David Cohen, M.D.·Published 7 May 2009·11 min read
Key points
Over the last decade the concept of schizophrenia as a neurodevelopmental disorder has taken a strong hold, although 'neurodevelopmental' is often used with a wide range of meanings.
As a result, the brain in schizophrenia is characterized by increased neuronal density, decreased intraneuronal space and reduced overall brain volume.
2000a) which supports neuropathological findings of increased neuronal density and reduced intraneuronal neurophil rather than neuronal loss (Selemon et al.
Two different types of progressive brain change have been described in schizophrenia.
Neurodevelopmental models of schizophrenia
Over the last decade the concept of schizophrenia as a neurodevelopmental disorder has taken a strong hold, although 'neurodevelopmental' is often used with a wide range of meanings. It is possible to distinguish 'early' and 'late' neurodevelopmental models, with a third 'risk' model incorporating ideas from developmental psychopathology (Hollis & Taylor 1997).
The 'early' neurodevelopmental model emerged from the ideas of Fish (1957) who proposed that the neuropathology in schizophrenia was of perinatal origin. The 'early' neurodevelopmental model views the primary cause of schizophrenia as a static 'lesion' occurring during fetal brain development (Murray & Lewis 1987; Weinberger 1987). The putative 'lesion' could be of either neurogenetic or environmental origin (e.g. virus infection or fetal hypoxia). Two main lines of evidence support the 'early' neurodevelopmental model. First, there is an absence of gliosis in the postmortem brains of schizophrenic patients, which suggests a neurodevelopmental rather than a neurodegenerative pathology. Secondly, a more indirect line of evidence includes the association of schizophrenia with premorbid social and cognitive impairments (Foerster et al. 1991; Done et al. 1994; Jones et al. 1994), pregnancy and birth complications (Lewis & Murray 1987; McNeil 1995) and minor physical anomalies (Gualtieri et al. 1982; Guy et al. 1983). According to this 'early' model, during childhood the 'lesion' is relatively silent giving rise only to subtle behavioural symptoms (premorbid social and cognitive impairments). However, in adolescence, or early adult life, the 'lesion' interacts with the process of normal brain maturation (e.g. myelination of corticolimbic circuits and/or synaptic pruning and remodelling) to manifest itself in the form of psychotic symptoms.
There are several weaknesses in the 'early' neurodevelopmental model. First, it fails to provide a satisfactory account of the long latency between the putative perinatal damage/lesion and the typical onset of symptoms in late adolescence or early adult life. Secondly, an early neurodevelopmental insult on its own cannot account for the finding of increased extracerebral (sulcal) cerebrospinal fluid (CSF) space in schizophrenia. Diffuse loss of brain tissue limited to the pre- or perinatal periods would result in enlargement of the lateral ventricles but not increased extracerebral CSF space (Woods 1998).
The 'late' neurodevelopmental model, first proposed by Feinberg (1983, 1997), argues that the key neuropathological events in schizophrenia occur as a result of abnormal brain development during adolescence. The current formulation of the 'late' neurodevelopmental model proposes that excessive synaptic and/or dentritic elimination occurs during adolescence producing aberrant neural connectivity and psychotic symptoms (Woods 1998; McGlashen & Hoffman 2000). This 'late' model characterizes schizophrenia as a progressive late onset neurodevelopmental disorder in contrast to the 'early' model that proposes a static lesion during the perinatal period. The 'late' model predicts that progressive structural brain changes and cognitive decline will be seen in adolescence around the onset of psychosis.
Written and revised by
David Cohen, M.D.
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The excessive synaptic pruning during adolescence proposed in the 'late' model is simply an amplification of the normal process of neuronal remodelling with progressive pruning and elimination of synapses that begins in early childhood and extends through late adolescence (Huttenlocher 1979; Purves & Lichtmen 1980). These major regressive changes in adolescence with remodelling of neural connections are likely to be under genetic control with synaptic elimination in schizophrenia representing an extreme of normal variation (Feinberg 1983). In the 'late' model, premorbid abnormalities in early childhood are viewed as non-specific risk factors rather than early manifestations of an underlying schizophrenic neuropathology.
Both the 'early' and 'late' models suppose that there is a direct and specific expression of the eventual brain pathology as schizophrenic disorder. A third viewpoint, the 'risk' model, proposes that early and/or late brain pathology acts as a risk factor rather than a sufficient cause so that its effects can only be understood in the light of an individual's exposure to other risk and protective factors (Hollis & Taylor 1997). This latter formulation provides a probabilistic model of the onset of schizophrenia in which aberrant brain development is expressed as neurocognitive impairments that interact with the environment to produce psychotic symptoms. The following sections examine how well current neurobiological research evidence supports these competing neurodevelopmental models of schizophrenia.
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Neuropathology
In the postmortem brains of schizophrenic patients there is an absence of gliosis which is the necessary hallmark of neurodegeneration (Roberts et al. 1986). The prominent neuropathology in schizophrenia is not the classic form involving neuronal cell death, but instead a loss or reduction in dendritic spines and synapses which are the elements of neural connectivity (Garey et al. 1998; Glantz & Lewis 2000). As a result, the brain in schizophrenia is characterized by increased neuronal density, decreased intraneuronal space and reduced overall brain volume.
