The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus

Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.     

Elevated neuron number in the limbic thalamus in major depression

OBJECTIVE: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders. METHOD: Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain. RESULTS: There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects. CONCLUSIONS: The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.     

Efferent projections of reuniens and rhomboid nuclei of the thalamus in the rat

The nucleus reuniens (RE) is the largest of the midline nuclei of the thalamus and exerts strong excitatory actions on the hippocampus and medial prefrontal cortex. Although RE projections to the hippocampus have been well documented, no study using modern tracers has examined the totality of RE projections. With the anterograde anatomical tracer Phaseolus vulgaris leuccoagglutinin, we examined the efferent projections of RE as well as those of the rhomboid nucleus (RH) located dorsal to RE. Control injections were made in the central medial nucleus (CEM) of the thalamus. We showed that the output of RE is almost entirely directed to the hippocampus and "limbic" cortical structures. Specifically, RE projects strongly to the medial frontal polar, anterior piriform, medial and ventral orbital, anterior cingulate, prelimbic, infralimbic, insular, perirhinal, and entorhinal cortices as well as to CA1, dorsal and ventral subiculum, and parasubiculum of the hippocampus. RH distributes more widely than RE, that is, to several RE targets but also significantly to regions of motor, somatosensory, posterior parietal, retrosplenial, temporal, and occipital cortices; to nucleus accumbens; and to the basolateral nucleus of amygdala. The ventral midline thalamus is positioned to exert significant control over fairly widespread regions of the cortex (limbic, sensory, motor), hippocampus, dorsal and ventral striatum, and basal nuclei of the amygdala, possibly to coordinate limbic and sensorimotor functions. We suggest that RE/RH may represent an important conduit in the exchange of information between subcortical-cortical and cortical-cortical limbic structures potentially involved in the selection of appropriate responses to specific and changing sets of environmental conditions.     

Clinical study of cerebral blood flow in unilateral chronic subdural hematoma measured by 99mTc-HMPAO SPECT]

Cerebral blood flow (CBF) measured by 99mTc-HMPAO SPECT before operation was studied in 60 patients with unilateral chronic subdural hematoma. The regional CBF was measured in 26 regions of the fronto-occipital 10 cortices, putamen, thalamus and cerebellar hemisphere on both sides. Sixty cases with unilateral chronic subdural hematoma were classified into four groups on the basis of clinical symptoms: 17 cases with headache (headache group), 34 cases with hemiparesis (hemiparesis group) and 9 cases with consciousness disturbance or dementia (consciousness disturbance group), and into three groups on the basis of the degree of midline brain shift on MRI: 7 cases of mild shift group, 24 cases of moderate shift group and 29 cases of severe shift group. The average CBF in 60 patients in each region indicated that the regional CBF was reduced in frontal, occipital cortices and cerebellum on the non-hematoma side, and in putamen and thalamus on the hematoma side. In the headache group, the regional CBF reduction on the non-hematoma side was found in only frontal and occipital cortices compared with the corresponding regions on the hematoma side. In the hemiparesis group, the regional CBF was reduced in frontal and occipital cortices on the non-hematoma side and in putamen and thalamus on the hematoma side. The part of CBF reduction in both hemispheres was also noted in the hemiparesis group. In the consciousness disturbance group, the CBF reduction was markedly noted in whole brain. The CBF reductions in frontal and occipital cortices on the non-hematoma side and in putamen, thalamus and cerebellum on the hematoma side was not mutually related with the degree of midline brain shift. We concluded that the disturbance of CBF in chronic subdural hematoma was started from frontal and occipital cortices on the non-hematoma side observed in the headache group, and which was extended to putamen and thalamus on the hematoma side and a part of both hemispheres observed in the hemiparesis group. And such disturbance was finally observed as the CBF reductions in whole brain in the consciousness disturbance group.     

