The Etiology of Schizophrenia and the Origin of Language:

Overview of a Theory
Marcelo T. Berlim, Betina S. Mattevi, Paulo Belmonte-de-Abreu, and Timothy J. Crow
Schizophrenia is present in all human populations
with approximately the same incidence. Why does
such illness persist given that it is associated with a
reproductive disadvantage? What is the balancing advantage? A possible explanation is linked to human
language. According to this hypothesis schizophrenia
occurs as a manifestation of genetic diversity associated with languagethe function by which Homo sapiens has separated from other primate species. Language originated by a genetic mutation that allowed

the cerebral hemispheres to develop with a degree of

specialization (or lateralization) reected in cerebral
asymmetries. Individuals with schizophrenia show
lesser structural and functional brain asymmetries
than the population as a whole, and this nding can
be interpreted as a delay, or failure in, establishing
hemispheric dominance for language. We review recent evidence supporting this theory.
Copyright 2003, Elsevier Science (USA). All rights reserved.

False facts are highly injurious to the progress of

science for they often endure long; but false views (. . .)
do little harm, as everyone takes a salutary pleasure in
proving their falseness, and when this is done, one path
toward error is closed and the road to truth is often at
the same time opened.
Charles R. Darwin1 (1809-1882)

toms associated with signicant affective disturbance) exemplies the crisis of the quest for categorical disease entities among the psychoses. Thus,
no objective genetic boundary can be drawn between illnesses that are predominantly affective
and those that are predominantly schizophrenic,
and one searches in vain for any single feature that
can be regarded as pathognomonic of any of these
syndromes. In sum, it seems that there are no
disease entities, only continua of variation.2,5,7
While a categorical concept is compatible with
an environmental (exogenous) etiology, a continuum suggests rather that the disorder represents a
component that is intrinsic to the individual, i.e., an
extreme of variation in the normal population.5,7

THE CONTINUUM OF PSYCHOTIC ILLNESS

HE NOTION that there are discrete categories

of disease underpins most modern psychiatric classications, and exerts a profound inuence
on etiological thinking. However, in the absence of
a demonstrable etiology or pathology of mental
disorders, a number of criticisms of this arbitrary
categorical approach have been expressed.2-7
Since Kraepelin, it has been widely held that
schizophrenia and affective (manic-depressive)
psychoses are distinct entities with different patterns of symptoms, treatments, outcomes, and, by
implication, etiologies.2,4 This dichotomy has fared
so well that no respectable textbook is without
separate chapters on the two diseases. Whereas
Kraepelin was right to insist that there are prototypical affective and schizophrenic illnesses and
that form of illness predicts outcome, there is a
question whether there are really two etiologically
distinct diseases.8,9 Indeed, Kraepelin10 himself
may well have developed doubts in later years.
Recent evidence from family studies, which
shows a partial overlap in familial susceptibility
for schizophrenic and bipolar disorders,11 ts more
readily with the notion that there exists a continuum of variation that stretches from the typical
manic-depressive patient at one end to the typical schizophrenic patient at the other.2,6,12 Moreover, the creation of the concept of schizoaffective
disorder (characterized by schizophrenic symp-

THE ROLE OF ENVIRONMENTAL FACTORS

Studies looking for specic environmental contributors to schizophrenias etiology have failed to
achieve this objective. For example, in the two
most recent case-control studies,13,14 with a larger
number of schizophrenics than any of their predecessors and in which controls were tightly matched
to cases, the authors failed to nd any substantial
evidence that the incidence of obstetric complications (obtained from structured records) in people
From the Schizophrenia Research Group, Department of
Psychiatry and Forensic Medicine, Federal University of Rio
Grande do Sul (UFRGS), Porto Alegre, Brazil; Department of
Psychiatry, Warneford Hospital, Oxford University, Oxford,
UK; and the Prince of Wales International Centre for Research
on Schizophrenia and Depression (POWIC), Oxford, UK.
Address reprint requests to Marcelo T. Berlim, M.D., Rua
Santana 312/201, CEP 90040-370, Porto Alegre, RS, Brazil.
Copyright 2003, Elsevier Science (USA). All rights reserved.
0010-440X/03/4401-0040$35.00/0
doi:10.1053/comp.2003.50003

