The aetiology of schizophrenia: The neurobiology of schizophrenia.
- Functional neurobiology of schizophrenia
- Cerebral activity
- Structural neurobiology of schizophrenia
- Macroscopic brain changes
- Interpretation of the neuropathology
- Further reading
The neurobiology of schizophrenia may be divided into functional and structural aspects. Significant progress has been made in both areas as a result of the development of imaging modalities and the emergence of molecular techniques to study the underlying cellular processes.
Functional neurobiology of schizophrenia
Functional neurobiology encompasses neurochemistry, which can be measured in postmortem brains or in vivo, as well as neurophysiological and neuropsychological approaches.
A wide range of neurochemical systems and parameters have been investigated in schizophrenia, and a diverse collection of abnormalities reported. (1)
Discussion is limited here to three areas of current interest.
The dopamine hypothesis of schizophrenia has been neurochemically pre-eminent since the 1960s. It proposes that the symptoms of schizophrenia result from dopaminergic overactivity, whether due to excess dopamine, or to an elevated sensitivity to it, for example because of increased numbers of dopamine receptors. The hypothesis originated with the discovery that effective antipsychotics were dopamine (D2) receptor antagonists, and that dopamine-releasing agents such as amphetamine produce a paranoid psychosis. It received support from various findings of increased dopamine content and higher densities of D2 receptors in schizophrenia. (2) However, despite its longevity there is still no consensus as to precisely what the dopamine hypothesis explains, nor the nature of the supposed abnormality. There are two main difficulties. First, antipsychotics have marked effects on the dopamine system, seriously confounding most studies. Second, molecular biology has revealed an unexpected complexity of the dopamine receptor family, increasing the potential sites of dysfunction and mechanisms by which it might occur.
Striatal D2 receptor densities are increased in schizophrenia, but it is unclear what proportion, if any, is not attributable to antipsychotic medication. (3) Statistical methods have been used to argue that there is a genuine schizophrenia-associated elevation, but this must be balanced against negative positron emission tomography (PET) studies of D2 receptors in drug-naive first-episode cases. For D1 and D3 receptors there are reports of their altered expression in schizophrenia, but these are either unconfirmed or contradicted by other studies. Controversy has surrounded the D4 receptor following a report that it was upregulated several-fold in schizophrenia, seemingly independent of medication. However, the result appears to have been due to a ‘D4-like site' not the true D4 receptor, and the status of the latter in schizophrenia is unknown. (4) Overall, the position of dopamine receptors in schizophrenia is still contentious and the case for their involvement unproven. In contrast, there is emerging evidence for a presynaptic abnormality, with three studies of drug-free subjects showing elevated dopamine release in response to amphetamine. (5) This implies a dysregulation and hyper-responsiveness of dopaminergic neurones in schizophrenia, a potentially important finding needing further investigation.
Suggestions of 5-hydroxytryptamine (5-HT, serotonin) involvement in schizophrenia arose because the hallucinogen lysergic acid diethylamide (LSD) is a 5-HT agonist. Recently, interest has focused on the 5-HT 2A receptor. (4) A high affinity for the receptor may explain the therapeutic advantages of atypical antipsychotics, and variants in the gene are a minor risk factor for non-response to clozapine and for schizophrenia. Many studies have found a lowered 5-HT 2A receptor expression in the frontal cortex in schizophrenia, and there is a blunted neuroendocrine response to 5-HT 2 agonists. Elevated cortical 5-HT 1A receptors are also a replicated finding. The 5-HT 1A and 5-HT 2A receptor abnormalities are both seen in subjects not on medication at death, but neither has been investigated in drug-naive or first-episode patients.
Hypotheses for the involvement of 5-HT in schizophrenia include the trophic role of the 5-HT system in neurodevelopment, interactions between 5-HT and dopaminergic neurones, and impaired 5-HT 2A receptor-mediated activation of the prefrontal cortex. (6)
Phencyclidine and other non-competitive antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor produce a psychosis closely resembling schizophrenia. This has driven the hypothesis of glutamatergic dysfunction in schizophrenia. (7) In support, there is now considerable evidence for glutamatergic abnormalities in schizophrenia. In the medial temporal lobe, for example, glutamatergic markers are decreased and there is reduced expression of non-NMDA glutamate receptors. However, a different pattern is seen in other brain regions and affecting other glutamate receptor subtypes, precluding any simple conclusion regarding the nature of the abnormality in schizophrenia. Mechanisms proposed to explain glutamatergic involvement in schizophrenia centre on its interactions with dopamine, and subtle forms of glutamate-mediated neurotoxicity.
