron formation and migration
Žaround the second trimester. and young adult life. Al-
though this is a long time period, it focuses our thinking
about pathophysiology and etiology by suggesting the
importance of examining the molecular processes that
regulate and shape brain development and the external
factors that may influence those processes w1x. The most
typical age of onset is during the late teens and early
twenties, a time when brain maturation is reaching comple-
tion w19x, suggesting that one component of the etiology
must involve a neurodevelopmental process related to these
final stages of ‘brain sculpturing’, such as pruning or
activity-dependent changes Žpsychological experiences that
affect plasticity..
4.3. Hypothesis three: The pathology is a ‘disease of
neuronal connectiÕity’
The study of the neuropathology of schizophrenia is
sometimes called a ‘graveyard’. The search for a single
neuropathology, which began with Kraepelin’s team Žand
included Alzheimer, Nissl, and Brodmann., has not been
successful in finding a ‘marker’. Perhaps this is because
we have been looking in the wrong place or thinking in the
wrong way. The brain abnormalities that have been identi-
fied in schizophrenia, using techniques that range from
neuropathology to neuroimaging, have implicated multiple
regions throughout the brain: frontal cortex, temporal cor-
tex, thalamus, hippocampal complex, basal ganglia, and
even the cerebellum w10–15,20,24,28–31,36,40,44,50,
57,58,61–63x. This suggests that the pathology of the
illness is probably not focal or ‘localizable’ to a single
region. Coupled with the absence of a pathological neural
marker such as plaques and tangles, research to date
suggests that the pathology may involve distributed neural
circuits and neurotransmitter systems w15,17,18,31,38,41,
42,61x. That is, schizophrenia is ‘a disease of neuronal
connectivity’. Perhaps the search must refocus on those
mechanisms that influence and continually shape and re-
shape neural connectivity at the level of dendrites, spines,
synapses, neurotransmitters, and signal transducers. These
mechanisms cannot be visualized and measured using the
traditional methods of neuropathology, which is why those
methods led to a ‘graveyard’. However, a host of newer
tools are now being applied to this question, with increas-
ingly interesting results, as evidenced by many presenta-
tions at this symposium.
4.4. Hypothesis four: The phenotype is defined by a mental
metaprocess rather than by clinical symptoms
When the connectivity and communication within neu-
ral circuitry is disrupted, patients display diverse impair-
ments in cognition and diverse symptoms, the complex and
varied signs and symptoms of schizophrenia. This clini-
cally observed presentation of schizophrenia may not in
fact represent the true phenotype, since it is comprised of
varied symptoms that derive from diverse systems, occurs
in non-overlapping patterns, and does not breed true. In-
 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
stead, the phenotype may perhaps be best defined by a
process that lies behind the symptoms, or a metaprocess,
sometimes also referred to as an endophenotype, which is
a ‘final common pathway’ that defines the illness. This
way of thinking about schizophrenia is very similar to the
way that we think about cancer, which is also a disease
with diverse clinical presentations that are due to a more
fundamental process. For cancer it is misregulation of cell
proliferation. For schizophrenia it is misregulation of infor-
mation processing in the brain. Several different models
have been proposed to define or describe this mental
metaprocess. Following the search for unitary processes
originally suggested by Bleuler and Kraepelin, these mod-
els seek to identify a single fundamental process that
defines the illness. Examples provided in this Nobel sym-
posium include the work of Frith w39x, Holzman w46x, and
Goldman-Rakic w43x. Our work and that of others provide
additional alternative examples w17,25,26,32,37,51,56,67x.
This strategy may offer a more powerful method for
identifying the neural and molecular mechanisms of the
illness and for developing animal models for molecular
and pharmacologic research.
References
w1x S. Akbarian, N.J. Sucher, D. Bradley, A. Tafazzoli, D. Trinh, W.P.
