Schizophrenia-an evolutionary enigma? - Martin Bru nea,b
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Neuroscience and Biobehavioral Reviews 28 (2004) 41–53
www.elsevier.com/locate/neubiorev
Schizophrenia—an evolutionary enigma?
Martin Brünea,b,*
a
Centre for Psychiatry and Psychotherapy, University of Bochum, Alexandrinenstr. 1-3, Bochum 44791, Germany
b
Centre for the Mind, a joint venture, Research School of Biological Sciences, Australian National University and University of Sydney,
Sydney, NSW, Australia
Received 14 July 2003; accepted 23 October 2003
Abstract
The term ‘schizophrenia’ refers to a group of disorders that have been described in every human culture. Two apparently well established
findings have corroborated the need for an evolutionary explanation of these disorders: (1) cross-culturally stable incidence rates and (2)
decreased fecundity of the affected individuals. The rationale behind this relates to the evolutionary paradox that susceptibility genes for
schizophrenia are obviously preserved in the human genepool, despite fundamental reproductive disadvantages associated with the disorders.
Some researchers have therefore proposed that a compensatory advantage must exist in people who are carriers of these genes or in their first-
degree relatives. Such advantages were hypothesised to be outside the brain (e.g. greater resistance against toxins or infectious diseases), or
within the social domain (e.g. schizotypal shamans, creativity). More specifically, T.J. Crow has suggested an evolutionary theory of
schizophrenia that relates the disorders to an extreme of variation of hemispheric specialisation and the evolution of language due to a single
gene mutation located on homologous regions of the sex chromosomes.
None of the evolutionary scenarios does, however, fully account for the diversity of the symptomatology, nor does any one hypothesis
acknowledge the objection that the mere prevalence of a disorder must not be confused with adaptation. In the present article, I therefore
discuss the evolutionary hypotheses of schizophrenia, arguing that a symptom-based approach to psychotic disorders in evolutionary
perspective may improve upon the existing models of schizophrenia.
q 2004 Elsevier Ltd. All rights reserved.
Keywords: Schizophrenia; Genetics; Human evolution; Trade-off; Dysconnectivity; Brain maturation; Heterochrony; Language; Social brain; Catatonia;
Symptom-related approach
1. Introduction cannot fully explain the comparable frequencies of these
disorders across cultures, let alone the clinical resemblance
The term ‘schizophrenia’ originally proposed by Eugen of psychotic syndromes in different cultures [4]. Twin and
Bleuler in 1908 in a scientific meeting refers to a group of adoption studies have clearly demonstrated that genetic
disorders characterised by severe cognitive, emotional and factors play a significant role in the transmission of
behavioural symptoms [1]. These disorders usually manifest schizophrenia; this, however, does not rule out that
in late adolescence or early adulthood, although childhood environmental influences also contribute to the manifes-
precursor symptoms are frequent, [2]. It seems obvious that tation of schizophrenia [5 – 8]. The incidence rate of ‘core
schizophrenic disorders are ubiquitous and occur in schizophrenia’ of roughly 1% in human populations exceeds
virtually every human society. The prevalence and inci- a mere chance effect due to high mutation rates, e.g. [9 – 11],
dence rates are supposed to be cross-culturally similar and it is widely accepted that the fecundity of people with
(recently reviewed in Ref. [3]). This would suggest that schizophrenia, particularly of males, is reduced by about
intrauterine virus infections, nutritional conditions or other 50% compared to healthy individuals [12].
exogenous influences during the foetal period, for example, These findings create an evolutionary puzzle: why has
natural selection allowed genes to persist in the human
* Address: Centre for Psychiatry and Psychotherapy, University of
Bochum, Alexandrinenstr. 1-3, Bochum 44791, Germany. Tel.: þ 49-234-
genome that increase the likelihood of suffering from these
5077-155; fax: þ 49-234-5077-235. devastating disorders, despite the reproductive disadvantage
E-mail address: martin.bruene@ruhr-uni-bochum.de (M. Brüne). of schizophrenia? In fact, the persistence of schizophrenia
0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2003.10.00242 M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53
suggests that (1) genes related to the disorder convey infection than non-carriers [35]. Huxley and co-workers
advantages in terms of survival or reproduction (genetic proposed that schizophrenic individuals might either be
polymorphism) or (2) genes associated with schizophrenia more resistant to infectious diseases, or had an unknown
may be linked to other genes that have an advantage reproduction advantage (particularly female schizophrenic
(pleiotropy). patients). Regarding the latter assumption they drew
Evolutionary-based explanations of schizophrenia could, parallels to a possibly increased female fertility in
therefore, be informative if they accounted for (1) a haemophilia, whereas males having the condition faced a
plausible mechanism for the preservation of these genes in high reproductive disadvantage. Thus Huxley et al. [9]
the global human genepool, (2) potential sex differences, for located the compensation of reduced fecundity of male
example, in age at onset of schizophrenia, and, most schizophrenic patients outside the nervous system. Drawing
importantly, (3) the multi-faceted symptomatology of from this hypothesis, Erlenmeyer-Kimling [13] found in a
schizophrenic disorders; (4) they should, however, also be retrospective analysis of live-born offspring of schizo-
consistent with neuropsychological, developmental and phrenic patients that the cumulative mortality rate from
evolutionary findings regarding the human brain. birth to age 15 of females was significantly lower compared
A host of evolutionary hypotheses regarding schizo- to the mortality rate of females of non-schizophrenic control
phrenia has been published over the past 40 years or so that families. Moreover, an increased survival rate among
may be loosely distinguished according to three central offspring of schizophrenic persons emerged for both sexes
topics, although considerable overlap exists: one set of in the first year of life; a finding that was at odds with
hypotheses focuses on the survival advantage of hetero- previous studies carried out in the 1920s [13]. More
zygous gene carriers, e.g. [9,13,14]; a second group of specifically in terms of what such a survival advantage
hypotheses concentrates on the impaired ontogenetic could be, Carter and Watts [14] made an interesting
neurodevelopment in schizophrenia, in part related to discovery in a study assessing the resistance to infectious
aspects of heterochronic processes and neural connectivity diseases, rate of accidents and injuries and the fertility of
[15 –18]; a third array centres around the hypothesis that first-degree relatives of schizophrenic patients. They found
schizophrenia represents a trade-off of the evolution of a diminished rate of virus infections, a lower rate of
human ‘sociality’, e.g. [19 – 21]. The most sophisticated accidents and increased fertility in first-degree relatives of
theory proposed by T.J. Crow in a number of seminal patients with schizophrenia. They tentatively interpreted
articles relates schizophrenia to the evolution of language their findings in a way that suggests that genes associated
and cerebral asymmetry [10,11,22– 32]. Although a number with schizophrenia could convey a survival advantage in
of excellent review articles on the presumed evolutionary relatives and thus explain the persistence of such genes in
background of schizophrenia have been published in recent the population.