Interpretation of the neurochemical data
In addition to the three neurotransmitters mentioned above, schizophrenia is associated with alterations in many other systems, including g-aminobutyric acid (GABA), neuropeptides, adrenoreceptors, and second messengers. (1) However, there is still no clear picture as to the cardinal neurochemical deficits. One important point, relating to the neuropathology to be discussed below, is that the presence of structural abnormalities, however slight, must be taken into account. That is, a change in the level of a neurotransmitter, receptor, or any other molecule, may be due to dysfunction of the neurones producing it, or a change in the cellular constituents of the tissue, rather than being indicative of a specific abnormality. This applies to in vivo functional imaging as well to postmortem neurochemistry. While an obvious point to make, it has not always been appreciated in schizophrenia research, perhaps because of the belief that the brain is structurally normal.
Cerebral activity in schizophrenia has been extensively investigated using PET to measure regional cerebral blood flow and glucose utilization. Single-photon emission CT and functional magnetic resonance imaging ( MRI) have also been applied.
Hypofrontality—decreased activity in the frontal lobes—has been widely studied in schizophrenia since the first report in 1974. The current view is that, whilst hypofrontality does occur in unmedicated subjects, (8) it is not an invariable finding, (9) and its interpretation is still debated. (10) It is seen most clearly when subjects are performing tasks, such as the Wisconsin Card Sorting Test, which require activation of the frontal lobes.
The most comprehensive analysis correlating regional cerebral activity with the clinical features of schizophrenia is that by Liddle and colleagues, showing that the three subsyndromes of chronic schizophrenia identified by factor analysis have their own characteristic patterns of blood flow. (11) For example, subjects with psychomotor poverty are hypofrontal whereas those with prominent positive symptoms have increased activity in the temporal lobe, especially in the hippocampus. Other studies show that the latter region does not activate normally during cognitive tasks.
One conclusion drawn from these studies is that there is no one site of dysfunction in schizophrenia. Rather, its pathophysiology reflects abnormalities in various distributed circuits integrating specific cortical areas and subcortical nuclei. (8,12) The model of schizophrenia as a disorder of disturbed neural connectivity is considered further below.
There are two aspects of sensorimotor functioning in schizophrenia relevant to the study of its neurobiology. First, evoked potentials (electrical activity in the brain measured after a brief sensory stimulus) are altered. In particular, the P300 component is reduced and delayed in response to auditory and visual stimuli, indicative of impaired sensory processing and further implicating the temporal lobes in the pathophysiology of the disorder. (13) Second, there is a high rate of eye movement abnormalities in schizophrenia,(14) especially affecting smooth pursuit tracking, suggestive of impairment in the neural pathways subserving oculomotor control.
Neuropsychological data provide a further line of support for the involvement of certain brain areas and their connections in the neurobiology of schizophrenia.
Intellectual impairment is a feature of schizophrenia. (15) It is present in first-episode, untreated patients, and worsens in the first few years of illness, warranting the label dementia in severe, chronic cases (see below). (16) Against a background of global decrement (17) there is evidence for greater deficits in semantic memory, executive functioning, and attentional domains. (18) Anatomically, this neuropsychological pattern is in keeping with the preferential involvement of temporal lobe and frontostriatal circuits in schizophrenia identified by functional imaging.
Structural neurobiology of schizophrenia
Alzheimer, a colleague of Kraeplin, began the search for the neuropathology of schizophrenia. However, only recently has progress been made. The major advances have come from structural imaging (CT and MRI) scans, and the findings have, in turn, encouraged a renaissance of histopathological studies.
Macroscopic brain changes
Contemporary research into the structural basis of schizophrenia can be traced to a seminal report describing dilatation of the lateral ventricles and cerebral atrophy, as seen on CT scans, in chronic schizophrenia. (19) This finding, which was consistent with earlier pneumoencephalographic data, has been followed by many other CT and MRI studies with ever-improving resolution and sophistication of analysis. The key results are described below.