Hetrick, S.G. Potkin, C.A. Sandman, W.E. Bunney, E.G. Jones,
Selective alterations in gene expression for NMDA receptor subunits
in prefrontal cortex of schizophrenics, J. Neurosci. 16 Ž1. Ž1996.
19–30.
w2x American Psychiatric Association, Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition ŽDSM-IV., American Psychi-
atric Press, Washington, DC, 1994.
w3x N.J.C. Andreasen, James Joyce: A portrait of the artist as schizoid,
JAMA 224 Ž1973. 67–77.
w4x N.J.C. Andreasen, A. Canter, The creative writer: Psychiatric symp-
toms and family history, Comp. Psychiatry 15 Ž1974. 123–131.
w5x N.J.C. Andreasen, The artist as scientist: Psychiatric diagnosis in
Shakespeare’s Tragedies, JAMA 235 Ž1976. 1868–1872.
w6x N.C. Andreasen, Negative symptoms in schizophrenia: Definition
and reliability, Arch. Gen. Psychiatry 39 Ž1982. 784–788.
w7x N.C. Andreasen, S. Olson, Negative versus positive schizophrenia:
Definition and validation, Arch. Gen. Psychiatry 39 Ž1982. 789–794.
w8x N.C. Andreasen, H.A. Nasrallah, V.D. Dunn, S.C. Olson, W.M.
Grove, J.C. Ehrhardt, J.A. Coffman, J.H.W. Crossett, Structural
abnormalities in the frontal system in schizophrenia: A magnetic
resonance imaging study, Arch. Gen. Psychiatry 43 Ž1986. 136–144.
w9x N.C. Andreasen, Creativity and mental illness: Prevalence rate in
writers and their first-degree relatives, Am. J. Psychiatry 144 Ž1987.
1288–1292.
w10x N.C. Andreasen, Brain imaging: Applications in psychiatry, Science
239 Ž1988. 1381–1388.
w11x N.C. Andreasen, J.C. Ehrhardt, V.W. Swayze, R.J. Alliger, W.T.C.
Yuh, G. Cohen, S. Ziebell, Magnetic resonance imaging of the brain
in schizophrenia: The pathophysiological significance of structural
abnormalities, Arch. Gen. Psychiatry 47 Ž1990. 35–44.
w12x N.C. Andreasen, K. Rezai, R. Alliger, V.W. Swayze, M. Flaum, P.
Kirchner, G. Cohen, D.S. O’Leary, Hypofrontality in neuroleptic-
naive and chronic schizophrenic patients: Assessment with xenon-133
single-photon emission computed tomography and the Tower of
London, Arch. Gen. Psychiatry 49 Ž1992. 943–958.
111
w13x N.C. Andreasen, L. Flashman, M. Flaum, S. Arndt, V. Swayze, D.S.
O’Leary, J.C. Ehrhardt, W.T.C. Yuh, Regional brain abnormalities
in schizophrenia measured with magnetic resonance imaging, JAMA
272 Ž1994. 1763–1769.
w14x N.C. Andreasen, S. Arndt, V. Swayze, T. Cizadlo, M. Flaum, D.
O’Leary, J. Ehrhardt, W.T.C. Yuh, Thalamic abnormalities in
schizophrenia visualized through magnetic resonance image averag-
ing, Science 266 Ž1994. 294–298.
w15x N.C. Andreasen, D.S. O’Leary, T. Cizadlo, S. Arndt, K. Rezai, L.L.
Ponto, G.L. Watkins, R.D. Hichwa, Schizophrenia and cognitive
dysmetria: A positron-emission tomography study of dysfunctional
prefrontal-thalamic-cerebellar circuitry, Proc. Natl. Acad. Sci. USA
93 Ž18. Ž1996. 9985–9990.
w16x N.C. Andreasen, Linking mind and brain in the study of mental
illnesses: A project for a scientific psychopathology, Science 275
Ž1997. 1586–1593.
w17x N.C. Andreasen, S. Paradiso, D.S. O’Leary, Cognitive dysmetria as
an integrative theory of schizophrenia: A dysfunction in cortical-
cerebellar circuitry? Schizophr. Bull. 24 Ž2. Ž1998. 203–218.
w18x N.C. Andreasen, Understanding the causes of schizophrenia, N.
