Reasonable people adapt themselves to the world. Unreasonable
people attempt to adapt the world to themselves. All progress,
therefore, depends on unreasonable people.

Schizophrenia is a complex and widespread disorder, giving rise to a great burden of suffering and impairment in both patients and their families. It is human nature to seek mean- ing behind experiences, and indeed patients with schizo- phrenia seek meaning in the bizarre and perplexing phe- nomena of their psychoses. So too, in our scientific endeavour to understand this complex disorder, it is im- portant to undertake a search for the meaning of the exis- tence of schizophrenia in the human species.

In recent years, a number of researchers have sought to adopt an evolutionary perspective to explain the continued persistence of clearly maladaptive psychiatric disorders. In the field of schizophrenia research, Crow and others have pioneered an evolutionary approach to understanding the meaning of this distressing illness. They have asked ques- tions about the evolutionary origins of schizophrenia and about why it is maintained in the human genome.

An evolutionary theory of
schizophrenia: Cortical connectivity,
metarepresentation, and the
social brain

in the face of reduced fecundity has caused some to argue that an evolutionary advantage exists in unaffected relatives. Here, I critique this adaptationist approach, and review \u2013 and find wanting \u2013 Crow\u2019s \u201cspeciation\u201d hypothesis. In keeping with available biological and psychological evidence, I propose an alternative theory of the origins of this disorder. Schizophrenia is a disorder of the social brain, and it exists as a costly trade-off in the evolution of complex social cognition. Paleoanthropological and comparative primate research sug- gests that hominids evolved complex cortical interconnectivity (in particular, frontotemporal and frontoparietal circuits) to regulate so- cial cognition and the intellectual demands of group living. I suggest that the ontogenetic mechanism underlying this cerebral adapta- tion was sequential hypermorphosis and that it rendered the hominid brain vulnerable to genetic and environmental insults. I argue that changes in genes regulating the timing of neurodevelopment occurred prior to the migration of Homo sapiens out of Africa 100,000 \u2013 150,000 years ago, giving rise to the schizotypal spectrum. While some individuals within this spectrum may have exhibited unusual cre- ativity and iconoclasm, this phenotype was not necessarily adaptive in reproductive terms. However, because the disorder shared a com- mon genetic basis with the evolving circuitry of the social brain, it persisted. Thus schizophrenia emerged as a costly trade-off in the evo- lution of complex social cognition.

trist at the Department of Psychiatry of Nelson Man- dela School of Medicine of the University of KwaZulu in Natal, South Africa, and is in private practice part time. He was trained in Medicine and Psychiatry at the University of Cape Town, South Africa, and is a Fellow of the College of Psychiatry of South Africa. From 2001 to 2003, he was a Research Fellow in the Department of Psychiatry at the University of Edinburgh in Scot- land. Burns has done research on brain imaging in schiz- ophrenia under the auspices of Professor Eve Johnstone and, in 2003, obtained an M.Sc. degree at the Univer- sity of Edinburgh for this research. He is the co-author (with David Semple, Roger Smyth, Rajan Darjee, and Andrew McIntosh) of The Oxford Handbook of Psychi-

ledge. Burns is the winner of the 2002 Aaron Beck Award of the Across Species Comparisons of Psycho- pathology Society.

This paper critically assesses these models drawing on evidence from various fields including psychiatry, psychol- ogy, paleoanthropology, and primatology; finds them want- ing; and proposes an alternative and more integrated the- ory of the origins of schizophrenia that is in keeping with all the available evidence. The central argument I propose here is that schizophrenia reflects the severe end of a spec- trum of disordered frontotemporal (FT) and frontoparietal (FP) connectivity, which is related to the evolution of metarepresentation and the \u201csocial brain\u201d in the human line. I argue that schizophrenia exists as a costly trade-off at two stages of cognitive evolution.

I suggest that the first trade-off occurred between 16 and 2 million years ago (mya), when human ancestors evolved complex cerebral interconnectivity and specialised neural circuits to regulate social cognition and the intellectual de- mands of group living. Owing to anatomical constraints on foetal brain size, these changes evolved by a heterochronic process that prolonged brain maturation. This meant that the human brain, with its complex and recently evolved cir- cuitry, became increasingly susceptible to complex gene in- teractions and/or genetic insults. This susceptibility was the trade-off for the advantages gained in social cognition.

The second trade-off occurred approximately 100,000 \u2013 150,000 years ago, when genetic changes in some individu- als resulted in aberrant connectivity in these cortical cir- cuits. The exact mechanisms responsible at both the geno- typic and phenotypic level is debateable and will be discussed in this paper. I argue that the expression of this genetic change is variable in different individuals and that, in some cases, milder expression may have manifested as extraordinary creativity and iconoclastic thinking. While this milder phenotype may have featured significantly in the emergence of human culture, there is little evidence that it conferred a reproductive advantage. Therefore, in contrast to authors who argue for a heterozygous or schizo- typal advantage, I suggest a different genetic mechanism that may account for the persistence of schizophrenia. If the genes for schizophrenia were in some way intimately as- sociated with genes regulating the development of complex cortical connectivity, and if these regulatory genes were ad- vantageous during hominid evolution, then the genes for the disorder would persist by virtue of their association with the adaptive genes. Thus, schizophrenia would represent a trade-off in the evolution of the highly organised brain of modern Homo sapiens.