There is enlargement of the cerebral ventricles. Comprehensive reviews of the lateral ventricle-to-brain ratio indicate an increase of 20 to 75 per cent, with an effect size of 0.70, corresponding to a 43 per cent non-overlap between cases and controls. (20,21) Volumetric MRI shows a median 40 per cent increase in ventricular size. (22) The ventricular enlargement is accompanied by a loss of cortical volume averaging 3 per cent. (22,23) Greater reductions occur in temporal lobe (4–12 per cent), especially medial temporal structures (hippocampus, parahippocampal gyrus, and amygdala). (24) Several, though not all, postmortem studies of schizophrenia have confirmed these features, which have recently been shown in childhood-onset cases as well.
Monozygotic twins discordant for schizophrenia have provided valuable information. In virtually all pairs, the affected twin has the larger ventricles and smaller cortical and hippocampal size.(25) The discordant-monozygotic twin study design allows two conclusions to be drawn. First, that structural abnormalities are a consistent finding in schizophrenia, their identification being aided by controlling for random genetic and environmental influences on neuroanatomy. Second, that the alterations are associated with expression of the schizophrenia phenotype rather than merely with the underlying shared genotype. Family studies support this interpretation, in that schizophrenics have bigger ventricles and smaller brains than their unaffected relatives. However, relatives who are obligate carriers (that is to say those unaffected by schizophrenia but who seem to be transmitting the gene(s)) have larger ventricles than other relatives; moreover both groups of relatives have larger ventricles and smaller brain structures than control subjects from families without schizophrenia. (26) These data indicate that a proportion of the structural pathology of schizophrenia may be a marker of genetic liability to the disorder. (A similar conclusion applies to the neuropsychological and neurophysiological indices mentioned above.)
Imaging studies have not established clearly whether there are volume differences in subcortical structures in schizophrenia; one firm conclusion is that the striatal enlargement sometimes reported is, unlike all other volume changes, due to antipsychotic medication. Finally, good evidence for a reduced size of the thalamus has emerged from postmortem studies.
Progression, heterogeneity, and clinicopathological correlations
Ventricle-to-brain ratio in schizophrenia follows a unimodal distribution, indicating that ventricular enlargement is not restricted to a subgroup but is present to a degree in all cases.(20) Conversely, it is important to emphasize that, despite group differences, there is a significant overlap between subjects with schizophrenia and controls for every structural parameter. For this reason, and the fact that the changes are of uncertain diagnostic specificity, schizophrenia remains a clinical rather than a neurobiological diagnosis.
The structural abnormalities are present in first-episode cases, excluding the possibility that they are merely a consequence of chronic illness or its treatment. Furthermore, their magnitude does not correlate with duration of the disease, suggesting that the alterations are largely static after onset. However, some longitudinal studies, spanning 4 to 8 years, find continuing divergence from controls. The issue, which remains controversial, is important as it bears upon the timing, progressive nature, and possible heterogeneity of schizophrenia (see below).
Some studies indicate that male schizophrenics show greater structural changes than do females, but other studies do not. Similarly, there are few established correlations between brain structure and the symptoms or course of schizophrenia. For example, the expectation that enlarged ventricles might be a correlate of poor outcome has not been consistently demonstrated.
Contemporary histological studies have addressed two main areas. First, to clarify the frequency and nature of neurodegenerative abnormalities in schizophrenia. Second, to investigate the cellular organization (cytoarchitecture) of the cerebral cortex and other components of the limbic system (hippocampus, prefrontal cortex, and thalamus).
Neurodegeneration and schizophrenia
The issue of gliosis (reactive astrocytosis) has been extensively investigated since an influential report (27) that gliosis was common in schizophrenia, especially in the diencephalon around the third ventricle. As gliosis is a sign of past inflammation , this finding supported aetiopathogenic scenarios for schizophrenia involving infective, ischaemic, autoimmune, or neurodegenerative processes. However, many subsequent investigations have not found gliosis, and Bruton and colleagues (28) found that it was only present in cases exhibiting coincidental neuropathological abnormalities, indicating that gliosis is not an intrinsic feature of schizophrenia but merely of superimposed pathological changes which occur by chance in some cases.
The gliosis issue is esoteric but has considerable implications. The gliotic response is said not to begin until the end of the second trimester in utero, and hence an absence of gliosis is taken as prima facie evidence of a disease process occurring before this time. Unfortunately, both the absence of gliosis, and its interpretation, are less clear than often assumed. First, detecting gliosis is surprisingly difficult, and it can be argued that the data do not wholly rule out its occurrence in (a subtype of) schizophrenia. Second, despite the widely cited time point at which the glial response is said to begin, the matter has not been well investigated; therefore it is prudent not to use this to time the pathology of schizophrenia with spurious accuracy. Furthermore, it is a moot point whether the subtle kinds of morphometric disturbance described in schizophrenia, whenever and however they occurred, would be sufficient to trigger detectable gliosis.