Engl. J. Med. 340 Ž1999. 645–647.
w19x E. Armstrong, A. Schleicher, H. Omran, M. Curtis, K. Zilles, The
ontogeny of human gyrification, Cereb. Cortex 1 Ž1995. 56–63.
w20x P.E. Barta, G.D. Pearlson, R.E. Powers, S.S. Richards, L.E. Tune,
Auditory hallucinations and smaller superior temporal gyrus volume
in schizophrenia, Am. J. Psychiatry 147 Ž1990. 1457–1462.
w21x D.W. Black, N.C. Andreasen, Schizophrenia, Schizophreniform, and
Delusional ŽParanoid. Disorders, in: The American Psychiatric As-
sociation Textbook of Psychiatry, Washington, 1999, pp. 425–478.
w22x E. Bleuler, ŽTranslated by J. Zinkin, 1950., Dementia Praecox or the
Group of Schizophrenias, International Universities Press, New York,
1911.
w23x F. Bloom, Advancing a neurodevelopmental origin for schizophre-
nia, Arch. Gen. Psychiatry 50 Ž1993. 224–227.
w24x B. Bogerts, Recent advances in the neuropathology of schizophrenia,
Schizophr. Bull. 19 Ž1993. 431–445.
w25x D.L. Braff, M.A. Geyer, Sensorimotor gating and schizophrenia:
Human and animal model studies, Arch. Gen. Psychiatry 47 Ž1990.
181–188.
w26x D.L. Braff, Information processing and attention dysfunctions in
schizophrenia, Schizophr. Bull. 19 Ž1993. 233–259.
w27x D. Brian, Einstein: A Life, Wiley, New York, 1996.
w28x M.S. Buchsbaum, D.H. Ingvar, R. Kessler, R.N. Waters, J. Capel-
letti, D.P. Kammen, C. King, J. Johnson, R.G. Manning, R.W.
Flynn, L.S. Mann, W.E. Bunney, L. Sokoloff, Cerebral glucography
with positron tomography, Arch. Gen. Psychiatry 39 Ž1982. 251–259.
w29x M.S. Buchsbaum, K.H. Neuchterlein, R.J. Haier, J. Wu, N. Sicotte,
E. Hazlett, R. Asarnow, S. Potkin, S. Guich, Glucose metabolic rate
in normals and schizophrenics during the continuous performance
test assessed by positron emission tomography, Br. J. Psychiatry 156
Ž1990. 216–227.
w30x M.S. Buchsbaum, T. Someya, C.Y. Teng, L. Abel, A. Najafi, R.J.
Haier, J. Wu, W.E. Bunney Jr., PET and MRI of the thalamus in
never-medicated patients with schizophrenia, Am. J. Psychiatry 153
Ž1996. 191–199.
w31x M. Carlsson, A. Carlsson, Schizophrenia: A subcortical neurotrans-
mitter imbalance syndrome? Schizophr. Bull. 16 Ž1990. 425–432.
w32x B. Crespo-Facorro, S. Paradiso, N.C. Andreasen, D.S. O’Leary, G.L.
Watkins, L.L.B. Ponto, R.D. Hichwa, Recalling word list reveals
cognitive dysmetria in schizophrenia patients. A PET study, Am. J.
Psychiatry 156 Ž1999. 386–392.
w33x T.J. Crow, Positive and negative schizophrenic symptoms and the
role of dopamine, Br. J. Psychiatry 137 Ž1980. 383–386.
w34x I. Feinberg, Schizophrenia: Caused by a fault in programmed synap-
tic elimination during adolescence? J. Psychiatr. Res. 17 Ž1982.
319–334.
w35x B. Fish, Neurobiological antecedents of schizophrenia in children:
112 N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
Evidence for an inherited, congenital neurointegrative defect, Arch.