years [18,33,34], none has sufficiently addressed the More recently, researchers have proposed a ‘develop-
important question of what evolutionary hypotheses may mental instability’ model of schizophrenia that in many
precisely add to present-day schizophrenia research, or what respects also relies on the assumption of a selection
the possible implications of the evolutionary approach for advantage outside the nervous system (reviewed in Ref.
current psychiatric nosology are. [36]). This theory suggests that schizophrenia may emerge
In the present article, I shall therefore firstly summarise due to an individual’s incapacity to ‘buffer’ the negative
the divergent evolutionary concepts of schizophrenia and effects of multiple mutations, pathogens and toxins. Central
secondly discuss some issues of evolutionary approaches to to this line of argumentation is that the so-called ‘fluctuating
the understanding of psychotic symptoms. asymmetry’ (FA), that is, a near-normally distributed
asymmetry of bilateral characters that are on average
symmetrical in the population, is greater in twin pairs
2. Are there selection advantages of schizophrenia- concordant for schizophrenia than in discordant pairs.
related genes outside the nervous system? Greater FA may therefore indicate an imprecise expression
of the developmental design due to genetic or environmen-
The question of a possible survival and reproductive tal causes [36]. This could explain, for example, why
advantage of heterozygous carriers of schizophrenia patients with schizophrenia have a greater number of minor
susceptibility genes was first raised by Huxley et al. [9]. physical abnormalities such as hypertelorism that could be
They argued that the incidence rate of approximately 1% in indicative of an incomplete early cell migration. Other
human populations would lie well above a plausible characteristics putatively associated with a developmental
mutation level and hence provided evidence for a balanced instability in schizophrenia are a greater homozygosity of
(poly)morphism. That is, genes that on the one hand blood alleles, a lower premorbid intelligence, a reduced
increase the risk of developing schizophrenia, may also cortical volume, and a relative instability of functional and
have beneficial effects in other domains, similar to the case anatomical lateralisation of brain functions in schizophrenia
of sickle-cell anaemia, where heterogeneous carriers of the [36]. Similarly, it has been proposed that the accumulation
allele are relatively better protected against malaria of potentially deleterious mutations, genetic variability dueM. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53 43 to pathogen – host co-evolution and homozygosity at key 3. Neurodevelopmental hypotheses of schizophrenia alleles may affect developmental stability (and FA) in many ways (reviewed in Ref. [37]). 3.1. Heterochrony Early hypotheses speculating on advantages outside the nervous system have been criticised for a number of The term ‘heterochrony’ was coined by Ernst Haeckel reasons: Polimeni and Reiss [34], for instance, have recently [41]. It refers to changes in developmental timing of tissue argued that the study by Carter and Watts [14] was or morphological structures during ontogeny in relation to statistically flawed by a lack of a Bonferroni corrected the timing of their development in ancestral species. statistical analysis of the data. In addition, Carter and Watts Speeding up or slowing down the growth curves of different did not convincingly rule out the possibility that the reduced morphological characters in relation to each other results in rate of infections and injuries in first-degree relatives of divergent large-scale shaping of the entire body, parts of the schizophrenic patients could be due in part to a reduced body or in specific changes on the molecular level. Haeckel exposure to viral diseases or accident-prone situations. had proposed that ontogeny briefly and incompletely These individuals might carry, for example, an increased recapitulated phylogeny. This view was challenged, for load of schizoid personality traits, which could account for instance, by De Beer [42], who advocated that the reverse their being ‘less social’ relative to control subjects in the might apply, i.e. that phylogeny was the result of ontogeny general population. rather than its cause. (Both positions are going to be A more general argument refers to the fact that natural reconciled, for instance, in the work of McKinney and selection acts on the phenotype rather than on the genotype. McNamara [41]). Thus, potential compensatory advantages of genes associ- With respect to schizophrenia it has therefore been ated with schizophrenia rather ought to be expected in the suggested that the brain development in schizophrenic behavioural, emotional or cognitive domain. However, patients could be due to dysfunctional genes regulating the recent research has revealed a higher activity of natural speed of maturation. On the grounds of the recapitulation killer cells in a schizophrenic sample [38], which may lend theory Millar [43] proposed that schizophrenia represented some support to the assumption of a compensatory a condition of insufficient recapitulation of the final advantage outside the nervous system. In addition, a gene developmental steps during adolescence. He argued that, that causes Tay-Sachs disease, which typically manifests in according to MacLean’s distinction between the ‘reptilian’, early childhood and is characterised by debilitating altera- the ‘palaeomammalian’ and the ‘neomammalian’ brain (i.e. tions in the central nervous system by accumulation of a upper brainstem, limbic system, and neocortex), many GM2 