Adolescent Social Isolation Affects Schizophrenia-Like Behavior in the MAM-E17 Model of Schizophrenia

Social isolation (SI) during adolescence may induce schizophrenia-like behavior. In the present study, we investigated whether adolescent SI might affect the development of schizophrenia-like behavior in the MAM-E17 neurodevelopmental model of schizophrenia. Rats were socially isolated for 10 days during adolescence (postnatal days (P) 30–40), followed by resocialization until late adolescence (P45–P48) or early adulthood (P70–P75); behavioral and neurochemical studies were performed at these ages. The behavioral studies analyzed locomotor activity, social interaction, recognition memory, and sensorimotor gating; GAD65 and GAD67 protein levels were measured in the prefrontal cortex. The results showed that SI did not affect locomotor activity, but it prevented the social interaction deficits induced by MAM administration at both of the analyzed age points. However, SI induced a deficit in recognition memory in the MAM group during adolescence, which was not observed in the MAM-treated, socially housed rats at this age. In adulthood, impairments in recognition memory were detected in both MAM groups. In contrast, SI did not accelerate the appearance of sensorimotor gating deficits in MAM animals during adolescence, and sensorimotor gating impairments were observed in both MAM groups during adulthood. Adolescent SI rearing did not affect any examined behavioral responses in the VEH-treated groups. SI altered the levels of GAD65 and GAD67 proteins during adolescence in both groups; however, the decrease in the level of GAD65 protein was observed only in the adult MAM-SI group. Thus, SI rearing during a defined period of adolescence might have specific effects on the emergence of schizophrenia-like abnormalities in MAM-treated animals.     

Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia

Background

Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses.

The prefrontal cortex in the Göttingen minipig brain defined by neural projection criteria and cytoarchitecture

In an attempt to delineate the prefrontal cortex (PFC) in the Göttingen minipig brain the distribution of reciprocal thalamocortical projections was investigated using anterograde and retrograde tracing techniques and evaluated in relation to the specific cytoarchitectonic organization. Tracers were visualized using standard immunohistochemistry or evaluated in vivo using manganese (Mn²⁺) as an MRI paramagnetic tracer. The in vivo tract tracing turned out to be very sensitive with a high correspondence to the histological labelling. Tracers injected into the mediodorsal thalamus labelled the medial and rostral pole of the frontal lobe as well as the anterior cingulate, anterior insular and dorsomedial frontal cortices. Subsequently, the reciprocity and specificity of these connections were tested from injections into the traced frontal cortices indicating that the PFC has cortical connections to different parts of the MD nucleus. Although the granular layer IV, characteristic of primate PFC could not be identified, both cytoarchitectonic and connectional data suggests that the Göttingen minipig has a structurally divided prefrontal cortex. Stereological estimates of PFC volume showed that the Göttingen minipig PFC constitutes about 24% of the total neocortex volume and 10% of the total brain volume.     

The prefrontal cortex in the Göttingen minipig brain defined by neural projection criteria and cytoarchitecture

In an attempt to delineate the prefrontal cortex (PFC) in the Göttingen minipig brain the distribution of reciprocal thalamocortical projections was investigated using anterograde and retrograde tracing techniques and evaluated in relation to the specific cytoarchitectonic organization. Tracers were visualized using standard immunohistochemistry or evaluated in vivo using manganese (Mn²⁺) as an MRI paramagnetic tracer. The in vivo tract tracing turned out to be very sensitive with a high correspondence to the histological labelling. Tracers injected into the mediodorsal thalamus labelled the medial and rostral pole of the frontal lobe as well as the anterior cingulate, anterior insular and dorsomedial frontal cortices. Subsequently, the reciprocity and specificity of these connections were tested from injections into the traced frontal cortices indicating that the PFC has cortical connections to different parts of the MD nucleus. Although the granular layer IV, characteristic of primate PFC could not be identified, both cytoarchitectonic and connectional data suggests that the Göttingen minipig has a structurally divided prefrontal cortex. Stereological estimates of PFC volume showed that the Göttingen minipig PFC constitutes about 24% of the total neocortex volume and 10% of the total brain volume.     

Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia.

