The Neurodevelopmental Hypothesis of Schizophrenia

Clare Holtam

• Introduction to Schizophrenia
• The Aetiology of Schizophrenia
• Neuropathology
• The Premorbid Child
• Aetiological Factors
• Mechanisms of delayed onset
• Conclusion

Introduction

Schizophrenia is a term used to describe a group of mental illnesses which are 
diverse in nature and cover a broad range of cognitive, emotional and behavioural 
disturbances. 

It is a common disorder with up to 600,000 sufferers in the UK. The incidence and 
prevalence rates are considered to be consistent World wide at 0.15-0.20 per 1000 
per year and 2-4 per 1000 per year, respectively. The lifetime risk of schizophrenia 
in the general population is about 1% but for first-degree relatives of sufferers this is 
increased to 10%. (1)

Core features of schizophrenia include: auditory hallucinations, particularly in the 
third person; changes in thought construction and form; and bizarre delusions in 
which, for example, the patient believes their thoughts to be available to others or 
that they are influenced by outside forces. These positive psychotic phenomena 
comprise the key diagnostic features, and usually occur together with changes in an 
individual's behaviour or social functioning. In addition, there may be negative 
features, such as restriction of the range of emotions (blunting of affect) and 
decreased ability to initiate thoughts and ideas (poverty of thought). 

Currently, operational criterion-based systems are used to diagnose schizophrenia; 
examples of such systems include the International Classification of Diseases, tenth 
edition (ICD-10) (1) and the Diagnostic and Statistical Manual of Mental Disorders, 
fourth edition (DSM-IV). (2)

Schizophrenia is divided into a number of subtypes, although many patients present 
with symptoms and behaviours belonging to more than one category. The most 
common subtype of schizophrenia currently found in the UK is paranoid 
schizophrenia which has a later age of onset and a more insidious course than the 
others. 

Schizophrenia has a dramatic influence on the lives of sufferers and their families 
often striking in early adult life just when individuals would be experiencing most 
independence and starting a productive career. In addition to the social and 
psychological anguish it causes schizophrenia creates a huge economic burden for 
society. In the UK 5.4% of the total National Health Service inpatient costs are 
attributable to schizophrenia. When inpatient, outpatient, primary care, 
pharmaceutical, community and social services expenses are combined the total cost to the UK of 
2.6 billion per year is estimated. (4)

The Aetiology of Schizophrenia

The cause of schizophrenia is unknown. During this century various theories have 
been proposed to ranging from social and psychological ideas to biological, genetic 
and environmental hypotheses. A brief overview some of these theories is presented 
below. 

In 1948 Fromm-Reichmann suggested a 'schizophrenogenic' mother, one who is 
both overprotective and hostile to her children, caused schizophrenia. Lidz proposed 
the disorder was the consequence of 'marital skew 'and' marital schism. (5, 6) 
Marital skew describes the situation where one parent dominates the other. Marital 
schism is when parents have contrary views which are thought to cause a child to 
have divided loyalties. However, subsequent studies failed to confirm such ideas (7, 
8) and it is suggested the findings were the result, as opposed to the cause of 
schizophrenia. Disorders of communication within families have also been 
suggested to be of aetiological significance. (9, 10) 

Life events have been proposed to be a cause of schizophrenia. This suggestion is 
based on the finding that schizophrenics experience significantly more life events in 
the three weeks prior to the onset of the illness and that life events appear to 
precipitate relapses. (11-15)

Biochemical theories of schizophrenia include the dopamine and glutamate 
hypotheses. (16) The dopamine hypothesis was based on the pharmacological 
findings that the drugs stimulating central dopamine receptors, can produce a 
disorder indistinguishable from schizophrenia; and that anti-psychotic drugs block 
dopamine receptors. All the new information produced by studies into 
schizophrenia, however, cannot be accounted for simply by abnormalities with 
dopamine. 