ganglioside, may have been selected because it symptoms of schizophrenia could be related to an confers a relative protection against tuberculosis [39]. insufficient suppression of the phylogenetically old ‘repti- Thus an advantageous effect of a gene or genes associated lian’ brain system. with schizophrenia outside the nervous system is well An opposing view, however, emerged from the so-called conceivable. ‘neoteny’ hypothesis of human evolution. Since the 1920s The ‘developmental instability model’ [36] of schizo- several scientists argued that neoteny, literally ‘holding on phrenia that suggests that polygenetic design flaws related to to youth’, would account for the major physiological and FA may be involved in the origin of psychotic disorders, behavioural changes of human beings compared to the great also postulates that environmental factors such as toxins and apes, and as such, may be called the ‘hallmark of human viruses play an important role. If this were the case, evolution’ (overview in Ref. [17]). This assumption was however, one would expect dissimilar incidence rates across based on the observation that adult human beings super- different environments [32], which has in fact been ficially resembled juvenile apes, thus, it had been deduced controversially debated, e.g. [40], and the comparison of that humans retain juvenile features into adulthood incidence and prevalence rates also critically depends on compared to apes and their putative common ancestor. diagnostic conventions. Many physiological peculiarities have subsequently been At this stage it may therefore be concluded that studies ascribed to neoteny such as relative hairlessness, the focussing on the potentially greater resistance to infectious rounded shape of the human skull, and eventually brain diseases in schizophrenic patients—or their first-degree size. Moreover, in respect of behaviour it has been relatives-—need to be replicated in larger samples. Further, suggested that playfulness, curiosity and intelligence derive the ‘developmental instability model’ requires testing in from a shift towards neoteny in human evolution [44]. cross-cultural comparison applying rigorous diagnostic Bemporad [45] has therefore argued that the lack of criteria. But it may well be worth pursuing these ideas, curiosity in schizophrenic patients and other behavioural given the fact that theoretically, even the natural mutation symptoms may point to a ‘failure of neoteny’ in these rate could account for such a complex disease like disorders [45]. In addition, Crow [25] has reasoned that a schizophrenia, if, as Ernst Mayr pointed out, more than defective neotenic development may account for an six loci would produce similar phenotypic effects (quoted insufficiently established cerebral dominance in one or the after Ref. [14]). other hemisphere (see below).
44 M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53
Without explicitly referring to heterochrony, Saugstad however, conversely that schizophrenia might be charac-
[16,46,47] has reasoned that the asymmetry of hemispheric terised by an overshoot of synaptic pruning. This model
development is related to the speed of maturation, and that predicts that an earlier onset would be associated with more
psychiatric disorders may therefore arise at the extreme of rapid deterioration and reduction of hallucinations with
maturational rates. Schizophrenia, in particular, would be further pruning, as is in fact the case in chronic
related to a delay of maturation leading to reduced schizophrenia [53].
connectivity, reduced dendritic branching, and eventually Relating schizophrenia to heterochrony in human
to a diminished number of neurons due to a prolonged evolution, the speed of brain maturation or cerebral
pruning process (the reverse condition would apply to bipolar connectivity represents an interesting theoretical approach.
affective disorder and to autism, the latter being associated However, it conveys some pitfalls. For example, I have
with a premature developmental arrest). Saugstad also argued elsewhere [17], in line with the work of McKinney
conjectured that acceleration (earlier onset of puberty) in and McNamara [41], that impaired neoteny does not provide
the past 50 years or so might account for the alleged a suitable developmental model for the existence of
decreasing number of the most severe cases of schizophrenia schizophrenic disorders, simply because neoteny is not the
[47], as this would counterbalance the maturational delay only heterochronic process involved in human brain
typical of schizophrenia. Surprisingly, Saugstad has never evolution, and hence in the evolution of cognitive
referred to Ewald Hecker who, on behalf of his teacher Karl mechanisms. Rather, hypermorphosis, which involves the
Ludwig Kahlbaum, had described hebephrenia in 1871. postponement of growth and differentiation, adds new
Hecker had already speculated that hebephrenia was characters by ‘overstepping’ the ancestral form. Hypermor-
characterised by a lack of maturation, indicated by a phosis is, therefore, critical for brain evolution and human
‘pathologically permanent state of puberty’ [48]. cognition, because the neoteny-related retention of juvenile
characteristics of the ancestral species into adulthood of the
3.2. Connectivity theory descendant alone would in fact lead to reduced cognitive
capacities in the descendants [41]. Needless to say that
In relation to the issue of brain maturation in general, the neither the mental capacities of healthy persons or of
aetiology of schizophrenia has been repetitively linked to a schizophrenic patients are comparable with the mentality of
dysfunctional intra- and interhemispheric connectivity juvenile apes [17].