BACKGROUND: The thalamus is a brain region of interest in the study of schizophrenia because it provides critical input to brain regions such as the prefrontal, cingulate, and temporal cortices, where abnormalities have been repeatedly observed in patients with schizophrenia. Postmortem anatomic studies have rarely investigated the thalamus in this population. METHODS: Postmortem tissue was obtained from the left hemisphere of eight male schizophrenic patients and eight male age-matched control subjects. The optical dissector stereologic procedure was used to count neurons in the mediodorsal (MD) and anteroventral/anteromedial (AV/AM) nuclei of the thalamus. RESULTS: The number of neurons and volume of the MD were significantly reduced by 35% and 24%, respectively. The MD cell number reduction was a consistent finding; every control subject had more and every schizophrenic subject had fewer than 3.5 million neurons. Neuron number was also significantly reduced (16%) in the AV/AM nuclei. CONCLUSIONS: The present data indicate that schizophrenia is associated with robust reductions in nerve cell numbers in nuclei that communicate with the prefrontal cortex and limbic system. These thalamic anatomic deficits may be responsible, in part, for previous reports of such prefrontal cortical abnormalities as reduced synaptic density, reduced volume, and metabolic hypofunction.     

Brain volume and dysexecutive behavior in schizophrenia

Objective

Behaviors associated with frontal/executive impairments are common in patients with schizophrenia. Our aim was to reconfirm that morphological brain abnormalities in schizophrenia patients would overlap the areas underpinning frontal systems behavior, and examine whether any specific association exists between abnormalities of brain structures and frontal behavioral deficits in schizophrenia patients.

Method

Twenty-six schizophrenia patients and 26 matched healthy controls underwent structural magnetic resonance imaging and their frontal function was assessed by a self-rating questionnaire, Frontal Systems Behavior Scale (FrSBe). We applied voxel-based morphometry (VBM) to investigate regional brain volume alternations.

Result

Compared with healthy controls, schizophrenia patients showed reduced gray matter volume in multiple frontal and temporal structures, namely, the bilateral dorsolateral prefrontal cortices (DLPFC), bilateral medial prefrontal cortices, left ventrolateral prefrontal cortex, bilateral anterior cingulate cortices, and bilateral superior temporal gyri. The scores on the executive dysfunction subscale of the FrSBe were correlated with volume reduction in the bilateral DLPFC in the patient group.

Conclusion

Our result suggests that pathology of the DLPFC could be the neural basis of real-life dysexecutive behaviors in schizophrenia patients.     

Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia

Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory gamma-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.     

Regional specificity of aberrant thalamocortical connectivity in autism

Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region‐specific TC connectivity in ASD. Resting‐state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7–17 years) and 45 age, sex, and IQ‐matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions. Hum Brain Mapp 36:4497–4511, 2015. © 2015 Wiley Periodicals, Inc .     

Cerebral blood flow in corticobasal degeneration and progressive supranuclear palsy

To compare brain perfusion between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), we investigated regional cerebral blood flow (rCBF) semiquantitatively with single-photon emission computed tomography and [123I]iodoamphetamine in six patients with CBD and five with PSP. Compared with 12 age-matched control subjects, the average of the left and right rCBF values for the CBD patients was significantly reduced in the inferior prefrontal, anterior cingulate, medial premotor, sensorimotor, posterior parietal, and superior temporal cortices as well as in the basal ganglia and thalamus, whereas only the medial premotor cortex was significantly hypoperfused in the PSP patients. Compared with the PSP patients, the CBD patients showed significantly decreased rCBF in the inferior prefrontal, sensorimotor, and posterior parietal cortices, but not in the subcortical regions. Compared with the controls, interhemispheric differences of rCBF were significant in the inferior prefrontal, sensorimotor, and posterior parietal cortices of the CBD patients but in only the medial prefrontal cortex of the PSP patients. These results indicate that rCBF reductions are more extensive and asymmetric in CBD than in PSP, although the two diseases share medial frontal involvement.     