There is a need to integrate recent biological findings from schizophrenia research into an evolutionary framework based on current insights into the evolution of the human brain. The rationale for using evolutionary theory as an ex- planatory paradigm for the schizophrenic spectrum of dis- orders comes from attempts to reconcile several seemingly contradictory epidemiological observations. First, from the International Pilot Study of Schizophrenia conducted in nine countries (World Health Organization 1973), it ap- pears that globally, schizophrenia has an incidence of ap- proximately 1% and there is remarkable consistency cross- culturally in the core symptoms of the disorder. One of the \u201cfirst-rank\u201d findings of this study was that the evidence

points to a significant genetic component in the transmis- sion of schizophrenia (Jablensky 1988; Sartorius et al. 1986). Other evidence suggests that this is a polygenetic disorder (Kendler et al. 2000). Second, it is widely accepted that schizophrenia is associated with lower fecundity (Lar- son & Nyman 1973) and increased early mortality (Brown 1997). Third, as many authors have noted, there is evidence that some highly gifted and creative individuals either man- ifest schizotypal traits themselves or have a first-degree rel- ative with schizophrenia (Karlsson 2001; Post 1994).

These observations have led some writers to speculate on why a clearly maladaptive disorder such as schizophrenia should have remained in the human genome at a constant prevalence rate (Allen & Sarich 1988; Crow 1995c; Farley 1976; Stevens & Price 2000). Importantly, such specula- tions assume the prevalence of schizophrenia has remained constant for millennia. According to a strict interpretation of Darwin\u2019s theory of natural selection (Darwin 1859), a phenotype that exhibits reduced fertility and earlier mor- tality should be subject to negative selection and disappear over a number of generations. That it persists has caused some to suggest that the disorder must have some inherent adaptive value to survive the process of natural selection. Furthermore, the well-founded notion of a spectrum in the expression of the genotype has provided a suitable model for considering just where the adaptive value might reside. Crow has proposed that psychotic illness should be viewed as lying on a \u201ccontinuum of variation\u201d (Crow 1995b; 1998a). It seems that there may be at least two dimensions to this spectrum \u2013 one stretching from schizophrenia to the affec- tive psychoses and the other from disorder to trait to \u201cnor- mality.\u201d Evidence from neuroimaging and neuropsychology studies suggests that schizotypal people have milder but similar deficits to patients with schizophrenia (Buchsbaum et al. 1997a; 1997b; Cadenhead et al. 1999; Dickey et al. 2002a; 2002b). That these deficits are also found in relatives of patients with schizophrenia suggests a genetic cause (Byrne et al. 1999; Lawrie et al. 2001). This supports the idea of a genetic continuum. So, instead of vainly attempt- ing to conjure up some aspect of this disabling disorder that might be considered \u201cadaptive,\u201d it is legitimate to focus on individuals in the schizotypal spectrum and seek to identify adaptive traits in this population that may compensate for the former group\u2019s lack of fitness. Therefore, a popular as- sumption among evolutionary psychiatrists is that unaf- fected individuals in the schizotypal spectrum may be at some kind of reproductive advantage, thus compensating for the apparent disadvantage of the schizophrenic pheno- type.

This argument has resulted in links being drawn between schizotypy and genius, and between divergent thinking and creativity, as if these associations automatically imply that these individuals have a selective advantage. And herein may lie the error. The evidence is not convincing that schizotypal individuals have areproductive advantage. In fact, the studies of relative fertility in schizotypal disorder are contradictory and most fail to demonstrate an advantage (Avila et al. 2001; Haukka et al. 2003; Kendler et al. 1998). The recent study by Haukka and colleagues is large enough and has sufficient power to confirm this position (Haukka et al. 2003). An exception is a study by Avila and colleagues

that demonstrates an increased number of children in first- degree relatives of people with schizophrenia (Avila et al. 2001) and thereby supports the notion of enhanced fitness in carriers. However, most authors who favour this concept of enhanced fitness in unaffected individuals typically rely on anecdotes regarding a handful of historical figures. For example, Stevens and Price cite case histories of paranoid and almost certainly schizotypal \u201cgurus\u201d such as David Ko- resh and Jim Jones as examples of reproductively success- ful individuals within the spectrum (Stevens & Price 2000). They propose that these individuals performed an essential function in ancestral groups, splitting populations as they outgrew resources. This particular \u201cgroup selection\u201d model is problematic, not least because group-splitting has been observed in wild chimpanzees (Goodall 1990), suggesting that this is by no means a human-specific phenomenon. Similarly, Karlsson has demonstrated an increased inci- dence of psychotic illnesses, including schizophrenia, in a cohort of particularly gifted artists, philosophers, and politi- cians, and while it is not explicitly stated, Karlsson implies that this association might explain the persistence of schiz- ophrenia (Karlsson 1973; 2001). While these data are in- triguing, the assumption that social, political, or creative advantage automatically translates into reproductive ad- vantage is erroneous. The constant prevalence of schizo- phrenia does not necessarily imply that the schizotypal genotype is adaptive; there are other mechanisms that could account for this. It is worth noting that several other brain disorders, for example learning disability and idio- pathic epilepsy, also exhibit constant prevalence rates.