Family, twin, adoption and epidemiological studies provide considerable evidence 
for the genetic contribution to the aetiology of schizophrenia. (1) However, despite 
numerous linkage and association studies with candidate genes for schizophrenia no 
one gene for schizophrenia has been found and results have largely been negative or 
inconsistent. (17) The possibility that schizophrenia is a single gene disorder has 
been excluded (18) and transmission is now thought to involve multiple susceptible 
loci. (1)

Although twin studies provide compelling evidence for genetics in the causation of 
schizophrenia they also establish the importance of environmental influences. The 
findings that both affected and unaffected monozygotic twins pass the same 
increased risk of development of schizophrenia to their children; (19, 20) and in 
monozygotic twins discordant for schizophrenia the affected twin has larger 
ventricles and less temporal lobe grey matter than the unaffected twin (21, 22) 
suggests the involvement of more than just genetics in the aetiology of the disorder. 
The environmental factors implicated in the aetiology of schizophrenia are discussed 
in the following section. 

The neurodevelopmental hypothesis of schizophrenia proposes that a proportion of 
schizophrenia is the result of an early brain insult, either pre or perinatal, which 
affects brain development leading to abnormalities which are expressed in the mature 
brain. (23-26) This idea is not new, Kraeplin and others throughout the 20th century 
argued that some cases of schizophrenia probably resulted from insults that cause 
cerebral maldevelopment. (27, 28) The cause of the brain lesion is postulated to be 
either from the inheritance of abnormal genes, which impair brain development, or 
from some fetal or neonatal adversity. 

The following section discusses the strength of the neuropathological, clinical and 
epidemiological findings evidence in support of the neurodevelopmental hypothesis. 
Firstly, reports of neuropathology will be evaluated followed by data from studies of 
premorbid children with abnormalities which are interpreted to represent cerebral 
maldevelopment. The third section reviews studies that have attributed the cerebral 
abnormalities to specific aetiological factors. Finally, there will be a discussion of 
the mechanisms proposed to explain how and why the onset of the illness is delayed 
until 20-30 years after the initial insult. 

Neuropathology

Post-mortem and brain imaging studies into schizophrenia have shown the disorder 
to be associated with disturbances in cerebral structure. However, researchers have 
reported different brain regions to be affected to varying extents. A meta-analysis of 
40 MRI studies (29) described the following abnormalities in the brains of 
schizophrenics:

Volume reductions:

• Whole Brain (3%)
• Temporal lobe (left 6% right 9.5%)
• Amygdala/hippocampal complex (left 6.5%, right 5.5%)

• Volume is increased in the lateral ventricles (left 44%, right 36%)
• Grey matter is reduced but white matter volumes may be increased

 

These brain abnormalities are thought to be neurodevelopmental in origin, as 
opposed to neurodegenerative, because of reports they are found in newly diagnosed 
patients as well as chronic schizophrenics, (30-35) and as they appear to be non-
progressive. (36-41) Also, it is argued that if the disease process of schizophrenia 
were progressive then so would be the neuropsychological profile; but the cognitive 
deficits found in schizophrenia show no deterioration over the course of the illness. 
(42) However, reports of changing brain volumes in schizophrenia are inconsistent 
(43), and since 1989 there have been both positive (44-46) and negative (47, 48)
longitudinal computed tomography findings of progressive volume loss in 
schizophrenia; and both positive (49-51) and negative (38, 52) longitudinal magnetic 
resonance imaging results in follow-up investigations of first episode schizophrenia. 
In addition, there is evidence for progressive ventricular enlargement in childhood-
onset schizophrenia. (53) Moreover, the failure to find conclusive evidence of brain 
volume loss over time is not proof that neuronal degeneration does not occur in 
schizophrenia unless it is assumed that there is a temporal relationship between 
degeneration and symptomatic illness. 

Many imaging studies also report the presence of excessive extracerebral CSF in 
schizophrenia. (54-55) This is difficult to explain using a model of an early static 
defect in brain development as brain volume triples between birth and the age of five 
years and any increase in extracerebral volume would tend to be filled up by the 
outward growth of the brain. 

