The neurodevelopmental hypothesis of schizophrenia has become a paradigm broadly accepted in today’s research in schizophrenia and its spectrum.
This article traces the historical development of the neurodevelopmental hypoth- esis of schizophrenia up until the time of its explicit formulation in 1987, by Weinberger and by Murray and Lewis, with a main focus on the seminal contribution of Barbara Fish to its conception and elaboration.
The neurodevelopmental model of schizophrenia in the 1980s
As new tools for investigative medical research were developed and refined, findings from studies utilizing postmortem brains, neuroimaging, and other emerging technologies added fresh support to the observational data on disrupted neurodevelopment in schizophrenia. This included evidence of structural brain anomalies such as enlarged ventricles with decreased cerebral vol- ume, morphological deviations that appeared to be non- progressive, and an absence of cell gliosis or of other evidence of a degenerative brain disease.
Meanwhile, in 1982, Feinberg, building initially on evidence collected in his research on sleep, proposed a novel neurobiological model of disrupted neurodevelopment in schizophrenia that he had been refining over time.
This model, highly in uential in its own right, postulated that schizophrenia was caused by errors in synaptic pruning in adolescence, although it was yet to be determined whether these abnormalities related to the elimination of too many, too few or the wrong synapses. Feinberg’s observations added vital corroboration for schizophrenia as a neurodevelop- mental disorder, albeit now positing a critical period of vulnerability in adolescence.
This burgeoning body of support for neurodevelop- mental aberrations in schizophrenia led to models pro- viding a robust etiological framework for understanding the disease. Already in 1981, Strauss and Carpenter had outlined an interactive developmental concept of schizophrenia implicating genetic and gestational vulner- abilities, and the interplay between them. Meanwhile, a potential role for immune mechanisms interfering with fetal brain development was suggested by findings of associations with maternal exposure to in uenza53 and other viral infections,54 albeit not consistently replicated.
By the late 1980s, this convergence of evidence was more formally articulated in independent publications by Weinberger and Murray and Lewis as a comprehensive neurodevelopmental hypothesis of schizophrenia. The model of neurodevelopment that they proposed was able to take account of the peculiarities of schizophrenia, including peak onset in late adolescence/ early adulthood with a long delay between putative risk exposure and illness onset. In essence, these formula- tions of the neurodevelopmental model described a disruption of normal development of the central nervous system in utero or early infancy which manifested itself in adulthood as schizophrenia, but which also gave rise to de cits in psychophysiological and neurological functioning in childhood and early adolescence—as earlier observed by Fish.
Both sets of authors argued speci cally for a subtle disease process or “brain lesion” that affected critical circuits in the brain in early development, with full-blown consequences evident many years later in ado- lescence or early adulthood as schizophrenia, when the affected brain areas reached physiological maturity. For Weinberger, the original theory was open as to the etiology of the “lesion,” whether it was genetically or envi- ronmentally determined, or both, with explicit reference to the potential impact of obstetric complications. The early articles by Murray and Lewis3,4 were concerned primarily with obstetric complications as key environmental causes of the neurodevelopmental deviations observed, outlining the evidence and potential underlying mechanisms for their effects.
Research into the role played by obstetric complications expanded in the years that followed, as access to and linkage across whole-population registers of midwives and psychiatric cases facilitated the growth of a new wave of risk factor epidemiological studies of schizophrenia, overcoming the limitations of clinical follow-up hampered by the long interval between risk exposure and disease outcome. Further re nements of the model gave scope for the integration of the early neurodevelopmental disruption observed by Fish and the later disruption described by Feinberg into 2- or even multi-hit versions of the model that accounted for the impact of varying permutations of genetic, obstetric, and other environmental insults along the developmental tra- jectory to schizophrenia.
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