Dubrovsky has critiqued the \u201cadaptationist programme\u201d of many contemporary evolutionary psychologists and psychi- atrists (Dubrovsky 2002). He observes that too often there is a focus on explaining variants in human behaviour and experience in terms of their potential adaptive qualities in the ancestral environment. In some cases this has resulted in the construction of so-called Just So stories as substitutes for objective scientific theories on the origins of behaviour.

There may be more plausible evolutionary genetic mod- els for schizophrenia (Bailey 2000). For example, genes for the disorder may be expressed phenotypically as a spec- trum, and some in the spectrum may have special cognitive abilities, but the schizotypal genotype does not, in itself, confer a reproductive advantage. However, if schizotypal genes are associated in some way with genes that code for some faculty essential to the human condition, then the dis- order may persist by virtue of this association. In other words, maladaptive traits survive into the next generation because they are associated, at a genetic level, with traits that are highly adaptive and which confer a reproductive advantage on the individual. I will argue that these \u201cadap- tive genes\u201d are genes that are involved in regulating the evo- lution and development of the social brain in humans.

There are several mechanisms that can be considered to explain this association between maladaptive and adaptive genes. The first is that the loci for schizotypal genes may be close on the chromosome(s) to the loci for the adaptive genes, and that they are \u201cdragged\u201d in selection. Sober makes the distinction between selection for a trait andse-

scribes the process of discriminating between phenotypes, but this process is not entirely \u201cclean,\u201d and linked traits that do not necessarily increase fitness may be \u201cdragged\u201d along in the inheritance process (i.e., selection of a trait). There- fore, while there may be selection for the social brain, there may in conjunction be selection of schizophrenia. A second possibility is that schizotypal genes are defective alleles of the adaptive genes, but the problem with this scenario is that one would expect defective alleles to have been se- lected against during evolution. A third possibility is that genes (subsequently responsible for schizophrenia) were already embedded in the genome before the social brain evolved in all its complexity in modern humans. In this scenario, the emergence of novel neural architecture may have served to activate the schizotypal genes. In other words, the genes responsible for schizophrenia existed prior to modern Homo sapiens (perhaps with neutral or even adaptive functions). With the emergence of a novel brain environment, characterised by a host of novel gene functions, the previously benign schizotypal genes changed (either through mutation or altered expression or gene in- teraction) and became the malignant genes responsible for schizophrenia.

For want of a better term, I will call this model (in which maladaptive genes are associated with adaptive genes) the \u201cpleiotropic model\u201d of selection and will draw on it in con- structing an evolutionary theory of schizophrenia. But first I should briefly consider two other possibilities.

It is possible that the genes for schizophrenia represent random mutations or \u201cneutral genes\u201d and are not subject to natural selection. In 1968, Kimura put forward a revolu- tionary thesis that shook the biological community, for he suggested that most mutations responsible for molecular variability in populations are neutral (rather than advanta- geous) and became fixed as a result of random genetic drift (Kimura 1968). Given that human ancestors experienced several significant \u201cbottlenecks\u201d during evolution, with dra- matic reductions in population size, it is possible that the mutations responsible for the schizotypal spectrum were neutral and were fixed in the human genome by random ge- netic drift.

It is also possible that care-giving behaviour by a family or group may have allowed individuals with less adaptive schizotypal traits to survive. There is some evidence that Neanderthals and early Homo sapiens cared for those with disabilities. For example, burial sites have been discovered where individuals have lived to a fair age with deformities, with which they could not have survived without care (Stringer & Gamble 1993; Trinkaus & Shipman 1993). Fur- thermore, observations of caring behaviour by chim- panzees towards sick or disabled group members (Aureli & de Waal 2000; Goodall 1990) suggest that care-giving be- haviour has ancient origins.

As I have said, in terms of schizophrenia, I prefer the no- tion of the pleiotropy model. It follows, therefore, that we need to ask: Are there unique human faculties that might be associated with the origins and persistence of schizo- phrenia in Homo sapiens? Crow has suggested that there are \u2013 language and laterality (Crow 1995b; 1997a). He has suggested that a speciation event gave rise to the human ca- pacity for language, and that this evolutionary change in the brain provided the neural and cognitive substrate for a dis- order such as schizophrenia. He suggests that this specia- tion event occurred approximately 100,000 \u2013150,000 years