Nevertheless, compelling evidence in support of the neurodevelopmental hypothesis 
comes from studies of cortical cytoarchitecture which discovered neurons in 
schizophrenic brains to be misplaced, mis-sized and disorganised. (56-59) Such 
findings are difficult to explain in any other than neurodevelopmental terms as they 
are suggestive of impaired neuronal migration which takes place during the second 
trimester of pregnancy. However the findings remain controversial. (60)

Gliosis is the neural scarring which accompanies brain lesions other than those which 
occur during early development and is regarded as a characteristic feature of 
neuronal degeneration. In schizophrenic brains the balance of neuropathological 
evidence is strongly against excessive gliosis being characteristic of schizophrenia. 
(61-68) Also, there is no evidence of increased glial membrane turnover signals in 
magnetic resonance spectroscopy in either chronic schizophrenia or at the time of 
disease onset. (69) This is supportive of the idea that the damage to the brain in 
schizophrenia occurs early in life and is not due to a neurodegenerative process. 
However, earlier studies of schizophrenic brains did report gliosis, (70) although this 
could be explained by technical issues; with results being dependent on specific 
staining procedures (71) or vulnerability to long fixation times. (72) In addition, 
some researchers report that the brain can respond to injury with gliosis as early as 
the 20th week of gestation (73) and certainly throughout the third trimester (74) 
suggesting that any perinatal brain injury should result in gliosis. 

In schizophrenia there is a failure to develop normal cerebral asymmetries. (75-80)
Since normal human brain asymmetries are formed early in development, during the 
second trimester of gestation, these findings suggest the occurrence a pathological 
event interfering with this stage of development. However, such findings remain 
controversial and are only suggestive, not conclusive, of deviant neurodevelopment. 
(81-83)

In some studies, pathological changes appear to affect the left side of the brain more 
severely than the right. (20, 60, 76, 84, 85) This is potentially explicable in 
neurodevelopmental terms as the left hemisphere of the brain is thought to develop 
more slowly than the right hemisphere during early to mid gestation and so could be 
more vulnerable to injury or vulnerable for a longer period of time. 

Further evidence in support of the neurodevelopmental hypothesis is the aberrant 
expression of developmental and plasticity associated markers such as the embryonic 
isoform of the neural adhesion molecule (NCAM) (86) and the growth-associated 
protein 43 (GAP-43) (87) in the brains of schizophrenics. 

Finally, sulcal-gyral abnormalities have been reported in some post-mortem studies 
of schizophrenic brains. (88, 89) Since gyrification in the human brain is largely 
intrauterine between weeks 16 and 29 (90) such abnormalities are highly suggestive 
of a process affecting the fetal brain at this stage of development. However, these 
studies were not conducted blind and may not have accounted sufficiently for the sex 
differences in the sulcal-gyral pattern. (91) Nevertheless, the findings have since 
been confirmed in a later study (92) 

The Premorbid Child

If schizophrenia is caused by an aberration in the developing brain then it is 
reasonable to expect some subtle abnormalities of neural function and developmental 
anomalies to be present in early life. 

Several lines of circumstantial data support this possibility. Preschizophrenic 
children have a higher incidence of: neuromotor abnormalities; delayed attainment of 
developmental milestones; and behavioural and intellectual abnormalities. (93-96)
They are also often described as having 'schizoid' personality traits such as being 
socially withdrawn, aloof and preferring to play alone. (94, 97) One study, using old 
home movie tapes, revealed that in the first two years of life children who were to 
become schizophrenic had reduced responsiveness, less positive affect and less eye 
contact. (98) Another study reported that children who go on to develop 
schizophrenia perform less well than their contempories in tests of 
neuropsychological and academic performance. (99) 75% of people who go on to 
develop schizophrenia have 'soft' neurological signs as children. These include: 
slightly abnormal gaits in children; dysgraphaesthesia; proprioceptive errors; tics; 
twitches and epileptic attacks. (93, 94) The results of these studies, while open to 
other interpretations, are consistent with the possibility of brain maldevelopment. 
Nevertheless, despite all these reports, many children who go on to develop 
schizophrenia have shown high levels of social, academic and occupational 
functioning. So it appears there is a subgroup of schizophrenics who have been 
subtly impaired for years before the onset of overt positive schizophrenic symptoms, 
implying a proportion of schizophrenia is attributable to a neurodevelopmental 
defect. 

