Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Implications of normal brain development for the pathogenesis of schizophrenia

Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression

A review of MRI findings in schizophrenia

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

The role of inflammation in depression: from evolutionary imperative to modern treatment target

• The volume of several parts of the basal ganglia and of the limbic system was measured by planimetry of myelin-stained serial sections in postmortem brains of 13 schizophrenic patients and nine control cases. The medial limbic structures of the temporal lobe (amygdala, hippocampal formation, and parahippocampal gyrus) and the pallidum internum were significantly smaller in the schizophrenic group, whereas the pallidum externum showed only a modest trend toward volume reduction. The volumes of the putamen, nucleus caudatus, nucleus accumbens, and the bed nucleus of the stria terminalis did not differ between patients and controls. The volume reductions of the limbic temporal structures and of the pallidum internum of schizophrenics are interpreted as degenerative shrinkages of unknown etiology.

Basal Ganglia and Limbic System Pathology in Schizophrenia: A Morphometric Study of Brain Volume and Shrinkage

Immunological aspects in the neurobiology of suicide : Elevated microglial density in schizophrenia and depression is associated with suicide

Objective This study examined the pathomorphology of the caudate nuclei in first-episode schizophrenic patients with minimal previous neuroleptic exposure. Method Magnetic resonance imaging (MRI) of the brain was used to examine longitudinally the caudate pathomorphology in 29 first-episode schizophrenic patients and 10 healthy comparison subjects. MRI scans were obtained after the subjects entered the study and at 18-month follow-up. The patients were treated with standardized neuroleptic regimens during the 18-month period. Volumetric assessments of the cerebral cortex, lateral ventricles, and caudate nuclei were performed on T1-weighted coronal brain sections. In addition, the patients were systematically evaluated for psychopathology at baseline and during treatment. Results Caudate volumes increased 5.7% in the patients during the 18-month treatment interval, whereas they decreased 1.6% in the comparison subjects over the same time period. Greater amounts of antipsychotic medication received by patients before the first scan and younger age at the time of the first scan were associated with larger increases in caudate volume. Conclusions Caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.

Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs.

Pathomorphology of the limbic system has been described in post-mortem studies of schizophrenia. To determine whether this could be detected in living patients and was not secondary to the treatment or the chronicity of the disease itself, we measured the volumes of the hippocampus-amygdala complex and adjoining temporal horns of 34 patients in their first episode of schizophrenia and 25 normal volunteers using T1 weighted contiguous coronal magnetic resonance images of 3.1 mm width. The results demonstrate abnormal medial temporal lobe morphology in a subgroup of patients at the onset of their illness. There were clear laterality effects and sex differences: hippocampal tissue was significantly smaller only in the left hemisphere of male patients, whereas enlargement of the whole temporal horn or its anterior portion was present on the left side in both sexes. Dysfunction of the limbic mesiotemporal structures might explain some of the clinical features of the disease.

Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.

To investigate whether volume reduction of the hippocampal formation of schizophrenics, as described previously, is paralleled by loss of neurons and fibre systems, tissue volumes and cell numbers of all parts of the hippocampal formation in post mortem brains of 13 schizophrencis and 11 agematched controls belonging to the Vogt collection were determined. Volumes of the whole hippocampal formation (P < 0.01), the whole pyramidal band (P < 0.001) and the hippocampal segments CA1/CA2 (P < 0.01), CA3 (P < 0.05), CA4 (P < 0.01) were decreased, whereas no significant volume reduction of the alveus and fimbria hippocampi and presubiculum/subiculum could be found. The perforant path showed a trend towards volume reduction (P < 0.1). The absolute number of pyramidal cells (tissue volume × cell density) was diminished in CA1/CA2 (P < 0.05), CA3 (P < 0.05) and CA4 (P < 0.05), but was not significantly changed in the prosubiculum/subiculum, the presubiculum/parasubiculum and the granular cell layer of the dentate fascia. Pyramidal cell loss in CA1/CA2, CA3, CA4 was more distinct in the paranoid patients than in catatonics. The findings are discussed with respect to current hypotheses of limbic dysfunction in schizophrenia.

Bernhard Bogerts

Papers

Basal Ganglia and Limbic System Pathology in Schizophrenia: A Morphometric Study of Brain Volume and Shrinkage

Immunological aspects in the neurobiology of suicide : Elevated microglial density in schizophrenia and depression is associated with suicide

Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs.

Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia.

Cell loss in the hippocampus of schizophrenics.