EEG alpha oscillations: The inhibition–timing hypothesis

A review of MRI findings in schizophrenia

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.

Earlier efforts to localize the symptoms of schizophrenia in a single brain region have been replaced by models that postulate a disruption in parallel distributed or dynamic circuits. Based on empirical data derived from both magnetic resonance and positron emission tomography, we have developed a model that implicates connectivity among nodes located in prefrontal regions, the thalamic nuclei, and the cerebellum. A disruption in this circuitry produces "cognitive dysmetria," difficulty in prioritizing, processing, coordinating, and responding to information. This "poor mental coordination" is a fundamental cognitive deficit in schizophrenia and can account for its broad diversity of symptoms.

/pdf/cognitive-dysmetria-as-an-integrative-theory-of-rcudlh6a5w.pdf

“Cognitive Dysmetria” as an Integrative Theory of Schizophrenia: A Dysfunction in Cortical-Subcortical-Cerebellar Circuitry?

The reduced neuropil hypothesis: a circuit based model of schizophrenia

Objective; This study reports the first paired measurements ofglucose metabolism and size of thalamic regions in never-medicated schizophrenic patients using coregistered magnetic resonance imaging (MRI) templates. Method: Positron emission tomography with [‘8F]fluorodeoxyglucose and matching MRI scans were obtained in 20 never-medicated patients with schizophrenia and 15 normal volunteers. Methods for thalamic edge finding, statistical testing ofshape differences with chi-square maps, and MRI localization ofmajor thalamic subregions were developed. Results: Patients with schizophrenia showed a diminished metabolic rate in the right thalamus, with a loss ofthe normalpattern ofrightgreater than left asymmetry. Division into anterior/posterior segments revealed that the left anterior and right posterior showed the decrease. Differences were greater for metabolism in the weighted thalamic area (ratexarea) than for rate per unit area, a finding consistent with reported greater decreases in total neuron number than of neuron density in the thalami of schizophrenic patients. The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region. Conclusions: The reduced thalamic activity observed in this study lends further support to the concept of deficits in sensory filtering in schizophrenia. (Am J Psychiatry1996; 153:191-199)

Toshiyuki Someya

Papers

PET and MRI of the Thalamus in Never-Medicated Patients With Schizophrenia