A review of MRI findings in schizophrenia

This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

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.

Schizophrenia has often been conceived as a disorder of connectivity between components of large-scale brain networks. We tested this hypothesis by measuring aspects of both functional connectivity and functional network topology derived from resting-state fMRI time series acquired at 72 cerebral regions over 17 min from 15 healthy volunteers (14 male, 1 female) and 12 people diagnosed with schizophrenia (10 male, 2 female). We investigated between-group differences in strength and diversity of functional connectivity in the 0.06-0.125 Hz frequency interval, and some topological properties of undirected graphs constructed from thresholded interregional correlation matrices. In people with schizophrenia, strength of functional connectivity was significantly decreased, whereas diversity of functional connections was increased. Topologically, functional brain networks had reduced clustering and small-worldness, reduced probability of high-degree hubs, and increased robustness in the schizophrenic group. Reduced degree and clustering were locally significant in medial parietal, premotor and cingulate, and right orbitofrontal cortical nodes of functional networks in schizophrenia. Functional connectivity and topological metrics were correlated with each other and with behavioral performance on a verbal fluency task. We conclude that people with schizophrenia tend to have a less strongly integrated, more diverse profile of brain functional connectivity, associated with a less hub-dominated configuration of complex brain functional networks. Alongside these behaviorally disadvantageous differences, however, brain networks in the schizophrenic group also showed a greater robustness to random attack, pointing to a possible benefit of the schizophrenia connectome, if less extremely expressed.

https://www.jneurosci.org/content/jneuro/30/28/9477.full.pdf

Functional Connectivity and Brain Networks in Schizophrenia

Previous studies have shown that the orbital and medial prefrontal cortex (OMPFC) is extensively connected with medial temporal and cingulate limbic structures. In this study, the organization of these projections was defined in relation to architectonic areas within the OMPFC. All of the limbic structures were substantially connected with the following posterior and medial orbital areas: the posteromedial, medial, intermediate, and lateral agranular insular areas (Iapm, Iam, Iai, and Ial, respectively) and areas 11m, 13a, 13b, 14c and 14r. In contrast, lateral orbital areas 12o, 12m, and 12l and medial wall areas 24a,b and 32 were primarily connected with the amygdala, the temporal pole, and the cingulate cortex. Data were not obtained on the posteroventral medial wall. Three distinct projections were recognized from the basal amygdaloid nucleus: 1) The dorsal part projected to area 12l; 2) the ventromedial part projected to most areas in the posterior and medial orbital cortex except for area Iai, 12o, 13a, and 14c; and 3) the ventrolateral part projected to orbital areas 12o, Iai, 13a, 14c, and to the medial wall areas. The accessory basal and lateral amygdaloid nuclei projected most strongly to areas in the posterior and medial orbital cortex. The medial, anterior cortical, and central amygdaloid nuclei and the periamygdaloid cortex were connected with the posterior orbital areas. The projection from the hippocampus originated from the rostral subiculum and terminated in the medial orbital areas. The same region was reciprocally connected with the anteromedial nucleus of the thalamus, which received input from the rostral subiculum. The parahippocampal cortical areas (including the temporal polar, entorhinal, perirhinal, and posterior parahippocampal cortices) were primarily connected with posterior and medial orbital areas, with some projections to the dorsal part of the medial wall. The rostral cingulate cortex sent fibers to the medial wall, to the medial orbital areas, and to lateral areas 12o, 12r, and Iai. The posterior cingulate gyrus, including the caudomedial lobule, was especially strongly connected with area 11m.

Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys.

Objective: The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateralprefrontal cortex duringperformance ofthe Wisconsin Card Sorting Test. The present study was an investigation ofthe relationship between hippocampalpathology and prefrontal hypofunction in the same twin pairs. Method: Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampalvolume andxenon-inhalation rCBF testingfor determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. Results: The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group ofunaffected twins. Conclusions: This finding is consistent with the notion that schizophrenia involves pathology ofand dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance ofcognitive tasks requiring working memory. (Am J Psychiatry 1992; 149:890-897)

Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

The ratio of albumin in cerebrospinal fluid (CSF) to serum may serve as an index of the integrity of the blood-CSF barrier, with increases in this ratio indicating increased permeability. The ratio of immunoglobulin G (IgG) in CSF to serum (divided by the albumin ratio to correct for variance in blood-CSF permeability) represents an index of the endogenous production of IgG in the central nervous system (CNS), with increases reflecting a possible infectious and/or autoimmune process stimulating central IgG synthesis. We analyzed simultaneously collected CSF and serum samples from 46 schizophrenic subjects, 8 of whom were studied both on and off neuroleptic treatment, and samples from 20 normal controls. The data indicated increases in CSF/ serum albumin ratios or CSF/serum IgG indices in 22% and 20%, respectively, of the schizophrenic patients. Only 3 patients showed elevations in both indices. Comparison of values on and off neuroleptics indicated no significant effect of neuroleptics on these indices.

R.L. Suddath

Papers

Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia

Quantitative magnetic resonance imaging in twin pairs discordant for schizophrenia

Polydipsia-hyponatremia: Evidence for specific cerebral structural pathology and implications for the pathophysiology of schizophrenia

Analysis of cerebrospinal fluid monoamines in schizophrenic patients on and off neuroleptic treatment and compared with healthy controls