Comprehensive Psychiatry, Vol. 44, No. 1 ( January/February), 2003: pp 7-14

BERLIM ET AL

who subsequently develop schizophrenia is raised

in comparison to controls. Moreover, a review of
the literature on prenatal exposure to inuenza
virus and its relation to schizophrenia concluded
that there were substantial discrepancies between
studies concerning the size of the putative effect,
and contradictions concerning its existence.15
More recently, Battle et al.,16 using one of the
largest samples of schizophrenic patients in the
literature to date, showed that prenatal exposure to
both inuenza or measles was not predictive of
schizophrenia prevalence. Similar conclusions regarding the irrelevance of environmental factors
can be drawn from recent studies on discordant
monozygotic twins: no consistent differences between well and ill twins were identied. Discordance may therefore represent an intrinsic and random developmental rather than an extrinsic
environmental difference between the twins. Additionally, the observations that adoption away from
a family with psychosis does not reduce risk,2 that
early separation of monozygotic twins does not
reduce concordance rates,17 and that onset of illness in siblings is at the same age and not at the
same time18 all suggest that schizophrenia is probably independent of the environment, i.e., it is
intrinsic and therefore presumably genetic in origin.
THE UNIVERSALITY OF SCHIZOPHRENIA

In contrast to the conclusion that no clear boundaries between psychotic illness can be drawn, are
ndings concerning homogeneities in its incidence.
The World Health Organization (WHO) Ten Country Study of Incidence19 (carried out in Japan,
India, Northern Europe, and Hawaii, among other
centers), showed that as the criteria for a diagnosis
of schizophrenia were more closely drawn (by the
presence of nuclear symptomsdisorders of the
experience of thought, and certain types of auditory hallucinations, that arguably constitute a pathology of the relationship between thought and
language) the previous discrepancies in incidence
between different research centers lost their statistical signicance. Thus, schizophrenia may be seen
as a disease of humanity, appearing with similar
incidence in populations that differ widely in geographic, climatic, and social environment, and that
have been separated for thousands of years. This
illness, it seems, may be traced back to the origins

of our species, i.e., to the speciation event for

modern Homo sapiens.7,20
THE NEED FOR AN EVOLUTIONARY THEORY

Given that: (1) schizophrenia seems to be genetic in origin, (2) its onset occurs a mean 2 to 3
years earlier in males than females and coincides
with the reproductive phase of life, and (3) it is
associated with a substantial decrease in fecundity
(of approximately 30% in females and 70% in
males) probably due to the difculty that individuals with this illness have in establishing a pair
bond, why is the gene (or genes) responsible for it
not rapidly eliminated from the human population?2,7,20 The fact of constancy across cultures
suggests that the balancing advantage is not restricted to a subpopulation but is present in the
population as a whole. Thus, an evolutionary theory is required to explain how the signicant genetic variation (that includes a component that is
disadvantageous) is maintained in the face of continuing selection.
SCHIZOPHRENIA AS THE PRICE OF THE
SPECIATION EVENT

What balancing advantage, common to human

populations and still under selective pressure,
might be associated with schizophrenia? If the
predisposition is a part of variation that crosses the
population as a whole, and if it can be traced back
to the origin of Homo sapiens (i.e., to the so-called
speciation event dated to 100,000 or more years
ago in East Africa21,22), one plausible conclusion is
that the genetic variation or the mechanism that
gives rise to this illness is associated with the
feature that characterizes our species, and language
(in the broad sense of an ability to communicate
with the use of symbols) stands out as the most
biologically relevant feature, and the one that can
be most readily understood in terms of a neural
mechanism.23 Language is described as the function that separated modern humans from the earlier
hominids24-28 and that enabled human species to
multiply in numbers, cover the surface of the
globe, and change the environment in a way that no
previous species had done.7
Human language has characteristics (e.g., arbitrary association of the signthe wordwith its
meanings, grammatical structure, embedding of
clauses) that are absent in other primate communication systems (e.g., vervet monkeys can com-