Furthermore, the decrease in dentritic spine density appears to be both region and disease specific. A reduction in dendritic spine density has been reported on pyramidal cells in layer III of the temporal cortex (Garey et al. 1998) and the dorsolateral prefrontal cortex (Glantz & Lewis 2000) but not on pyramidal cells in the visual cortex of schizophrenic patients (Glantz & Lewis 2000). These findings are compatible with the hypothesis of reduced cortical and/or thalamic excitatory glutaminergic inputs to the dorsolateral prefrontal cortex in schizophrenia.
Structural brain abnormalities
Neuroimaging and postmortem studies have shown that the brain as a whole and the frontal and temporal cortices in particular are smaller than in normal subjects (Andreasen et al. 1990; Nopoulos et al. 1995). Brain volume reductions in schizophrenia are specific to grey matter (Gur et al. 2000a) which supports neuropathological findings of increased neuronal density and reduced intraneuronal neurophil rather than neuronal loss (Selemon et al. 1995).
Across a range of neuroimaging studies, the volume of the hippocampus and amygdala is reduced bilaterally by 4.5 - 10% (Nelson et al. 1998; Gur et al. 2000a). Prefrontal grey matter volume is reduced by about 10% (Gur et al. 2000b). Enlargement of the third and lateral ventricles is a consistent finding, with ventricular volume increased by about 40% bilaterally (Lawrie & Abukmeil 1998). Ventricular enlargement is associated with neuropsychological impairment and negative symptoms (Vita et al. 1991). Studies of the basal ganglia have produced more inconsistent results, possibly as a function of the increase in basal ganglia volume associated with the use of traditional antipsychotics. Interestingly, when patients are switched to the atypical antipsychotic clozapine there is a reduction of basal ganglia volume (Chakos et al. 1995).
The brain changes reported in child and adolescent onset schizophrenia appear to be very similar to those described in adult onset schizophrenia, supporting the idea of an underlying neurobiological continuity. In the NIMH study of childhood onset schizophrenia (onset less than 12 years of age), subjects had smaller brains than normal subjects, with larger lateral ventricles and reduced prefrontal lobe volume (Jacobsen & Rapoport 1998). Similar to findings from adult studies, reduced total cerebral volume is associated with negative symptoms (Alaghband-Rad et al. 1997). The midsagittal thalamic area is decreased while the midsagittal area of the corpus callosum is increased (Giedd et al. 1996), suggesting that the reduction in total cerebral volume in childhood onset schizophrenia is brought about by a relative reduction in grey matter with sparing of white matter. Childhood onset patients have a higher rate of developmental brain abnormalities than controls, including an increased frequency of an enlarged cavum septum pelucidum (Nopoulos et al. 1998). Abnormalities of the cerebellum have also been found including reduced volume of the vermis, midsagittal area and inferior posterior lobe (Jacobsen et al. 1997a).
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Progressive brain changes
Two different types of progressive brain change have been described in schizophrenia. First, treatment with traditional antipsychotics appears to cause progressive enlargement of the basal ganglia, with these structures returning to their original size when patients are transferred to the atypical antipsychotic clozapine (Frazier et al. 1996). Secondly, there is evidence of progressive volume reductions in the temporal and frontal lobes during the first 2 - 3 years after the onset of schizophrenia (Gur et al. 1998). In the NIMH study of childhood onset schizophrenia, longitudinal repeated MRI scans through adolescence have revealed a progressive increase in ventricular volume and progressive decrease in cortical volume with frontal (11% decrease) and temporal lobes (7% decrease) disproportionately affected (Rapoport et al. 1997, 1999). Both patients and controls showed progressive reductions in frontal and parietal lobe volumes, with schizophrenic subjects showing a relatively greater loss of temporal lobe volume than controls (Jacobsen et al. 1998). The reduction seen in temporal lobe structures may occur rather later in the illness course than the reduction in frontal lobe and midsagittal thalamic structures. Progressive changes appear to be time limited to adolescence with the rate of volume reduction in frontal and temporal structures declining as subjects reach adult life.
Because progressive brain changes have been described after the onset of psychosis, it is possible that they are a consequence of neurotoxic effects of psychosis or, possibly, antipsychotic medication. Evidence that progressive brain changes precede the onset of psychosis is very limited. Pantelis et al. (2000) have provided a preliminary report of brain MRI findings in high-risk subjects scanned before and after the transition into psychosis.
For those subjects who developed psychosis there were longitudinal volume reductions in the medial temporal region (hippocampus, entorhinal cortex, inferior frontal and fusiform gyrus). There were no significant longitudinal changes in cases that remained non-psychotic. These are potentially important findings which, if replicated, would provide strong support for the idea that excessive developmental reductions in temporal lobe volume have a key role in the onset of psychosis.