Schizophrenic patients are also reported to have a higher prevalence of minor 
physical anomalies than the general population. (100) Dermatoglyphic asymmetry, 
(101-103) and cerebral anomalies, such as agenesis of the corpus callosum and 
cavum septum pellucidum, and developmental cysts, (104) are both found more 
commonly in schizophrenics and are both indicative of disturbed intrauterine 
development. Additionally, minor physical abnormalities including: low set ears; 
furrowed tongue; high arched palate; curved fingers; greater distance between the 
eyes and a single palmer crease are also found more frequently in schizophrenics, 
particularly in males and in those with a positive family history. (100, 105) Both the 
skin and the central nervous system are derived from the ectodermal tissue in utero, 
so such visible anomalies can be considered as external markers of damage to 
ectodermal structures of the fetus and as such can be interpreted as indirect support 
for the occurrence of aberrant neurodevelopment. Such anomalies are also found in 
other disorders of neurodevelopment such as Down's syndrome and intrauterine viral 
encephalopathies. However, this theory remains controversial (106) with the true 
frequency of these abnormalities in schizophrenia unknown and uncertainty as to 
whether all the morphological characteristics reported are actually pathological. 

Aetiological factors

If schizophrenia is a neurodevelopmental disorder the causes must act early in 
development. It is feasible that genes may be involved in the genesis of the brain 
abnormalities and the finding that environmental risk factors associated with 
schizophrenia act pre- or perinatally offers further support for the 
neurodevelopmental hypothesis. However, the presence of risk factors early in life 
does not necessarily mean that schizophrenia must be developmental in an overall 
sense, for example, there are early risk factors for stroke. 

People who develop schizophrenia are born in winter and spring slightly more 
frequently than the general population. (107) and several studies indicate that the 
increased risk for winter births is enhanced among those born in large cities and is 
greater the colder the winter. (108, 109) The possibility that this observed 
seasonality could be a statistical artefact or merely an accentuation of the 
seasonality seen in general births has generally been refuted. (110) The findings 
suggest the influence of some intrauterine factor that varies seasonally. 
Environmental factors proposed include infectious agents, nutritional factors, and the 
temperature variations at the time of conception. Maternal infection could affect 
fetal brain development through in utero infection; maternal fever; maternal 
antibodies crossing the placenta and acting as fetal anti-brain antibodies; or maternal 
use of analgesics. Support of infection as the cause of this phenomenon are the 
reports that viral entry into the CNS is promoted by exposure to cold (111) and the 
demonstration by rubella that viral infection in a pregnant women can cause 
permanent damage to the fetal nervous system. 

Maternal infection with the influenzae is also claimed to be associated with the later 
development of schizophrenia in the unborn child, particularly in females. (112-118) 
However, the existence and importance of this effect remains controversial, (119-
121) as although ecological studies show an association between schizophrenia and 
the timing of the great influenzae epidemics there is yet to be a convincing 
demonstration of this effect in individuals known to both have been exposed to 
influenzae in utero and to have developed schizophrenia. The mechanism by which 
maternal influenza increases the risk of schizophrenia in the unborn baby is not 
established. It is possible it is mediated through maternal antibodies to influenzae 
cross-reacting with neuronal proteins, a mechanism that has been observed in rabbits 
(122) or that certain mothers are genetically predisposed to produce a harmful 
immune response (123) Any theory attempting to explain this association must also 
account for why only a minority of mothers infected with influenzae during 
pregnancy have a child who becomes schizophrenic. 