Schizophrenia and Alzheimer's disease
The belief that Alzheimer's disease is commoner in schizophrenia (independent of any cognitive impairment) originated in the 1930s. It received some recent support from three uncontrolled, retrospective studies, and tangentially from data suggesting that antipsychotic drugs promote neurofibrillary tangles. However, a meta-analysis shows that Alzheimer's disease is not more common, and may even be rarer, in schizophrenia. (29) This applies even in elderly schizophrenic patients with prospectively assessed severe dementia, who show no evidence of any other neurodegenerative disorder. (30) Nor is there good evidence that antipsychotic drugs cause Alzheimer-type changes. How, therefore, is the cognitive impairment of schizophrenia explained? One possibility is that it is a more severe manifestation of whatever substrate underlies schizophrenia. Or, it may be that the brain in schizophrenia is more vulnerable to cognitive impairment in response to a normal age-related amount of neurodegeneration.
The cytoarchitecture of schizophrenia
If neurodegenerative abnormalities are uncommon in, and probably epiphenomenal to, schizophrenia, it begs the question as to what is the pathology of the disorder and how the macroscopic findings are explained at the microscopic level. The answer has been sought in the cytoarchitecture of the cerebral cortex, with measurements of parameters such as the size, location, distribution, and packing density of neurones and their synaptic connections (31).
Studies of neurones
Various cytoarchitectural alterations have been described in schizophrenia, of which three have generated particular interest: abnormal neuronal organization (dysplasia) in the entorhinal cortex, disarray of hippocampal neurones, and an altered distribution of neurones in the subcortical white matter. These findings are important because they support the hypothesis of an early neurodevelopmental anomaly underlying schizophrenia. However, none have been unequivocally and independently replicated, and for each there is at least one non-replication. (31)
A less well known yet seemingly more robust cytoarchitectural feature of schizophrenia is that many neurones are smaller than expected. This has been shown in three studies of pyramidal neurones in the hippocampus, and has also been reported in dorsolateral prefrontal cortex and cerebellar Purkinje cells. Some studies find that the neurones are also more closely packed. Outside the cerebral cortex, good cytoarchitectural data are limited to the thalamus, with a replicated finding that the dorsomedial nucleus, which is part of a circuit involving the prefrontal cortex, contains significantly fewer neurones than in normal subjects.
In summary, a range of differences in neuronal structure and organization have been reported to occur in schizophrenia. The abnormalities most often taken to be characteristic of the disorder—disarray, displacement, and paucity of hippocampal and cortical neurones—are features which in fact have not been well demonstrated. This undermines attempts to date the pathology of schizophrenia to the second trimester in utero based on their presence (see below). In contrast, decreased neuronal size and loss of thalamic neurones have been shown fairly convincingly. Some of the discrepancies in the literature may reflect regional heterogeneity in the cytoarchitectural pathology of schizophrenia; notably, the cingulate gyrus may have a different pattern of changes. (32)
Studies of synapses and dendrites
Synapses and dendrites represent a potential site for pathology undetectable using standard approaches. Because they are hard to visualize directly, proteins localized to these parts of the neurone are used as markers.
A consistent finding is that markers of presynaptic terminals are reduced in the hippocampus in schizophrenia. The magnitude of the loss varies according to the individual synaptic proteins studied, implying that the synaptic pathology is not uniform. There is some evidence for preferential decrements in excitatory connections, in keeping with the indications of glutamatergic involvement mentioned above. Presynaptic markers are also reduced in the dorsolateral prefrontal cortex. Complementing these changes, alterations in dendrites (the postsynaptic elements upon which most synapses project) have been shown in the hippocampus and neocortex. Although unproven, the simplest interpretation is that these changes reflect a reduction in the density of synaptic contacts being formed and received. (31)
Integrating the neuronal and synaptic findings
There is an encouraging convergence between neuronal and synaptic findings in schizophrenia. In particular, the decreases in presynaptic and dendritic markers are in keeping with the smaller neuronal cell bodies, since the size of the latter is proportional to the dendritic and axonal spread of the neurone. It is also consistent with the findings of increased neuronal density, in that dendrites and synapses are the major component of the neuropil and, if this is reduced, neurones will pack more closely together. Moreover, it also corresponds to the results of proton magnetic resonance spectroscopy studies of schizophrenia, which have shown reductions of the neuronal marker N-acetyl-aspartate, as one would predict if the neurones are on average smaller and have less extensive projections.