(recently readdressed in Ref. [18]). According to the Likewise, while there is certainly interindividual vari-
connectivity theory of psychotic disorders, functional ation of the developmental speed of brain maturation,
networks either may become incompletely, falsely or overly speculations on its relation to schizophrenia bear some
connected during ontogeny. Consistent with the time of inconsistencies. Some researchers have suggested, for
onset of schizophrenic disorders, adverse effects occurring instance, that schizophrenia emerges according to an
already during foetal cell migration may become clinically extremely late maturation [47], others, on the contrary,
manifest only in adolescence or early adulthood when assert that schizophrenia occurs due to a disruption of the
myelination is completed [49]. The sexual dimorphism in normal developmental delay of maturation, i.e. premature
myelination with males maturing later may also explain the ageing [45]. Moreover, recent studies have revealed
(converse) sex difference in onset of psychosis [49] due to a partially incompatible results regarding the age at onset of
prolonged period of enhanced susceptibility. More specifi- psychosis and the age of menarche of the affected female
cally, Horrobin [50] speculated that a defect in lipid individuals, a finding that does not unequivocally link
metabolism that evolved in recent hominid evolution schizophrenia to physical maturation alone [54]. Further, it
might lead to abnormal growth and insufficient myelination is still a matter of debate as to whether sex differences of age
of neurons in some individuals, which could manifest at onset have been definitively established in schizophrenia
clinically as schizophrenia. [55 –58].
With respect to the fact that a normal loss of cell Hypotheses regarding altered synaptic pruning or
connections during ontogeny occurs, Feinberg [51] myelination in schizophrenia are, though plausible, some-
suggested that schizophrenia might arise from insufficient what problematic because they disregard the relatively
synaptic ‘pruning’ during adolescence. More recently, typical ‘core’ symptomatology of the disorders. For
Rison [52] adopted this hypothesis, proposing that schizo- example, if defective myelination or excessive pruning
phrenia could be explained by a lack of normal switching occurs randomly, one would expect a broader spectrum of
from the foetal to the adult form of the NMDA-receptor symptoms in initial stages and possibly a more stable
during adolescence, resulting in an excess of excitatory symptom constellation in the course of psychosis [34].
synaptic transmission. The cost of insufficient pruning of
foetal NMDA-receptors, i.e. psychosis, could be balanced, 3.3. Is schizophrenia related to the evolution of ‘sociality’?
on the other hand, by a relative protection from neurode-
generative effects [52]. In a computer-simulated model of As already pointed out, since selection acts on the
synaptic pruning McGlashan and Hoffman [53] argued, phenotype rather than on the genotype it could be moreM. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53 45 fruitful to relate the putative preservation of susceptibility proposed, for instance, that shamanism and religious genes for schizophrenia more tightly to the actual leadership could have had beneficial effects on the group symptomatology that largely manifests within the social in human evolutionary history, which might explain the domain [21]. Kuttner et al. [19] proposed that the preservation of a genetic foundation of shamanism. Such uniqueness of schizophrenia in human beings was specifi- traits could, on the other hand, be associated with an cally linked to human characteristics that separate humans increased probability of developing psychotic symptoms from other animals. They argued that these differences and also account for the high prevalence of religious would lie in the highly complex social life, the superior delusions in contemporary schizophrenic patients [34,63]. intelligence and language. The ‘beneficial effects’ of Burns [18] has recently argued that schizophrenia may be schizophrenic traits could, for example, be related to ‘the seen as a trade-off of the evolution of social intelligence sphere of social behavior’, e.g. a relative protection from involving a dramatic increase in cortical connectivity in social stress [19]. In line with a once popular account of primates. He suggested a two-step model of the evolution- schizophrenia relating the development of the disorder in ary background of schizophrenia: in the first evolutionary individuals to pathological behaviour of their mothers, step some 5– 6 million years ago a more complex inter- and Kuttner and Lorincz [59] had hypothesised even earlier that intrahemispheric connectivity emerged especially in two a potential survival advantage of individuals who later fronto-temporal circuits, namely the anterior cingulum develop schizophrenia could be linked to the overprotective bundle and the uncinate fasciculus. These brain circuits behaviour of their ‘schizophrenoid mothers’. evolved due to increasing demands of the social environ- Kellett [60], referring to a presumed ‘heterozygous’ ment of early hominids and had been crucial for increasing advantage of schizophrenia genes, related schizophrenia to social cognitive capacities. In a second more recent the concept of ‘territoriality’. He argued that the (hetero- evolutionary step 150,000 years ago, some unknown genetic zygous) schizotype had a reproductive advantage compared mutation may have enhanced the vulnerability of these with more socially adapt individuals in evolutionary connections, which could be associated with the evolution scenarios where the need to establish territoriality would of metacognition and ‘theory of mind’. Thus, according to surpass the importance of pro-social behaviour. Burns, schizophrenia may be seen as a trade-off of the Similarly, Allen and Sarich [21] argued that schizo- evolution of the human ‘social brain’ [18]. phrenia might be regarded as a condition at one extreme on a A specific aspect of the evolution of intelligence is ‘sociality scale’. They concluded that the advantage of non- reflected in the discussion of creativity and psychosis. Data psychotic carriers of the gene(s) was their ability to balance from Iceland, which is supposed to have a fairly stable their own interests against the demands of group living more genepool over centuries, suggests a connection of excep- effectively under ancestral conditions, which in some cases tional creative potential in relatives of psychotic individuals might also emerge in their greater creative potential. with psychotic illness [64], although the association is Moreover, they viewed schizophrenia as a ‘disease of stronger for bipolar affective disorders than schizophrenia civilisation’, because the more complex a society and the [65]. This assertion is supported by anecdotal reports of further from the ancestral hunter–gatherer existence, the psychotic disorders in famous people such as Isaac Newton more pathological