Gen. Psychiatry 125 Ž1977. 1–24.
w36x M. Flaum, D.S. O’Leary, V.W. Swayze, D.D. Miller, S. Arndt, N.C.
Andreasen, Symptom dimensions and brain morphology in
schizophrenia and related psychotic disorders, J. Psychiatr. Res. 29
Ž1995. 261–276.
w37x R. Freedman, L.E. Adler, M.C. Waldo, E. Pachtman, R.D. Franks,
Neurophysiological evidence for a defect in inhibitory pathways in
schizophrenia: comparison of medicated and drug-free patients, Biol.
Psychiatry 18 Ž1983. 537–551.
w38x K.J. Friston, C.D. Frith, P. Fletcher, P.F. Liddle, R.S.J. Frakowiak,
Functional tomography: multidimensional scaling and functional
connectivity in the brain, Cereb. Cortex 6 Ž1996. 156–164.
w39x C.D. Frith, The Cognitive Neuropsychology of Schizophrenia,
Lawrence Erlbaum, East Sussix, 1992.
w40x C.D. Frith, K.J. Friston, S. Herold, D. Silbersweig, P. Fletcher, C.
Cahill, R.J. Dolan, R.S.J. Frackowiak, P.F. Liddle, Regional brain
activity in chronic schizophrenic patients during performance of a
verbal fluency task, Br. J. Psychiatry 167 Ž1995. 343–349.
w41x P.S. Goldman-Rakic, Changing concepts of cortical connectivity:
Parallel distributed cortical networks, in: P. Rakic, W. Singer ŽEds..,
Neurobiology of Neocortex, Wiley, New York, 1988, pp. 177–202.
w42x P.S. Goldman-Rakic, Topography of cognition: Parallel distributed
networks in primate association cortex, Annu. Rev. Neurosci. 11
Ž1988. 137–156.
w43x P.S. Goldman-Rakic, Working memory dysfunction in schizophre-
nia, J. Neuropsych. Clin. Neurosci. 6 Ž1994. 348–357.
w44x R.E. Gur, P. Cowell, B.I. Turetsky et al., A follow-up magnetic
resonance imaging study of schizophrenia: Relationship of neu-
roanatomical changes to clinical and neurobehavioral measures,
Arch. Gen. Psychiatry 55 Ž1998. 145–152.
w45x B.C. Ho, N.C. Andreasen, M. Flaum, Dependence on public finan-
cial support early in the course of schizophrenia, Psychiatr. Serv. 48
Ž1997. 948–950.
w46x P.S. Holzman, D.L. Levy, L.R. Proctor, Smooth pursuit eye move-
ments, attention, and schizophrenia, Arch. Gen. Psychiatry 45 Ž1976.
641–647.
w47x K.R. Jamison, Mood disorders and patterns of creativity in British
writers and artists, Psychiatry 52 Ž2. Ž1989. 125–134.
w48x P. Jones, R.M. Murray, The genetics of schizophrenia is the genetics
of neurodevelopment, Br. J. Psychiatry 158 Ž1991. 615–623.
w49x E. Kraepelin, R.M. Barclay, G.M. Robertson, Dementia Praecox and
Paraphrenia, E and S Livingstone, Edinburgh, 1919.
w50x P.F. Liddle, K.J. Friston, C.D. Frith, S.R. Hirsch, T. Jones, R.S.J.
Frackowiak, Patterns of cerebral blood flow in schizophrenia, Br. J.
Psychiatry 60 Ž1992. 179–186.
w51x R.W. McCarley, S.F. Faux, M.E. Shenton, P.G. Nestor, J. Adams,
Event-related potentials in schizophrenia: Their biological and clini-
cal correlates and a new model of schizophrenic pathophysiology,
Schizophr. Res. 4 Ž1991. 209–231.
w52x S.O. Moldin, I.I. Gottesman, At issue: genes, experience, and chance
in schizophrenia-positioning for the 21st century, Schizophr. Bull.
