Findings from this study suggest that in familial schizophrenia, mild head injuries occurring during childhood may be associated with the subsequent development of schizophrenia and a younger age at onset of psychosis. Psychosis occurred on average about 5 years earlier in subjects with a childhood head injury. To our knowledge, this is the first report of the possible effects of head injury on age at onset in schizophrenia. Although the head injuries reported herein were of minimal to mild severity consistent with concussions, younger age at onset of psychosis was significantly correlated with greater severity of head injury. The significant effects were found with preonset head injuries occurring at 10 years or younger and were restricted to narrowly defined schizophrenia. We found no apparent effects of sex or family membership on these findings in this sample. These results support the possibility that in individuals from families with an elevated genetic predisposition to schizophrenia, childhood head injury may interact with genetic effects to modify the expression and course of the disorder.
The study findings are consistent with the limited available literature that has suggested a significant association between schizophrenia and childhood head injury.6,7
However, the head injuries reported in those studies were of greater average severity than in the present investigation, family history of schizophrenia was unknown, and the relationship to the age at onset of psychosis was not reported.6,7
Genetic predisposition to schizophrenia was also unknown in a long-term outcome study of head injuries in more than 3000 Finnish men during wartime,19
which reported that schizophrenic psychoses were more strongly associated with mild head injuries without LOC and occurring before 20 years of age. Latency from injury to onset of illness in that study was longer than 10 years,19
similar to that in the present study. The importance of genetic predisposition was emphasized in a recent study of 45 patients ascertained through neuropsychiatric and medicolegal clinics who had a history of moderate to severe head injuries and later development of a schizophrenialike psychosis.8
That study reported that the factor most strongly differentiating these subjects from a sample matched on age, sex, and age at injury was a positive family history of psychotic illness; however, the mean latency from injury to onset of psychotic illness was about 4 years, and only 3 subjects had a childhood head injury (age, ≤10 years).8
In the only other report regarding head injury in familial schizophrenia, age at onset of psychosis and rates of preonset head injury were not reported,20
making it difficult to compare results with those from the present study.
The precise mechanisms by which head injury could play a role in the expression of schizophrenia are unknown, since limited knowledge is available about the pathogenesis of mild traumatic brain injury or schizophrenia. Indications of perturbed neurodevelopment in schizophrenia exist,2,21,22
but the neuropathology of schizophrenia during childhood is entirely unknown. Childhood head injuries may involve microscopic and/or molecular structural brain damage, including tension (tearing apart of tissues), compression, and shearing of brain tissue,23
and may result in serious sequelae, even in the absence of LOC.11,24
Evidence suggests that the primary impact of closed-head injury is of a diffuse, nonspecific nature, which is attributed to diffuse shearing and tearing of axonal fibers.23,25
Furthermore, although a child’s brain may better absorb injuries and may therefore be more resilient to focal damage,9
this quality has the potential to contribute to greater generalized shearing damage.23
Such effects could contribute to the disconnectivity hypothesized in schizophrenia. The effects of head injury in the developing brain can initially be silent and become evident only later when the compromised brain is challenged, eg, by age-appropriate behavioral demands.23,25
This may partially explain why some studies of mild childhood head injury find short-term neurobehavioral sequelae26
and others do not.11
A possible mechanism for associations between disease states and head injury that has long been proposed25
and recently reviewed27
is the cerebral reserve or threshold theory of causation. According to this model, individuals with greater vulnerability (eg, genetic vulnerability) to functional impairment have a lower brain reserve capacity (eg, reduced neuronal redundancy) and thus a lower tolerance for exceeding a neuropathological threshold, with or without acquired conditions such as head injury.27
This mechanism has been proposed for the observed association between head injury and neurodegenerative disorders such as Alzheimer disease and Parkinson disease.3–5
Although the pathogenesis of schizophrenia is hypothesized to be neurodevelopmental, with less evidence of neurodegeneration,22
a similar threshold mechanism may apply.6,20
Results from the present study and others8
support the likelihood that a postnatal event during neurodevelopment, such as childhood head injury, could interact with genetic predisposition in a dynamic pathway leading to expression of schizophrenia.21,22
An alternative explanation for our findings is that head injury may be related to an underlying genetic predisposition to schizophrenia. For example, head injuries may occur more frequently in children who are already exhibiting subtle premorbid features of schizophrenia such as motor developmental delays or other soft neurological signs such as incoordination.21
Damage resulting from the head injury could then accelerate the development of schizophrenia. The present study cannot distinguish between the possibility of such an iterative process and genetic endowment and head injury as separate factors in a pathogenetic pathway.
The main advantages of the present study relate to the familial schizophrenia sample used. The recent finding that narrowly defined schizophrenia is significantly linked to chromosome 1q21-q22 in most of the families studied14
provides evidence of relative genetic homogeneity in this sample. A familial sample, particularly one with enhanced genetic homogeneity, may facilitate the study of nonshared environmental factors in siblings, especially factors that are independent of genetic risk.28
Individual genetic susceptibility to schizophrenia cannot be assessed, however, until disease alleles have been identified and the specific penetrance of these alleles has been elucidated.
There are several limitations to the current study. As with all retrospective studies, the reliability of the information gathered on head injury is uncertain. We attempted to minimize recall and information bias by performing the initial data gathering masked to the specific hypotheses of the study, reviewing all available medical records, and using masked consensus ratings of head injury categorization. However, head injuries in most cases occurred decades before the interview, and mild childhood head injuries may be underreported,13
especially those occurring in infancy or those with no immediate sequelae. If one assumes that such errors occurred with equal frequency in the schizophrenia and unaffected groups, these errors would have led to an underestimation of the association between childhood head injury and schizophrenia. Alternatively, if subjects ascribed a causal connection between childhood head injury and schizophrenia, head injuries may be more likely to be reported by affected subjects than unaffected siblings. Such a reporting bias would overestimate the association. However, one would expect this overestimation to involve injuries more proximate to the onset of illness. This is not supported by results from the present study, which became nonsignificant when preonset head injuries through adolescence were included. Another limitation was that the scale used to evaluate head injuries was developed for adults and primarily used LOC as a measure of severity, which may not be appropriate for assessment of childhood head injuries.9,11
However, the scale included ratings for minimal head injuries with no LOC and head injuries that would be considered concussions. Two further limitations relate to the sample. Although post hoc analyses indicated that results remained significant for head injuries occurring at 15 years or younger, because of the small sample sizes involved, this study had insufficient power to determine conclusively an upper age limit of childhood head injuries for the observed associations. Also, ascertainment of a form of schizophrenia likely to be genetic meant that subjects with schizophrenia believed to result from a serious head injury would not have been included. Thus, head injuries in this sample were limited to a mild range, and results may not be applicable to more severe head injuries. Findings from the study by Sachdev et al,8
for example, suggest that more severe head injuries occurring at any time from childhood through early adulthood may be associated with development of a psychotic illness after a relatively short latency period, although genetic predisposition still appeared to be an important factor in this process.