conditions or deviations from the norm and John Nash (overview in Ref. [34]). were tolerated. The higher tolerance of social dysfunction in This multifaceted spectrum of attempts to establish an ‘modern’ societies might therefore explain the maintenance association of schizophrenia to the evolution of ‘sociality’ of schizophrenia genes in the population. warrants some comments. In fact, there are a number of In a similar vein, Stevens and Price [20] argued that the shortcomings in these accounts: it is very unlikely that the genetic susceptibility to develop schizophrenia emerged as preservation of genes predisposing to schizophrenia have an adaptation to facilitate group splitting. The group anything to do with an enhanced capacity to cope with splitting hypothesis holds that the group cohesiveness of stressful social environments. Contrariwise, schizophrenic human beings is limited. As Price put it, ‘just as a cell must persons are particularly vulnerable to social stress. More- divide, so too must a human group divide. The capacity to over, it is as yet unclear whether a presumed over- form a new belief system and reject the belief system of the protective or rejecting behaviour of mothers of persons natal group is characteristic of cult leaders and also of who later become schizophrenic is the cause of, or rather people with schizophrenia’ [61]. In other words, similar to a reaction to, subtle behavioural abnormalities of the others, Stevens and Price [20] postulated that selection latter, [66]. However, careful examination of attachment pressures on traits related to ‘asocial’ behaviour. This patterns in infants who have a high genetic risk of hypothesis has gained some influence, because it plausibly developing schizophrenia later in life could be useful in considers some sort of benefit of behaviour patterns that are clarifying the question as to what extent behavioural obviously non-social, or even overtly schizoid or paranoid, characteristics of mothers influence the manifestation of which are also characteristic of the ‘Odyssean personality’ schizophrenia. However, this would by no means explain [62] or have recently been associated with shamanism and the probably genetically mediated vulnerability to charismatic leadership [63]. Polimeni and Reiss have schizophrenia.
46 M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53
Kellett’s territoriality hypothesis [60] may be criticised white matter volume was related to a greater vulnerability
because it does not account for schizophrenic symptoms this would then lend some support to Burns’ and others’
except paranoid alertness [34], and, as de Waal [67] has dysconnectivity hypothesis [18,49,53]. It is less clear and
pointed out, ancestral human societies were probably more thus debatable, however, as to how Burns’ proposal
hierarchically organised than territorially organised. In specifically addresses the aetiology of schizophrenia, or
addition, Kellett’s approach [60], like Polimeni and Reiss’s rather, whether it represents a model that could be applied to
shamanism hypothesis [63], relies primarily on the group- other psychiatric disorders as well. This issue is being
selection theory put forward by Wynne-Edwards [68]. The addressed in more detail in the general discussion.
‘good for the species’ argument as a major evolutionary
force has, however, been refuted by the modern synthesis of
inclusive fitness theory in light of compelling evidence that 4. Crow’s theory of cerebral asymmetry, language,
selection operates at the genetic or at best the individual and the emergence of psychosis
level [69]. Also, the evidence that the schizoid group
splitter, shaman or charismatic leader might have conveyed Crow’s evolutionary theory of the origin of psychotic
an adaptive advantage (which paid off in terms of disorders is based mainly on the assumption that a lack of
reproductive success in human evolutionary history, and hemispheric dominance and specialisation of the language
hence led to the preservation of genes associated with area on the left side are at the core of psychosis. Crow has
schizophrenia) is fairly weak [18,19]. It appears unlikely accordingly hypothesised that a single gene regulating
that at any time in our evolutionary past selection has cerebral dominance was also involved in the origin of
operated in favour of the phenotype of the schizoptype psychotic disorders, and that the evolution of language
shaman, charismatic leader, or group-splitter as a hetero- would play a central role. He proposed that—given that the
zygous carrier of genes that may cause full-blown psychosis genomes of the chimpanzee and humans differ only in
if homozygous. If we assume, for instance, that lower back around 1.5% of base pairs—a crucial incident must have
pain and a slipped disc may be trade-offs or the result of a happened since the time these two species split from a
design flaw of our upright position and bipedalism, common ancestor some 5 million years ago. Central to his
schizotypy may be no more adaptive than minor lower line of argumentation is also that the empirical evidence for
back pain. Likewise, the hypothesis that schizophrenia Kraepelin’s original dichotomy of schizophrenia and
represents a trade-off of human creativity has not been bipolar affective disorders is weak; rather, according to
convincingly backed up by empirical studies [65,70,71], and Crow, the ‘functional’ psychoses would form a ‘double-
Polimeni and Reiss cautioned us that a link with continuum’: from the bipolar pole to the schizophrenic pole,
schizophrenia might be difficult to prove [34]. and from ‘normal’ to psychotic. The continuum hypothesis
Burns’ account of schizophrenia as a trade-off of the would imply that ‘the disorder represents a component that
evolution of a ‘social brain’ in primates [18], in contrast, is a is intrinsic to the individual, i.e. an extreme of variation on
fruitful model because it integrates developmental brain the normal population’ [10].
maturation, cerebral connectivity and cross-species findings One of the crucial differences between the great apes and
highlighting the evolutionary demands posed on individuals human beings is undoubtedly the capacity of having
by the social environment in ancestral conditions. Many sophisticated language. Crow conjectured that possibly
cognitive, emotional, and behavioural capacities ‘hard- only a single gene mutation might account for the huge
wired’ in the human brain evolved as adaptations to our cognitive and behavioural gap between the species and
social environment [72]. This includes the capacities, could thus be regarded as ‘the speciation event’. Provided
among others, (1) to infer what others think, intend, pretend the incidence rates of ‘core’ schizophrenia are cross-
and desire, referred to as having a ‘theory of mind’ [73], (2) culturally similar, the mutation in question must have
to ‘read’ signals of con-specifics such as facial expressions occurred before the diaspora of modern Homo sapiens from
of emotions [74], (3) to travel mentally in time back and Africa, perhaps 150,000 years ago [10].