SCHIZOPHRENIA AND LANGUAGE: A THEORY

municate eagle, leopard, or snake to other

vervets, but the signs which they use are xed),25-27
and the number of possible sentences is effectively
innite (e.g., there are of the order of 1020 grammatically meaningful sentences of 20 words or
fewer28) but each properly formed sentence can be
recognized as such by a competent speaker of that
language at rst hearing.24
While the capacity for language clearly evolved
from an earlier system of social interaction or
protolanguage, such abilities did not include the
grammatical framework for generating and manipulating symbols that is the hallmark of human
communication.29 Accordingly, it appears that the
transition was relatively abrupt, that is that it was
not a graduated response to environmental selection.27,30 Moreover, human syntactic ability require
a set of component mechanisms (e.g., use of null
and grammatical elements, subcategorization of
verbs) that function only as a whole and are unlikely to have evolved sequentially.26
Evidence that strengthens the relationship between schizophrenia and language comes from two
independent ndings: (1) schizophrenic illnesses
with the same features are present in the Australian
aboriginal and in the Japanese, Indian, and North
European populations that separated from the rest
of modern humans at least 50,000, and 10,000
years ago, respectively, and (2) human linguistic
ability, as demonstrated by the presence of representational capacity in rock art and other artefacts,
can be traced back in independent populations to
60,000 years.7,26,31 Its presence is therefore compatible with the introduction of the capacity at
some earlier time (e.g., 100 to 150,000 years ago)
as suggested by the genetic evidence for the origin
of modern human populations but not with an
association with a previous species. Thus, a parsimonious conclusion is that psychosis and language
are both linked to the genetic change that originated the species.
CEREBRAL ASYMMETRY AS THE NEURAL
BASIS FOR LANGUAGE

Such a speciation event introduced a new

principle to the function of the nervous system that
allowed hemispheres to develop with a degree of
independence toward a progressive specialization
with the establishment of dominance (or lateralization) for some critical component of language in
one or the other hemisphere. Whereas previously

the two hemispheres were closely matched in their

functions, by this change a portion of association
cortex was freed from the reciprocal inuence of a
contralateral homolog, and the exibility thus
added to the organisms behavior initiated a subsequent escalation of brain capacity. Generation by
generation marginal additions and subtractions to
the association cortices allowed behavior to become more exible and social structure more complex.20,32
But it should be noted that it is not brain size per
se that is correlated with language.26 Brain size in
Neanderthals was at least as great as in modern
Homo sapiens and this species apparently did not
have the representational capacity of modern humans. Some additional change was required. The
point at which lateralization was introduced in the
course of hominid evolution and its subsequent
modication thus acquire particular interest.33
The process of language lateralization can be
explained in terms of the time constraints on interhemispheric transmission through the corpus callosum (i.e., a signal delay between hemispheres of
approximately 25 ms)these limits being avoided
if the neural apparatus necessary to perform each
high resolution time critical task is gathered in one
hemisphere.34
But what component of language is present in
the dominant hemisphere, and what complementary structure is present in the nondominant
hemisphere? The hypothesis is that there are both
temporal and spatial aspects of language, and
that the two are segregated in the brain hemispheres because of the constraints on callosal
transmission. Accordingly, the linear (or temporal) output sequence of speech is presumably localized in the dominant hemisphere (and acts as a
frame), but this sequence also has access through
commissural bers to neural traces (i.e., contents,
in the form of a spatial contribution), perhaps at
multiple sites, in the nondominant hemisphere.
Such access to the spatially distributed information
could provide the basis for the recombinational
generativity of human language (see more detailed
review by Crow33).
Cerebral lateralization is observed in most individuals, and is reected in both functional (e.g.,
speech dominance, handedness) and anatomical
(e.g., Sylvian ssure length) cerebral asymmetries.35,36 Moreover, evidence that a gene for asym-

10

BERLIM ET AL

metry is under continuing selective pressure comes

from an index of relative hand skill recorded on
approximately 12,000 children at the age of 11
years in the UK National Child Development
Study.37,38 A particular disadvantage in cognitive
ability was associated with proximity to the point
of hemispheric indecision or equal hand skill.
Individuals who fail to develop unequivocal dominance in one or the other hemisphere are at risk of
developing schizophrenia, among other pathologies. The key point is that the dimension of lateralization that is crucial to the evolution of the
human capacity for language is associated with
signicant and persisting diversity in the population. The nature and the genetic origin of this
diversity now becomes the focus of interest.
IS SCHIZOPHRENIA A LATERALIZED BRAIN
DISORDER?

Among the morphological deviations reported in

individuals with schizophrenia, three changes appear relatively constant: (1) a degree of ventricular
enlargement,39-41 (2) a decrease in brain size42-44
(and perhaps more importantly in cortical
mass),44-46 and (3) reductions, absence, or reversals
of functional (e.g., disturbances in lateralized language processing), and anatomical cerebral asymmetries.36,47-54 According to Crow,7,32 the increase
in ventricular space and the reductions in cortical
mass may be a secondary consequence of the failure to develop cortical asymmetry, and all three
changes may be considered developmental in origin. Therefore, symmetry of development of the
cerebral cortex implies a smaller, and perhaps less
convoluted cortex, and this in turn means that the
ventricles (which decrease in size as the cortex
develops) will be larger. In sum, individuals with
schizophrenia may present a delay, or a failure in,
the process of establishing dominance for some
key aspect of language (the most lateralized brain
function) in one hemisphere.
Moreover, patients with schizophrenia are characterized by a more variable and less completely
lateralized pattern of manual preference, that is, an
increase in mixed or ambiguous handedness.32
Therefore, as conrmed by a recent meta-analysis,55 there is a strong association between the
disease process and the genetic determinants of
brains symmetry/asymmetry.