Several studies have found that obstetric complications during antenatal life or 
delivery are more frequent in patients with schizophrenia, especially in male, early 
onset schizophrenics. (124-133) However, a meta-analysis of such studies suggests 
that there may be considerable publication bias in the literature and that prospective, 
population based studies tended to be largely negative. (134) Acute late onset and 
female schizophrenic subjects do not seem to share the excess of obstetric 
complications which may be one reason why not all studies show such an 
association. (135-137) Ischaemia is the mechanism by which obstetric complications 
have been proposed to increase the risk of the later development of schizophrenia. 
Obstetric complications causing hypoxic ischaemia in the pre- or perinatal period 
can lead to intraventricular or periventricular bleeds, resulting in ventricular 
enlargement. (138) Furthermore, the pyramidal cells in the CA1 region of the 
hippocampus are among the most vulnerable in the human brain to mild ischaemia. 
Excitotoxic damage associated with perinatal hypoxia could also account for some of 
the neurochemical abnormalities that are found in schizophrenia. (139) However, 
pre-existing brain dysfunction may predispose to obstetrical complications and some 
investigators have interpreted the association between obstetric complications and 
schizophrenia as being an indication of fetal abnormality. (140) 

Maternal malnutrition in early gestation (141, 142) is another intrauterine 
environmental event which appears to increase the risk of developing schizophrenia 
in a dose dependent way. However, this study (142) did not control for the 
implication of social class both in access to food and on risk for schizophrenia. 
Nevertheless, four lines of evidence support prenatal nutritional deficiencies as a 
plausible set of risk factors for schizophrenia: (143) 

 

• Their effects are not incompatible with the epidemiology of schizophrenia
• They have adverse effects on brain development
• General malnutrition results in neuropathological anomalies of brain regions 
  implicated in schizophrenia
• Prenatal malnutrition affects maternal systems critical to the developing fetal 
  nervous system. 

In the light of the widely accepted data that genetic factors convey susceptibility to 
schizophrenia, it is not surprising that there have been speculation about genetic 
factors that may affect brain development in schizophrenia. Since approximately 
30% of the genome is expressed in the brain (144) and many genes are turned on and 
off during discrete phases of brain development, there are many potential candidate 
genes for aberrant neurodevelopment. It is suggested a mutation in a gene relating to 
brain development could result in the neuropathological deviations found in the 
developing brain. (145) Alternatively, it is hypothesized a genetic defect could 
predispose the schizophrenic brain to be adversely affected by intrauterine or 
perinatal environmental events. Another possibility is that the genetic control of 
brain development may be disrupted by adverse environmental events which results 
in the cerebral pathologies found in the brains of schizophrenics. (146) 

Mechanisms of delayed onset

It is easy to see how the neuronal abnormalities in the frontal and temporal lobes 
could result in an abnormal pattern of cortical connections and cause the premorbid 
abnormalities in children and the social and cognitive defects shown by 
schizophrenic adults. However, the neurodevelopmental hypothesis proposes that 
such pre or perinatal lesions can produce the positive symptoms of schizophrenia 2-3 
decades later. 

Animal studies have demonstrated that a brain lesion sustained in early life can 
remain quiescent until early adulthood after which time in influences behavioural and 
neuropharmacological phenomena that mimic schizophrenia. For example, neonatal 
damage in the temporal lobe has little effect in juvenile monkeys, but leads to 
behavioural and pharmacological abnormalities in adulthood. (147) Also, prenatal 
lesions in the hippocampi of rats remain apparently silent until adult life. (148-154) 
Nevertheless, although these studies do show that a defect in development can result 
in a latency before the onset of symptoms they do not demonstrate spontaneous late 
deterioration of function after an early lesion which is what occurs in schizophrenia. 
A study in monkeys have been interpreted as showing that prenatal lesions of the 
dorsolateral prefrontal cortex can remain undetected until sexual maturity when 
deficits in neuropsychological tests arise. (155) However, careful examination of the 
study does not support this interpretation; the performance of the 'lesioned' monkeys 
in the tests did not become poorer as they progressed from infancy into adulthood, 
the 'non-lesioned' monkeys just performed better. It should also be noted that the 
performance of monkeys who sustained lesions in infancy was always superior to 
those who sustained lesions in the juvenile period which is implies some degree of 
compensatory organization. So therefore this study, although frequently cited as 
supporting the neurobiological plausibility of the neurodevelopmental hypothesis, in 
fact it does not. 