forth [75], and, (4) language [31]. In the case of If such a cerebral dominance gene allows the hemi-
schizophrenia there is good empirical evidence that the spheres to develop independently from one another to a
brain functions involved in social interactions such as certain degree, and if males and females differ with respect
emotion recognition and theory of mind are specifically to their cerebral asymmetry—which is actually the case, as
impaired [76,77], summarised in Refs. [78]]. It is also well men usually have a greater anatomical cerebral asymmetry
buttressed by empirical studies in primates that some areas compared to women, and this difference is established early
in the human prefrontal cortex in particular are larger than in ontogeny—sexual selection may be involved in hemi-
expected for a primate of human body size, and that this spheric specialisation which in turn may also account for the
enlargement is associated with an increasing mass of white sex differences in age at onset of psychosis [25]. Sexual
matter rather than grey matter. In other words, axonal selection acting on sex differences in mate choice may
connectivity probably outpaced the number of neurons over explain the sexual dimorphism in lateralisation of brain
evolutionary time in primate phylogeny [79]. If increasing functions because women usually mate earlier than men andM. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53 47 hence would mature faster. Men, by contrast, would be more connection of the two hemispheres. In other words, an vulnerable due to a delayed maturation associated with the imprecise timing of the logical and the phonetic aspect of more pronounced cerebral asymmetry [25]. If sexual language could produce symptoms such that an individual’s selection was involved in a single gene mutation, as Crow own thoughts are perceived alien [30]. In support of this inferred, the most likely explanation would be to expect the assertion, DeLisi [83] found chronic but not first episode gene locus to be X –Y-homologous (in early accounts Crow schizophrenics to have a reduced sentence complexity. This suggested an X – Y-homologue in the pseudoautosomal finding was more evident in male patients, which could region of the sex chromosomes, but he later rejected this therefore be consistent with Crow’s hypothesis of anom- assumption, because such a location would not explain sex alous lateralisation. differences in age at onset, precursor symptoms and cerebral With respect to the proposed gene locus on X – Y asymmetry in psychosis, as the pseudoautosomal region of homologous regions of the sex chromosomes, a candidate the sex chromosomes is subject to crossing-over; [32]). area could be a sequence that was apparently transposed Indeed, there is some empirical evidence in support of from the X to the Y chromosome after the separation of the Crow’s ‘speciation’ theory. Children who later develop human and the chimpanzee line. More specifically, the psychotic disorders are more likely to be ambidextrous and Xq21.3 region that was obviously transposed to the short have more language disorders and behavioural disturbances arm of the Y, was subsequently split in a paracentric than children who as adults do not become psychotic. More inversion on the Y. A gene called ‘ProtocadherinXY’ might precisely, psychomotor retardation, delayed language therefore be involved in establishing hemispheric dom- development and other cognitive impairments were specifi- inance [32,84,85], although Kalsi and colleagues [86] cally observed in subjects who later developed schizo- previously failed to find a linkage of the XY pseudo- phrenia from the age of three on, compared with children autosomal region associated with increased susceptibility to who later suffered from other ‘functional’ psychoses or non- schizophrenia. Psychotic disorders could then arise at the psychotic disorders; other emotional and interpersonal extreme of variation due to a high mutation rate at this gene problems occurred across all diagnostic categories [80]. In locus, or due to epigenetic factors such as genomic addition, Crow, Done and Sacker [81] found pre-psychotic imprinting or X-inactivation [32]. A recent study, however, children to be impaired in reading abilities and in lateralised failed to replicate the result of a positive linkage of hand skills at the age of 7 and 11 years, relative to control schizophrenia to any particular region of the X-chromo- subjects. These findings suggest that psychosis-related some, indicating that in the first place epigenetic factors are developmental disturbances may be associated with a involved in the predisposition of psychosis [87]. delayed or incomplete hemispheric specialisation or unsuc- There are several objections against the validity of cessfully established dominance in one hemisphere. Crow’s evolutionary theory of psychosis as ‘the price Homo Moreover, some studies have revealed a reduced cerebral sapiens pays for language’, though plausible and consistent asymmetry in schizophrenic adults compared with healthy with many empirical studies. Firstly, Crow’s claim that subjects, and sex differences of normal asymmetry have schizophrenia emerges in hominid evolution as a trade-off been found disrupted in schizophrenia [82]. In addition, of lateralisation and functional specialisation of the hemi- there is a disparate spatial and verbal intelligence in persons spheres when language evolved in the ‘speciation event’ with aneuploidies of the sex chromosomes; in Turner’s some 150,000 years ago is questionable, because gradual syndrome (X0) verbal intelligence, a function of the evolution of language is more likely than a saltatorial dominant hemisphere, is better preserved relative to spatial emergence of such a complex faculty, although complex abilities, the latter represented in the non-dominant hemi- syntactical and semantic qualities of human language might sphere; whereas in Klinefelter syndrome (XXY) the reverse indeed have evolved from proto-language in a relatively applies, suggesting that the sex chromosomes are involved short period of time [88,89]. Asymmetry of the planum in establishing hemispheric dominance. Crow argued, temporale as the key region of the functional specialisation however, that, since normal males (XY) only have one X- of Wernicke’s language area is, however, already present in chromosome, but similar spatial and verbal intelligence, it is the chimpanzee [90], suggesting that a functional differen- likely that the presumed hemispheric dominance gene is tiation might have already evolved in the common ancestor also represented on the Y [32]. Crow [32] further assumed of humans and other apes, thus clearly preceding the advent that the structure of language in terms of its spatial and of modern humans. In addition, as recently pointed out by temporal organisation is segregated such that the spatial or Corballis [91], cerebral asymmetry of vocal control can be ‘logical’ component is represented in the non-dominant found in many ‘primitive’ animals such as frogs and birds, hemisphere and the temporal or ‘phonetic’ aspect in the whereas right-handedness is probably a human character- dominant hemisphere [10,31]. Therefore, for normal istic that evolved much later. Therefore, there is no language the interaction of the two hemispheres is crucial. unequivocal link of handedness and language to a single From this perspective it is plausible to draw parallels to the mutation in which cerebral dominance could have been nature of ‘first rank symptoms’ in schizophrenia, because established. Furthermore, the claim that schizophrenia is they may reflect a disruption of the normal transcallosal characterised by a less pronounced lateralisation could not