Functional brain imaging
The emergence of functional brain imaging technology has provided a unique opportunity to link symptoms and cognitive deficits in schizophrenia to underlying brain activity. Liddle et al. (1992) studied the relationship between symptom dimensions (negative, positive and disorganization) in adult schizophrenic subjects and regional cerebral blood flow (rCBF) using PET. Negative symptoms (e.g. affective blunting, avolition and alogia) were associated with reduced rCBF in the dorsolateral prefrontal cortex (DLPFC). Disorganization (e.g. formal thought disorder and bizarre behaviour) was associated with reduced rCBF in the right ventrolateral prefrontal cortex and increased rCBF in the anterior cingulate. Positive symptoms (e.g. hallucinations and delusions) were associated with increased rCBF in the left medial temporal lobe, and reduced rCBF in the posterior cingulate and left lateral temporal lobe. The most consistent association in the literature, across a variety of imaging methods, has been between negative symptoms and reduced frontal activity.
However, a simple description of 'hypofrontality' in schizophrenia does not capture the complex pattern of changes involving interconnected frontal areas and changes across time. In a PET study in childhood onset schizophrenia using the Continuous Performance Test (CPT), Jacobsen et al. (1997b) reported reduced activation compared with healthy controls in the mid and superior frontal gyrus, and increased activation in the inferior frontal, supramarginal gyrus and insula. The finding of hypofrontality in schizophrenia is a dynamic state-related phenomenon with evidence of remission of hypofrontality in asymptomatic patients (Spence et al. 1998). Localizationist models based on focal cerebral dysfunction in schizophrenia have tended to give way to more dynamic models of cerebral 'disconnectivity' based on dysfunctional neural networks or systems. Models of cerebral connectivity view normal higher brain function as depending on the integrated activity of widely distributed neurocognitive networks, rather than the activity of discrete brain areas in isolation (Bullmore et al. 1997). In normal individuals, the functional anatomy of a verbal fluency task (generation of words beginning with a given letter) can be examined using PET and has consistently shown activation of the left DLPFC and reciprocal deactivation of the superior temporal gyrus (STG). A number of investigators have reported a failure of normal STG deactivation (disconnectivity) in schizophrenic patients during a verbal fluency task (Friston et al. 1995; Dolan et al. 1996). However, left DLPFC - STG disconnectivity appears to be a state-related marker of psychosis as it is not found in asymptomatic schizophrenic patients (Dye et al. 1999; Spence et al. 2000) and may possibly be associated with active auditory hallucinations (Spence et al. 2000). In contrast, schizophrenic patients in remission do show reduced connectivity between the left DLPFC and anterior cingulate cortex relative to normal controls (Spence et al. 2000).
In summary, models of cerebral disconnectivity fit well with both neuropathological and functional neuroimaging data.
What is becoming clear is that functional disconnectivity may both identify state-related changes associated with current symptomatology as well as more stable trait-related markers of neurocognitive vulnerability to psychosis.
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Magnetic resonance spectroscopy: abnormal neuronal metabolism
Magnetic resonance spectroscopy (MRS) is an imaging technique that can be used to extract in vivo information on dynamic biochemical processes at a neuronal level. Proton (1H) MRS focuses on changes in the neuronal marker N-acetylaspartate (NAA). Studies in adult schizophrenic patients have shown reductions in NAA in the hippocampal area and DLPFC. Similar reductions in NAA ratios specific to the hippocampus and DLPFC (Bertolino et al. 1998) and frontal grey matter (Thomas et al. 1998) have been reported in childhood onset schizophrenia, suggesting neuronal damage or malfunction in these regions.
Pettegrew et al. (1991) used phosphorus-31 (31P) MRS in first-episode non-medicated schizophrenics and found reduced phosphomonoester (PME) resonance and increased phosphodiester (PDE) resonance in the prefrontal cortex. This result is compatible with reduced synthesis and increased breakdown of connective processes in the prefrontal cortex. A similar finding of reduced PME and increased PDE resonance has been reported in autistic adults, although they showed increased prefrontal metabolic activity, which was not seen in schizophrenic subjects (Pettegrew et al. 1991). It is possible that excessive synaptic elimination is not specific to schizophrenia, but its timing, location and extent may have crucial implications for the development of executive functions, and the risk of psychosis, in late childhood and adolescence.
Implications for neurodevelopmental models of schizophrenia
Taken together, the neuropathological and brain imaging findings provide considerable support for the idea of progressive neurodevelopmental changes in schizophrenia including excessive synaptic elimination resulting in aberrant neural connectivity. The 'early' neurodevelopmental model involving a static pre- or perinatal brain insult fails to account for the progressive nature of brain volume reductions in adolescence, and the fact that reduced brain volume is not accompanied by reduced intracranial volume. While early random events in fetal neurodevelopment (e.g. hypoxia, viruses) may affect baseline synaptic density, genetically determined excessive synaptic elimination as proposed by the 'late' neurodevelopmental model may be the neurobiological process underlying disorders in the schizophrenia spectrum (McGlashen & Hoffman 2000). What is unclear is whether excessive synaptic elimination in the prefrontal cortex (and possibly other brain regions) is a sufficient cause for psychosis to occur or whether it simply provides a vulnerable neurocognitive substrate that must interact with environmental stressors (e.g. cognitive or social demands) to produce psychotic symptoms.
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