It is possible that a similar process as is occurring in these animals with early brain 
lesions explains why preschizophrenic children do not show the positive symptoms 
of schizophrenia until early adult life. (156) 

A large proportion of all the cells generated in the developing nervous system die by 
the time it is mature. After peaking during childhood, synaptic density in the human 
frontal cortex declines by 30-40% by adulthood. A process of selective neuronal 
death and progressive synaptic elimination appears to operate throughout 
adolescence to eliminate early errors of connection and it is suggested that this 
sculpting of this nervous system might be abnormal in schizophrenia. (157-160)
Integrating this idea with the neurodevelopmental hypothesis results in the 
suggestion that the maldevelopment in utero sets the stage for secondary synaptic 
disorganisation in adolescence. This hypothesis has been supported by: phosphorus-
31 magnetic resonance spectroscopy studies of neural membrane phospholipid 
turnover. (161, 162)

Alternatively it is possible that lesion remains dormant until the normal processes of 
brain maturation in adolescence lead to the use of neuronal circuits that are not 
greatly developed in children. In support of this idea it has been found that in 
humans the development (myelination) of circuitry to and from the hippocampus is 
only complete in adolescence, providing a mechanism whereby a lesion affecting this 
area may not be apparent until these pathways are mature. (168) Also proposed have 
been the possibilities of abnormalities of neuronal sprouting (169) or adverse effects 
of stress related neural transmission. (165)

Finally, support for the neurobiological plausibility of the latency period in 
schizophrenia comes from studying human developmental disorders which also 
exhibit this phenomenon. Both temporal lobe epilepsy and metachromatic 
leukodystrophy provide a 'mock-up' of schizophrenia. (166, 167)

Conclusion

In summary, there is substantial amount of evidence in support of a 
neurodevelopmental basis for schizophrenia. A specific aetiology is not implicated 
and multiple genetic and environmental factors may be relevant. These causal 
factors interact, in an unknown way, to produce aberrant fetal development. It is not 
certain whether this early developmental aberration is necessary and/or sufficient to 
'cause' schizophrenia; probably it just leaves the individual susceptible to the 
disorder. If, and when the symptoms of schizophrenia occur is thought to be 
determined by the intervening processes of postnatal cerebral maturation. 

In order to advance the understanding of the aetiology of schizophrenia future 
research needs to concentrate on furthering the understanding of brain development 
and maturation. The genes, proteins and molecular mechanisms involved in normal 
neuronal proliferation, migration and synapse formation need to be determined. 
Hopefully, this knowledge will enable the mechanisms involved in aberrant 
neurodevelopment to be understood. Studies are needed to define the peripubertal 
trigger which causes the development of psychotic symptoms and explain how and 
why the disease remains latent for 20-30 years Another area warranting further study 
is the interactions between the genes and environmental factors associated with the 
development of schizophrenia. 

Few of the positive findings supporting the neurodevelopmental hypothesis are 
undisputed. These inconsistencies probably reflect the fact that schizophrenia is 
actually a group of pathogenically diverse disorders, of which only one has a 
neurodevelopmental origin. Indeed, this possibility seems likely because of the 
clinical diversity of schizophrenia and the many examples elsewhere in medicine 
where complex phenotypes turn out to be aggregates of discrete diseases. To date, 
however, attempts to subdivide schizophrenia have yet to provide any evidence of 
heterogenicity at the neurodevelopmental, or any other, pathogenetic level. 

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