48 M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53 be replicated in a recent study [92]. Likewise, from a genetic poses, however, a problem for Crow’s evolutionary theory point of view, the evidence of a X – Y homologous gene of schizophrenia, because it becomes, then, speculative involved in cerebral asymmetry and the evolution of whether the presumed stable incidence rate across cultures language is at best moderate. In addition, there are is a valid finding, and this problem may even persist if susceptibility genes of schizophrenia located on various restricting the schizophrenia concept to nuclear symptoms autosomal regions, suggesting that a single gene mutation is [10]. Moreover, with respect to cross-cultural similarity, unlikely to fully account for the emergence of psychotic mild male preponderance and earlier age at onset is disorders [93 – 101]. Two recently published meta-analyses probably not unique to schizophrenia, since the same failed to provide evidence for any particular candidate gene applies, for instance, to obsessive– compulsive spectrum locus for schizophrenia [102,103]. With respect to the disorders. presumed speciation event it is important to note that a Crow’s evolutionary theory of schizophrenia is never- crucial difference that genetically separates human beings theless a very useful concept for addressing psychiatric from other apes is that the human genome comprises 46 disorders from an evolutionary perspective. There is no chromosomes, including the sex chromosomes, whereas the doubt that language plays a key role in both human other great apes have 48 chromosomes. It is a well evolution and psychosis; however, his theory is too established finding that at some point in our hominid narrowly focused on a supposed single gene mutation evolution the chromosomes 12 and 13 found in the [111]. In a more general vein, a gene on a X/Y homolog chimpanzee and in the gorilla (and probably also in our region such as the ProtocadherinXY could conceivably be common ancestor) were combined to form the large human involved in regulating the heterochronic growth of the two chromosome 2 [104]. hemispheres, possibly reflecting a hypermorphotic shift on Secondly, from a clinical perspective, although plausible top of a general neotenic developmental trend in humans regarding some first rank symptoms of schizophrenia, relative to the other great apes. Crow’s theory hardly accounts for other psychotic or behavioural symptoms such as catatonia, negative symp- toms, and affective disturbances, although Crow asserts that 5. General discussion echolalia and echopraxia may arise from impaired com- munication between the two hemispheres [31]. Thirdly, A wealth of evolutionary hypotheses has addressed the Crow’s explanation of sex differences in age at onset of question of apparently constant incidence rates of schizo- psychosis appears somewhat circumstantial; he suggests phrenic disorders across different cultures and environ- that later brain maturation renders male brains more ments, despite the fact that individuals suffering from susceptible to psychosis and might therefore account for schizophrenia have a reduced fecundity compared with the the earlier onset of psychosis in men, whereas earlier general population. Evolutionarily speaking, natural selec- maturing female brains are relatively protected against the tion should have eliminated susceptibility genes of schizo- disorder. In Crow’s view sex differences in mate selection phrenia, if the apparent reproductive disadvantage was not may cause the divergent speed of brain development, with compensated for by any survival or reproductive advantages men favouring younger (and therefore faster maturing) in heterogzygote carriers or by advantageous effects of women, relative to women who prefer older men as pleiotropy. However, none of the evolutionary hypotheses potential sex partners. To me, this line of argument appears put forward so far meets all criteria mentioned in the in some respect circular. Furthermore, the gender effect on introduction, i.e. providing a convincing mechanism for the age at onset of schizophrenia is possibly even reversed in preservation of genes in the human genepool associated populations where infant mortality is high [105], a scenario with schizophrenia, explaining potential sex differences, which may more closely resemble the conditions of the and accounting for the multifaceted symptomatology. Thus ‘environments of evolutionary adaptedness’ of our species. none can be entirely refuted or accepted on the basis of the Fourthly, Crow [29] proposed a ‘double’ continuum of currently available evidence, although those invoking group psychosis. On the one hand, schizophrenic and affective selection would seem least consistent with modern evol- disorders are more accurately described as ‘dimensions of utionary theory, neither are they substantiated by empirical variation’ rather than categories or disease entities; on the studies. However, most hypotheses outlined above are open other hand, along with Kretschmer [106], psychotic states to empirical testing. They are therefore not evolutionary may arise at the boundaries of personality traits. Indeed, ‘just so stories’ comprising more or less plausible but there are many clues that this might be true. For instance, untestable explanations of schizophrenia. several studies on psychotic symptoms in non-clinical One needs to keep in mind the possibility that this line of populations have confirmed that phenotypic differences research is like chasing an illusion. For example, evolution- between patients and non-patients are quantitative rather ary hypotheses of schizophrenia that propose an adaptation than qualitative [107 – 109]. Also, obsessive-compulsive of heterozygous carriers of alleles are at risk to fall prey to disorder and delusions may overlap [110]. Many more the erroneous belief that every psychiatric disorder can examples exist in favour of the continuum hypotheses. This always be explained as an adaptation in one way or another