SCHIZOPHRENIC SYMPTOMS AS DISORDERS

OF LANGUAGE

Crow30,32 argued that some schizophrenic symptoms (particularly the positive ones, e.g., hallucinations, and formal thought disorders) can be best
understood as deviations in the interpretation and
organization of speech. He suggested that these
symptoms are all anomalies of indexicality, a component of the mechanism of hemispheric specialization for language that has the function of distinguishing speech generated by one individual
from that received from another. This way, experiences that thoughts are withdrawn from or inserted into ones head, and that ones thougths can
be heard by others may be related to the transition
from thought to speech output (i.e., to the motor
aspect, and to the frontal lobes). In contrast, experiences of hearing ones thoughts spoken aloud, a
running commentary on ones actions, or voices
that speak in the third person may be related to the
transition from heard speech to meaning (i.e., to
the sensory aspect, and to the occipito-parietotemporal regions). Delusions can be seen as a
pathological change in the symbolic value, that is
the meaning of categories of words. Moreover,
some negative symptoms, like poverty of speech,
can readily be understood as failures of verbal
uency, and others (e.g., affective attening) can
be seen as a loss of the meaning of signicant
symbols.
A SEX CHROMOSOMAL LOCUS

Crow47,56 and Crow et al.57 argued that the genetic predisposition to schizophrenia (and by implication to psychosis in general) is related to that
for cerebral asymmetry (see Weinberger et al.58
and Crow et al.59 for debate), and that the variation
determined by the asymmetry gene may be expressed as differing rates of relative hemispheric
development associated with different phenotypes
in terms of personality structure, and language
ability. Accordingly, a component of this genetic
variation may represent the vulnerability to schizophreniawhich may be seen as a boundary of
language ability and its correlates in personality.
Some lines of evidence are consistent with the
presence of a gene for asymmetry on the sex chromosomes: individuals who lack an X chromosome
(i.e., Turners syndrome) have right hemisphere
decits (e.g., nonverbal difculty with spatial

SCHIZOPHRENIA AND LANGUAGE: A THEORY

transformation), while individuals with an extra X

chromosome (e.g, Klinefelters syndrome) have
left hemisphere decits (e.g., difculty in temporal
sequencing, in word nding, and in arranging syntax).60-63 This led to the assumption that a gene (or
genes) for the relative growth of the two hemispheres is present on the X chromosome. But since
normal males have only one X but lack spatial
decits, there must be a complementary copy of
the gene in the Y chromosome.8,64
The rst version of the X-Y hypothesis was that
the gene for asymmetry, and therefore for psychosis, was located within the pseudo-autosomal region (the region of the short arms within which
there is recombination between X and Y in male
meiosis).65 This would account for an association
between psychosis and sex chromosome aneuploidies and for the same sex concordance effect,66,67 but it would not have explained the sex
differences in psychoses (e.g., age of onset, and
outcome), or in handedness (females being more
right-handed than males68). These sex differences
led Crow2,7,69 to a second version of the X-Y
hypothesisthat the gene was located in a region
of homology in which there was no recombination
between X and Y.70 Such a localization allows for
sequence divergence (whether in a protein coding
or control element) between X and Y copies, and
consequently can explain sex differences (i.e., sexual dimorphism) such as in handedness (mean
greater in females), cerebral anatomical asymmetries (mean greater in males), verbal uency (mean
greater in females), and spatial ability (mean
greater in males).
X/Y homologies commonly arise as a result of
transpositions from the X to the Y chromosome
with subsequent modications of and loss of sequences from the Y. Of particular interest is the
Xq21.3 region of homology with Yp (Xq21.3/
Yp11.2), as it arose as a result of a translocation
that occurred (2 to 3 million years ago) after the
separation of the lineages that led to the chimpanzee and Homo sapiens.71 Subsequently, a paracentric inversion split the block on the Y.72,73 The
recency of these events in an evolutionary time
scale makes any gene located within this regions
relevant to the characteristics that separate modern
humans from the great apes. One candidate gene
within this region is expressed in the central nervous
system as a protocadherin XY (PCDHXY)a

