Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.

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The neuropathology of schizophrenia. A critical review of the data and their interpretation.

Objective: The authors’ goal was to determine whether patients with schizophrenia differ from comparison subjects in regional brain volumes and whether these differences are similar in male and female subjects. Method: They conducted a systematic search for structural magnetic resonance imaging (MRI) studies of patients with schizophrenia that reported volume measurements of selected cortical, subcortical, and ventricular regions in relation to comparison groups. They carried out a meta-analysis of the volumes of these regions in the patients with schizophrenia and the comparison subjects using a random effects model; they also used random effects regression analysis to examine the influence of gender on effect sizes. Results: Fifty-eight studies were identified as suitable for analysis; these studies included 1,588 independent patients with schizophrenia. Assuming a volume of 100% in the comparison group, they found that the mean cerebral volume of the subjects with schizophrenia was smaller (98%), but the mean total ventricular volume of the subjects with schizophrenia was greater (126%). Relative to the cerebral volume differences, the regional volumes of the subjects with schizophrenia were 94% in the left and right amygdala, 94% in the left and 95% in the right hippocampus/amygdala, and 93% in the left and 95% in the right parahippocampus. Relative to the global ventricular system differences, the largest differences in ventricular subdivisions were in the right and left body of the lateral ventricle, where the volumes of schizophrenic subjects were 116% and 116%, respectively. For most regions, effect size was not significantly related to gender. Conclusions: Regional structural differences in patients with schizophrenia include bilaterally reduced volume of medial temporal lobe structures. There is a need for greater integration of results from structural MRI studies to avoid redundant research activity. (Am J Psychiatry 2000; 157:16‐25)

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.157.1.16

Meta-Analysis of Regional Brain Volumes in Schizophrenia

How the mind works

OBJECTIVE: Voxel-based morphometry is a method for detecting group differences in the density or volume of brain matter. The authors reviewed the literature on use of voxel-based morphometry in schizophrenia imaging research to examine the capabilities of this method for clearly identifying specific structural differences in patients with schizophrenia, compared with healthy subjects. The authors looked for consistently reported results of relative deficits in gray and white matter in schizophrenia and evaluated voxel-based morphometry methods in order to propose a future strategy for using voxel-based morphometry in schizophrenia research. METHOD: The authors reviewed all voxel-based morphometry studies of schizophrenia that were published to May 2004 (15 studies). The studies included a total of 390 patients with a diagnosis of schizophrenia and 364 healthy volunteers. RESULTS: Gray and white matter deficits in patients with schizophrenia, relative to healthy comparison subjects, were reported in a tota...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.162.12.2233

Regional Deficits in Brain Volume in Schizophrenia: A Meta-Analysis of Voxel-Based Morphometry Studies

Recent evidence in natural and semi-natural settings has revealed a variety of left-right perceptual asymmetries among ver- tebrates These include preferential use of the left or right visual hemifield during activities such as searching for food, agonistic re- sponses, or escape from predators in animals as different as fish, amphibians, reptiles, birds, and mammals There are obvious disad- vantages in showing such directional asymmetries because relevant stimuli may be located to the animal's left or right at rando m; there is no a priori association between the meaning of a stimulus (eg, its being a predator or a food item) and its being located to the ani- mal's left or right Moreover, other organisms (eg, predators) could exploit the predictability of behavior that arises from population- level lateral biases It might be argued that lateralization of function enhances cognitive capacity and efficiency of the brain, thus coun- teracting the ecological disadvantages of lateral biases in behavior However, such an increase in brain efficiency could be obtained by each individual being lateralized without any need to align the direction of the asymmetry in the majority of the individuals of the pop- ulation Here we argue that the alignment of the direction of behavioral asymmetries at the population level arises as an "evolutionarily stable strategy" under "social" pressures occurring when individually asymmetrical organisms must coordinate their behavior with the behavior of other asymmetrical organisms of the same or different species

/pdf/survival-with-an-asymmetrical-brain-advantages-and-4nfldlpjsp.pdf

Survival with an asymmetrical brain: Advantages and disadvantages of cerebral lateralization

Coren and Porac (1976) reported that objects looked larger in the right eye of right-eye dominant subjects and in the left eye of left-eye dominant subjects. This paper attempts to repeat that finding. Two circles of same or different size were presented haploscopically in a binocular three-field tachistoscope, to right or left visual half-field and to the upper or lower visual field, one to the right eye and one to the left. A total of 43 subjects reported which of the two circles was the larger, each subject carrying out 120 trials of the experiment. Overall subjects reported that the stimulus to the left eye was significantly larger than that presented to the right eye. There was no association with eye dominance, and therefore the Coren and Porac finding could not be repeated. There was however a very significant association with handedness, left-handed subjects tending to report that the stimulus in the right eye looked larger, and right-handed subjects reporting that the stimulus in the left eye looked larger.

