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

Background: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit hyperactivity disorder (ADHD) have been limited by small samples or measurement of single brain regions. Since the neuropsychological deficits in ADHD implicate a network linking basal ganglia and frontal regions, 12 subcortical and cortical regions and their symmetries were measured to determine if these structures best distinguished ADHD. Method: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were.82 or greater for all MRI measures. Results: Subjects with ADHD had a 4.7% smaller total cerebral volume ( P =.02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right>left asymmetry in the caudate ( P =.006), smaller right globus pallidus ( P =.005), smaller right anterior frontal region ( P =.02), smaller cerebellum ( P =.05), and reversal of normal lateral ventricular asymmetry ( P =.03) in the ADHD group. The normal age-related decrease in caudate volume was not seen, and increases in lateral ventricular volumes were significantly diminished in ADHD. Conclusion: This first comprehensive morphometric analysis is consistent with hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD.

Quantitative Brain Magnetic Resonance Imaging in Attention-Deficit Hyperactivity Disorder

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.

Learning and memory were assessed in 24 monozygotic (MZ) pairs of individuals discordant for schizophrenia or delusional disorder and seven normal pairs of MZ twins. On declarative memory tasks, the affected group displayed a pattern that might best be characterized as dysmnesic in that they performed significantly worse than the discordant unaffected group on story recall, paired associated learning, and visual recall of designs, but they learned over time, had relatively preserved recognition memory, and did not show profoundly accelerated rates of forgetting. Effortful, volitional retrieval from the lexicon, measured by verbal fluency, was also compromised in the affected group. On the other hand, procedural learning of the motor skill in a pursuit rotor task was relatively intact in the affected group. Comparisons of the normal group and unaffected group indicated that the latter group had very mild impairments in some aspects of episodic memory, namely, immediate and delayed recall of stories and delayed recall of designs. It is highly unlikely that the impairments observed in the affected group can be attributed to differences in genome, family environment, socioeconomic circumstance, or educational opportunity, as all of these were controlled by the twin paradigm. Rather, the impairments appear to be related to the intercession of disease. The neuropsychological profile is consistent with frontal lobe and medial temporal lobe dysfunction, as noted in this sample as well as other samples of schizophrenic singletons. Significant correlations between many measures of memory and global level of social and vocational functioning within the discordant group were also found. Thus difficulties in rapidly acquiring new information and propitiously retrieving old information may burden patients with schizophrenia in many of the transactions of everyday life.

Learning and memory in monozygotic twins discordant for schizophrenia

Objective: While a number ofstudies have suggested that women with schizophrenia have a less severe form of the disorder than men, the issue has been examined with neuropsychological measures only infrequently. Method: The authors compared neuropsychological test performances of men and women from four independent schizophrenic cohorts: two groups of inpatients with chronic courses at a research hospital (N= 12 8 and N=63), one group of consecutive admissions to a private psychiatric hospital (N=57), and one group of schizophrenic twins from discordant monozygotic pairs (N=20). Nearly 100 comparisons of neuropsychological test performances were made between men and women. Results: Not one cornparison significantly favored women, and few were even significantly different between the sexes. Conclusions: It cannot be ruled out that the disproportionate number of men in the chronic cohorts may have reflected either more frequent intellectual deterioration in men or a bias toward more severely impaired women. Yet, men and women in all groups performed similarly, including the groups in which the sex ratios were nearly equal and were not skewed toward chronicity. These results provide little support for the hypothesis that gender is associated with a unique pathogenesis of schizophrenia or is a marker for a distinct subtype of schizophrenia, at least to the extent that cognitive impairment is a primary manifestation of the underlying disease process. However, given the lack of female patients with later ages at onset and more affective symptoms, the results in this study should be considered relevant only for chronic patients with onset ofschizophrenia before age 30. (Am J Psychiatry 1995; 152:883-888)

Lack of sex differences in the neuropsychological performance of patients with schizophrenia.

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E.F. Torrey

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.

Learning and memory in monozygotic twins discordant for schizophrenia

Lack of sex differences in the neuropsychological performance of patients with schizophrenia.

Schizophrenia: fixed incidence or fixed thinking?

Correlations between abnormal hippocampal morphology and prefrontal physiology in schizophrenia.