Postmortem studies are limited to chronic schizophrenia, so it is impossible to prove that the cytoarchitectural abnormalities are not the result of the illness or its treatment. However, several lines of evidence suggest that this is not the case. First, as the structural brain abnormalities and lower N-acetyl-aspartate signals occur in unmedicated and first-episode schizophrenia, it is reasonable to assume that the cytoarchitectural differences which putatively underlie them are also present at this time. Second, no correlations with the duration of disease or medication exposure have been seen in any of the postmortem studies. Third, although antipsychotic treatment does have morphological consequences, the effect is largely restricted to the basal ganglia. (33)
Interpretation of the neuropathology
Neuropathology and neurodevelopment
The neurodevelopmental model of schizophrenia (see: Genetic and environmental risk factors for schizophrenia) has become the prevailing pathogenic hypothesis; indeed the principle is now largely unchallenged. The neurobiological data form an important component of the evidence in its favour.
A specific version of the theory is that the pathology of schizophrenia originates in the middle stage of intrauterine life. (34) An earlier timing is excluded since overt brain abnormalities would be seen if neurogenesis were affected, whilst the lack of gliosis is taken to mean that the changes must have occurred prior to the third trimester. However, this ‘strong' form of the neurodevelopmental model is weak on two grounds. First, because of the limitations of the absence-of-gliosis argument mentioned earlier. Second, the types of cytoarchitectural disturbance adduced in favour (neuronal disarray, malpositioning) are those suggestive of aberrant neuronal migration, a process which occurs at the appropriate gestational period; yet, as mentioned, these cytoarchitectural abnormalities have not been unequivocally shown in schizophrenia. By comparison, the other cytoarchitectural findings, such as alterations in neuronal size, synapses, and dendrites, are modifiable throughout life and hence could originate much later.
Other forms of the neurodevelopmental theory advocate processes such as cell adhesion, apoptosis, myelination, and synaptic pruning. Overall, a parsimonious view is that the neuropathological data are indicative merely of an essentially developmental, as opposed to degenerative, disease process, rather than as pointing to a particular mechanism or timing.
Neuropathology and connectivity
Bleuler's view that the key symptoms of schizophrenia are those of ‘psychic splitting' now have their counterparts in the functional imaging studies and neuropsychological models described above, which have implicated aberrant functional connectivity between different brain regions as the putative mechanism of psychosis. It is suggested that the cytoarchitectural features of schizophrenia represent its neuroanatomical basis. (31) However, functional connectivity does not presuppose an anatomical substrate, and the pathological evidence in schizophrenia must be considered on its own merits before attempts are made to integrate structure with function. Certainly, schizophrenia is not a disconnectivity syndrome akin to Alzheimer's disease, in which there is a frank loss of synapses and neurones, but rather a dysconnectivity or misconnectivity syndrome resulting from a disturbance in the precise organization of the neural circuitry.
Cerebral asymmetry and schizophrenia
Many neuropathological, neurochemical, neuropsychological, and electrophysiological studies of schizophrenia report lateralized abnormalities. Although there are also important negative findings, alterations in normal asymmetries and a left-sided preference of the pathology for the brain do seem to be more common than one would expect by chance. Two explanatory hypotheses exist. Crow's evolutionary theory is that schizophrenia, asymmetry, handedness, and language are causally linked to each other and to the same gene. (35) Alternatively, altered asymmetry in schizophrenia is viewed as an epiphenomenon of its in utero origins, a process which interferes with subsequent brain lateralization. (36) The issue remains under active investigation.
Despite the many uncertainties, there are now established facts about the neurobiology of schizophrenia. There is ventricular enlargement and decreased brain volume. Although the cellular correlates remain poorly understood, they involve the size, density, and organization of neurones and their synaptic contacts. In vivo studies show differences in cerebral metabolism and other parameters of cerebral function, with a pattern indicative of aberrant connectivity between brain areas. Dopaminergic, 5-HT, and glutamatergic systems are all affected, but the specific details of their involvement in schizophrenia, and how they relate to the functional and structural findings, are still frustratingly unclear.
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