11

molecule that may have a role in cell-cell interactions and that seems to be involved in segmental
brain morphogenesis and function.74,75
SEXUAL SELECTION AND THE SPECIATION
EVENT

Darwin1 believed that the brain of man had

evolved particularly by sexual selectionthe process of male competition and female choice by
which he considered a number of features (e.g.,
deers antlers) that are characteristic of one sex or
the other had evolved. Sexual selection provides a
mechanism for the evolution of specic (i.e., species-related) features that can account for rapid and
escalating evolutionary change. Through this process, while competing with a member of the same
sex, an individual gains reproductive advantage
(i.e., features are being selected not by the exigencies of the physical environment but by members
of the species).20,29
Crow2,29 suggested that changes in the sex chromosomes, particularly in the Y (because it is freed
from the constraints of recombination), provide a
pool of genetic variation that is potentially subject
to sexual selection because it is directly exposed to
female choice. Accordingly, gene variants which
by their effects on behavior maximize the attractiveness of the male as a potential mate would be
selected.
As noted above, transpositions from the X to the
Y generate a change in expression (i.e., an increase
in dosage) of a gene that is already established on
the X. Most such changes may be predicted to be
deleterious, being quickly selected out. But consider the case that such a gene (e.g., the cerebral
asymmetry determinant) has facilitated communicative ability that might be regarded by females as
attractive in a mate, or might be an advantage to a
male in the competition for females: that Y chromosome has the potential to increase its representation in successive generations. If this occurs, a
change in the population has taken place that is
specic to males. But because the gene is already
present on the X chromosome, there is the possibility of a subsequent change (in response to a
change in males) affecting the same characteristic
in females. Such a genetic change generates the
possibility of a runaway process of sexual selection
along the dimension that will differentiate the new
species from its predecessor (e.g., Homo sapiens
from earlier hominids).2,30

12

BERLIM ET AL

The above mechanism, in sum, provides a way

in which a single genetic change on the Y chromosome (e.g., the one that originated the asymmetry gene) could be propagated within the population, and by the mechanism of sexual selection,
will lead to a gradual transformation of the population as a whole. According to this concept, age at
procreation may be seen as representing the point
at which linguistic competence is maximized and
brain growth reaches a plateau. Moreover, some
individuals with extreme genetic variants of hemispheric specialization may be predisposed to develop the deviations of psychological function that
we describe as schizophrenia.30
PROBLEMS OF THE THEORY

The theory leaves a number of questions to be

answered:
(1) What are the dimensions of variation in language structure/personality in the normal
population?
(2) How is cerebral asymmetry to be accurately
assessed?
(3) How is a gene to be identied? No genetic
locus for cerebral asymmetry has been identied (but see Laval et al.76 and Geschwind
et al.77), and no genetic linkage for psychosis has been clearly established on the X
chromosome (see DeLisi et al.78). This nding appears damaging to the X-Y hypothesis
until it is appreciated that the search for
linkage throughout the genome has failed to
yield consistent evidence for a psychosis
locus.79 The alternative to the present theory
of the genetic predisposition is that schizo-

phrenia is a polygenic illness, i.e., that there

are many genes of small effect. How such
genes might account for the consistency of
the brain changes or worldwide prevalence
is unclear. No genes have been denitively
identied.80 Therefore strategies such as
those based on the asymmetry hypothesis
have to be considered.
(4) What is the nature of the genetic variation?
This may be epigenetic in origin, i.e., the
relevant variation may be related to gene
expression (e.g., by a process of methylation, imprinting or X inactivation), rather
than to DNA sequence divergence (although
such modulation would have to be transmitted through meiosis to account for a heritable component), or the locus may represent
a mutation hot-spot (i.e., a high mutation
site, such as the recently described
DXYS156 locus).29,33 An epigenetic
mechanism, for instance, might account for
discordance for asymmetry and psychosis in
monozygotic twins.
Obviously the theory can be mistaken: it constitutes a test-case against which alternatives can be
pitted. It is important to note, however, that scientic progress depends on the elimination, but also
on the generation, of erroneous concepts. Indeed,
what we should require of our concepts is that they
be formulated with sufcient clarity that the predictions they generate can be tested and found
wanting, and when this happens, science advances.
Therefore we need to understand both the Xq21.3/
Yp11.2 region and the protocadherin XY gene to
determine how the theory might be eliminated.

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