M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53 49 [112,113]. As Weiss Lane and Luchins [114] have pointed of ‘core schizophrenia’, since schizophrenic patients with out, a common fallacy in evolutionary psychiatry is to pronounced thought and language disturbances have been assume that ‘a trait is adaptive by virtue of its existence or found to be also markedly impaired in their theory of mind prevalence’. Traits or constellations of traits may also be abilities, e.g. [119]. As Sperber and Wilson [120] have prevalent in a population due to processes unrelated to reasoned, the pragmatic use of language requires an intact adaptation such as random mutation, genetic drift, and theory of mind because for proper conversation it is not segregation distortion (‘meiotic drift’). sufficient to comprehend the literal meaning of utterances Another problem that is probably most imperative to but also the ‘metaphorical’ content, and the latter is schizophrenia research, relates to the fact that there is not ultimately linked to a person’s capacity to connect to the one single psychopathological symptom, biochemical or mentality of her interlocutor. Thus this aspect of ‘social structural marker that is specific or unique to schizophrenia, brain’ evolution may well be reconciled with Crow’s such that Bentall and colleagues have even recommended emphasis on the evolution of syntactical and semantic abandoning the whole concept of schizophrenia [115]. qualities of human language. Similarly, the question raised by Crow [23,29] of continua Two further examples may illustrate how evolutionary versus ‘disease entities’ is not only critical for the driven hypotheses can inform about individual symptoms evolutionary discussion of schizophrenia but also for the associated with (but not specific to) schizophrenia: (1) validity of the classification of psychiatric disorders in Researchers have recently detected a novel cell type in the general. It could eventually well turn out that our diagnostic anterior cingulate which is specific for great apes and system relies on arbitrary and empirically flawed categories. humans while absent in monkeys and other mammals [121]. In other words, we must not overlook, as Burton-Bradley Contrary to previous assumptions that the anterior cingulate [116] put it, that our Western diagnostic system is, cortex (ACC) would represent a primitive stage of cortical particularly in a cross-cultural context, only of limited evolution, these so-called spindle cells have increased in value because it originated ‘in a few limited geographical size and number over evolutionary time indicating ence- areas of Europe, notably in Vienna, Munich, and Zürich’. phalisation during recent hominid evolution, and hence However, from a pragmatic point of view, simply being a novel adaptation. Functionally they may be involved discarding the concept of ‘schizophrenia’ might not only in control of impulsive behaviour, error recognition, and be difficult to sell to clinicians; more importantly there also perhaps other aspects of social behaviour [122]. Lesions of ought to be some alternative that is superior to the current the ACC, for instance, produce akinetic mutism and other (anachronistic) account and may, at least in part, resolve the behavioural deficits such as resisting the performance of diagnostic dilemma. automatic subroutines [123], which strikingly resembles I would like to suggest, in line with Bentall et al. [115] symptoms that may occur in schizophrenia such as stupor, Burns [18] and Crow [23,29], an approach based on mutism and stereotypies. Moreover, the fact that spindle individual symptoms inserted into an evolutionary frame- cells in humans emerge only postnatally, and findings that work that explicitly appreciates the concept of continua the survival of neurons in the hippocampus critically rather than disease entities in psychiatry. As previously depends on environmental input and enrichment, while discussed elsewhere [113] an observation-driven evolution- stress reduces their production, suggests that the develop- ary ‘bottom-up’ analysis may be most appropriate to address ment and arborisation of spindle cells may also crucially symptoms and syndromes. Many dysfunctions we call rely on environmental input. In other words, stress during ‘disorders’ may arise due to a mismatch of our modern early development may impair the functional development environmental conditions with the ancestral conditions to of the ACC [121], and hence may induce psychopathology, which our human mind once adapted. Others may rather be including psychotic symptoms. (2) Another cell type, regarded as trade-offs or design flaws, because ‘optimality’ referred to as ‘mirror neurons’ due to their selective firing in nature is nonexistent (otherwise, evolution would not when observing and imitating certain behaviours of con- happen). As such, many psychotic symptoms and syn- specifics, particularly hand movements, has been located in dromes may be considered trade-offs, primarily manifesting the ventral premotor cortex of monkeys that is probably themselves in domains related to the evolution of our ‘social homologous to Broca’s area in humans [124]. Mirror brain’ [18,72,117]. neurons also exist in Broca’s area and the superior temporal Such social brain disorders include, as already men- sulcus in humans. They are also selectively active when tioned, an overly active ‘theory of mind’ mechanism of observing hand and mouth movements and when executing cheater and deception detection such as in paranoia, or the the observed behaviour [124]. This has given rise to the incapacity to represent one’s own mental states as self- hypothesis that human language evolved in the first place generated and to understand the beliefs and desires of others from gestural communication, and that the human Brod- [76]. This faculty of the mind is likely to have evolved from mann area 44 is also involved in action understanding and the capacity in primates to monitor biological motion [118]. imitation [125]. Now, with respect to psychotic symptoms it Interestingly, there is a clear link of theory of mind and could be worth assessing, for example, whether a disinhibi- language, which might also throw some light on symptoms tion of mirror neuron activity is involved in a subset of
50 M. Brüne / Neuroscience and Biobehavioral Reviews 28 (2004) 41–53
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