23 Ž4. Ž1997. 547–561.
w53x C. Moorehead, Bertrand Russell: A Life, Viking, New York, 1992.
w54x R.M. Murray, S.W. Lewis, Is schizophrenia a neurodevelopmental
disorder? Br. Med. J. 295 Ž1987. 681–682.
w55x S. Nasar, A Beautiful Mind, Simon and Shuster, New York, 1998.
w56x K.H. Neuchterlein, M.E. Dawson, Information processing and atten-
tional function in the developmental course of schizophrenic disor-
ders, Schizophr. Bull. 10 Ž1988. 160–203.
w57x P. Nopoulos, I. Torres, M. Flaum, N.C. Andreasen, J.C. Ehrhardt,
W.T.C. Yuh, Brain morphology in first episode schizophrenia, Am.
J. Psychiatry 152 Ž12. Ž1995. 1721–1724.
w58x B. Pakkenberg, Pronounced reduction of total neuron number in
mediodorsal thalamic nucleus and nucleus accumens in schizophren-
ics, Arch. Gen. Psychiatry 47 Ž1990. 1023–1028.
w59x G.W. Roberts, N. Colter, R. Lofthouse, E.C. Johnstone, T.J. Crowe,
Is there gliosis in schizophrenia? Investigation of the temporal lobe,
Biol. Psychiatry 22 Ž1987. 1459–1468.
w60x N. Sartorius, A. Jablensky, A. Korten, Early manifestations and first
contact incidence of schizophrenia in different cultures: a prelimi-
nary report on the evaluation of the WHO collaborative study in the
determinants of outcome of severe mental disorders, Psychol. Med.
16 Ž1986. 909–928.
w61x L.D. Selemon, P.S. Goldman-Rakic, The reduced neuropil hypothe-
sis: A circuit based model of schizophrenia, Biol. Psychiatry 45
Ž1999. 17–25.
w62x M.E. Shenton, R. Kikinis, F.A. Jolesz, S.D. Pollak, M. LeMay, C.G.
Wible, H. Hokama, J. Martin, D. Metcalf, M. Coleman, R.W.
McCarley, Abnormalities of the left temporal lobe and thought
disorder in schizophrenia: A quantitative magnetic resonance imag-
ing study, N. Engl. J. Med. 327 Ž1992. 604–612.
w63x D.R. Weinberger, K.F. Berman, R.F. Zec, Physiological dysfunction
of dorsolateral prefrontal cortex in schizophrenia I: regional cerebral
blood flow ŽrCBF. evidence, Arch. Gen. Psychiatry 43 Ž1986.
114–124.
w64x D. Weinberger, Implications of normal brain development for the
pathogenesis of schizophrenia, Arch. Gen. Psychiatry 44 Ž1987.
660–669.
w65x D.R. Weinberger, B.K. Lipska, Cortical maldevelopment, anti-psy-
chotic drugs, and schizophrenia: a search for common ground,
Schizophr. Res. 16 Ž1995. 87–110.
w66x M. White, Isaac Newton: The Last Sorcerer, Addison-Wesley, Read-
ing, Mass, 1997.
w67x A.K. Wiser, N.C. Andreasen, D.S. O’Leary, G.L. Watkins, L.L.B.
Ponto, R.D. Hichwa, Dysfunctional cortico-cerebellar circuits cause
‘cognitive dysmetria’ in schizophrenia, NeuroReport 9 Ž1998. 1895–
1899.
w68x World Health Organization, Chapter V, Mental and Behavioral
Disorders Žincluding disorders of psychological development.: Diag-
nosis Criteria for Research, International Classification of Diseases,
Tenth Edition ŽICD-10., Geneva, 1990.
w69x B.T. Woods, Is schizophrenia a progressive neurodevelopmental
disorder? Toward a unitary pathogenetic mechanism, Am. J. Psychi-
atry 155 Ž12. Ž1998. 1661–1670.