Objects look different sizes in the right and left eyes.

Multivariate meta-analysis was performed on 39 studies of ventricular size in schizophrenia which used the ventricle:brain ratio (VBR). The size of the VBR was dependent both upon the date when studies were carried out (more recent studies showing a reduction in the difference between schizophrenics and controls), and upon the diagnostic criterion used in the studies. Methodological factors in study design seemed more important than the characteristics of the schizophrenic subjects, in determining the VBR. Our analysis suggests that there is a difference in VBR between schizophrenics and controls which would seem to be an indisputable characteristic of schizophrenia. However, the difference is smaller than has previously been thought, so that, although of undoubted theoretical interest in accounting for the aetiology of schizophrenia, it is probably too small to be of practical significance in diagnosis, or in the differentiation of subtypes.

Ventricular enlargement in schizophrenia. A meta-analysis of studies of the ventricle:brain ratio (VBR)

Objects look different sizes in the right and left eyes

The right shift (RS) theory of handedness (Annett, 1972, 1985) suggested that the high prevalence of human right-handedness and left hemisphere specialization for speech is due to a single factor which induces the typical pattern of cerebral specialization and incidentally displaces a chance distribution of manual asymmetry toward dextrality. The factor could be a single gene (rs+). An estimate of genotype frequencies based on the percentage of right hemisphere speakers suggested a genetic balanced polymorphism with heterozygote advantage. Studies of actual hand skill suggest that strong dextrality depends on a process which induces left hand weakness, probably associated with impairment of right hemisphere function. Non gene-carriers (rs-genotypes) avoid right hemisphere handicap but are at risk for the development of speech and speech dependent language processes. People with specific deficits of phonological processing have reduced bias to dextrality, as expected if they lack the rs+ gene. The presence of the rs+ gene is associated with poorer spatial ability and this is true for left-handers as well as right-handers. The higher proportion of nonright-handers among mathematicians and other talented groups may be due to the absence of rs++ genotypes, rather than to an intrinsic advantage for left-handers. Evidence for heterozygote advantage has been found in studies of educational achievement, especially in reading. Poor readers are more prevalent at both extremes of the laterality distribution. A critical test of the balanced polymorphism hypothesis asked whether a double dissociation exists between people with specific deficits of phonological versus visual memory for words, and reduced versus strong bias to dextrality respectively. Evidence for this double dissociation was found in school and university samples. Applying the model to dyslexia, children with specific reading difficulties classified for presence versus absence of poor phonology were found to differ for handedness as expected if the former are less dextral and the latter more dextral than controls. These findings are not due to pathology, but they are associated with differences in the handedness of relatives, as expected by the RS model. Criticisms of the balanced polymorphism model are shown to be ill-founded. Questions of interpretation of the theory are considered and needs for further research are indicated.

The right shift theory of a genetic balanced polymorphism for cerebral dominance and cognitive processing. Commentaries. Author's reply

Hand preference and hand skill was assessed in two broad age groups of children with autism, children with learning disabilities, and control schoolchildren. The first group comprised children ages 3–5 years and the second group of children ages 11–13 years. Degree of handedness remained relatively stable across age groups, particularly within the autistic and learning-disabled populations. The main difference was between the subject groups, with the normal controls more lateralized than either the children with autism or children with learning disabilities. As with degree of handedness, consistency of handedness also differed significantly between subject groups with the normal controls more consistent in their hand preference than the other two groups. In addition, younger children were less consistent in their hand preference than older children. However, the present study found noevidence of a dissociation of hand skill and hand preference in children with autism compared to children with learning disabilities and normal developing children.

I. C. McManus

Papers

Objects look different sizes in the right and left eyes.

Ventricular enlargement in schizophrenia. A meta-analysis of studies of the ventricle:brain ratio (VBR)

Objects look different sizes in the right and left eyes

The right shift theory of a genetic balanced polymorphism for cerebral dominance and cognitive processing. Commentaries. Author's reply

Hand preference and hand skill in children with autism