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.

Magnetic resonance imaging (MRI) provides accurate anatomical brain images without the use of ionizing radiation, allowing longitudinal studies of brain morphometry during adolescent development. Results from an ongoing brain imaging project being conducted at the Child Psychiatry Branch of the National Institute of Mental Health indicate dynamic changes in brain anatomy throughout adolescence. White matter increases in a roughly linear pattern, with minor differences in slope in the four major lobes (frontal, parietal, temporal, occipital). Cortical gray matter follows an inverted U-shape developmental course with greater regional variation than white matter. For instance, frontal gray matter volume peaks at about age 11.0 years in girls and 12.1 years in boys, whereas temporal gray matter volume peaks at about age at 16.7 years in girls and 16.2 years in boys. The dorsal lateral prefrontal cortex, important for controlling impulses, is among the latest brain regions to mature without reaching adult dimensions until the early 20s. The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.

Structural Magnetic Resonance Imaging of the Adolescent Brain

Reckless behavior in adolescence: A developmental perspective

Sixty-four autopsied brains of schizophrenic patients were neuropathologically examined and compared with 10 brains of non-schizophrenic controls. Clinical diagnoses were established retrospectively according to the Research Diagnostic Criteria and the International Classification of Diseases. We found:
 Generally, these anatomical abnormalities were asymmetric. The histological findings in the two limbic regions consisted mainly of poorly developed structure in the upper layers, with a heterotopic displacement of single groups of nerve cells in the entorhinal region. Particularly, the disturbed structure of the second layer Pre-α in medial and central fields of the entorhinal region, situated in the parahippocampal gyrus (group 2 a), suggests a disturbance of neuronal migration in a later phase of cortical development.

Prenatal developmental disturbances in the limbic allocortex in schizophrenics.

• Using a new and unbiased stereological technique, the total numbers of neuron and glial cells in the mediodorsal thalamic nucleus and the nucleus accumbens were found to be significantly reduced in schizophrenic patients compared with controls. The total neuron and glial cell number in the ventral pallidum and in the basolateral nucleus of amygdala did not differ in the two groups.

Pronounced Reduction of Total Neuron Number in Mediodorsal Thalamic Nucleus and Nucleus Accumbens in Schizophrenics

In an effort at replication of the original report (Rosenthal and Bigelow, 1972) of increased callosal thickness in schizophrenic brains, the corpus callosum was measured in a blind study of 64 brains autopsied between the years 1972 and 1976. Diagnosis was established by independent chart review. The mean corpus callosum mid sections of 21 early onset chronic schizophrenic brains were found to have a significantly greater thickness when compared with 8 subjects with late onset schizophrenia, 13 patients with neurological diagnoses, or 14 patients with other psychiatric diagnoses. These studies, if independently confirmed, should provide an impetus for testing the hypothesis that some chronic schizophrenic patients have an illness associated with a pathological process in the corpus callosum.

Corpus callosum thickness in chronic schizophrenia.

As a followup to a post-mortem study of the brains of schizophrenic and control subjects where the corpus callosum was found to be significantly thicker anteriorly in early onset compared to late onset schizophrenia, histological sections of 18 schizophrenic, 7 manic-depressive, and 11 medical/surgical control subjects were prepared using a stain for glia and a stain for callosal fibers. A quantitative study of the concentration of glial cells and interhemispheric callosal fibers revealed no difference between groups. A neuropathologist unaware of the tissue origin rated the histological sections for gliosis. There was significantly more severe gliosis in the callosi of the late onset schizophrenics compared to early onset schizophrenics as well as the control group. These preliminary findings suggesting callosal pathology are discussed, and the need for further studies is stressed.

A Histological Study of the Corpus Callosum in Chronic Schizophrenia

Low platelet monoamine oxidase activity and chronic marijuana use

The benefits and side effects of electroconvulsive therapy (ECT) given two vs three times per week were examined in depressed inpatients Twenty subjects were randomly assigned to one of two treatment conditions (unilateral ECT two or three times weekly) Examiners without knowledge of treatment condition rated depression and psychiatric status and administered tests of memory and visual-motor problem solving; subjects also provided self-ratings of depression Measures were collected before treatment and 2 and 4 weeks after treatment began Both schedules of treatment produced significant and equivalent improvements in psychiatric symptomatology, but visual memory impairment was significantly lower in the twice-weekly group

Effects of ECT given two vs. three times weekly.

• According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the ratelimiting enzymatic step in the synthesis of DA. No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment. There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes. The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.

Frederick P. Rauscher

Papers

Corpus callosum thickness in chronic schizophrenia.

A Histological Study of the Corpus Callosum in Chronic Schizophrenia

Low platelet monoamine oxidase activity and chronic marijuana use

Effects of ECT given two vs. three times weekly.

Inhibition of Dopamine Synthesis in Chronic Schizophrenia: Clinical Ineffectiveness of Metyrosine