Corticostriatal connectivity fingerprints: Probability maps based on resting‐state functional connectivity

Over the last decade, structure–function relationships have begun to encompass networks of brain areas rather than individual structures. For example, corticostriatal circuits have been associated with sensorimotor, limbic, and cognitive information processing, and damage to these circuits has been shown to produce unique behavioral outcomes in Autism, Parkinson's Disease, Schizophrenia and healthy ageing. However, it remains an open question how abnormal or absent connectivity can be detected at the individual level. Here, we provide a method for clustering gross morphological structures into subregions with unique functional connectivity fingerprints, and generate network probability maps usable as a baseline to compare individual cases against. We used connectivity metrics derived from resting‐state fMRI (N = 100), in conjunction with hierarchical clustering methods, to parcellate the striatum into functionally distinct clusters. We identified three highly reproducible striatal subregions, across both hemispheres and in an independent replication dataset (N = 100) (dice‐similarity values 0.40–1.00). Each striatal seed region resulted in a highly reproducible distinct connectivity fingerprint: the putamen showed predominant connectivity with cortical and cerebellar sensorimotor and language processing areas; the ventromedial striatum cluster had a distinct limbic connectivity pattern; the caudate showed predominant connectivity with the thalamus, frontal and occipital areas, and the cerebellum. Our corticostriatal probability maps agree with existing connectivity data in humans and non‐human primates, and showed a high degree of replication. We believe that these maps offer an efficient tool to further advance hypothesis driven research and provide important guidance when investigating deviant connectivity in neurological patient populations suffering from e.g., stroke or cerebral palsy. Hum Brain Mapp 38:1478–1491, 2017. © 2016 Wiley Periodicals, Inc.     

The early commitment of fetal neurons to the limbic cortex

The limbic-system-associated membrane protein (LAMP) is expressed early in cerebral cortical development by migrating and postmigratory neurons in limbic regions such as the prefrontal and perirhinal cortices (Horton and Levitt, 1988), but not by nonlimbic neurons such as in the primary sensory and motor cortices. In the present study, we used LAMP expression to evaluate the timing and potential cell-lineage and environmental determinants of the commitment of cerebral cortical neurons to limbic and nonlimbic phenotypes. The cerebral wall, containing either presumptive perirhinal or sensorimotor cortex, was removed prior to [embryonic day (E) 12, 14] or just after (E17) the onset of LAMP expression, labeled with fast blue, and placed into cavities in either perirhinal or sensorimotor regions of postnatal day (P) 1 hosts. Host animals were allowed to survive until at least P10, and surviving transplanted cells were counted and evaluated for LAMP expression. Sensorimotor cortical neurons transplanted at E14 or E17, in either homotopic or heterotopic locations, did not express LAMP. In contrast, a high percentage of perirhinal cortical neurons transplanted at either E14 or E17, whether situated in sensorimotor or perirhinal regions of the host, expressed the limbic marker protein. Surprisingly, neurons from E12 donors exhibited patterns of LAMP expression that reflected their new location in the host rather than their embryonic origin. The data suggest that there is an early pliant period in which precursor and early differentiating cells remain uncommitted to a particular cortical regional phenotype. After this period, one aspect of the molecular phenotype (determined by LAMP expression) of neurons destined for sensorimotor and allo- and mesocortical regions has become immutable by environmental factors in the host.     

Direct and indirect effects on the lateral geniculate nucleus neurons of prenatal exposure to methylazoxymethanol acetate

In this study the morphology of the lateral geniculate nucleus and occipital cortex in rats with methylazoxymethanol acetate (MAM Ac)-induced micrencephaly was examined. The aim was to examine the relative contributions of (a) the direct cytotoxic action of the drug on precursors of dorsal lateral geniculate nucleus (dLGN) neurons in the fetal brain and, (b) the postnatal degeneration of the dLGN following prenatal destruction of target neurons in the occipital cortex, to the final extent of damage to the dLGN. Exposure to MAM Ac on E13 produced severe necrosis in the fetal thalamus and caused a 77% deficit in neuronal numbers in the mature dLGN. Exposure to MAM Ac on E15 did not cause necrosis in the fetal thalamus but when animals exposed at this time were examined at 5 weeks postnatal age there was an 87% deficit in neuronal numbers in the dLGN. The hypothesis that this deficit was the result of postnatal death of the dLGN neurons following the destruction by MAM Ac of their normal target population in laminae iii and iv of the occipital cortex was supported by the observation of severe postnatal degeneration in the dLGN of animals exposed to MAM Ac on E15. The significance of these direct and indirect effects of the cytotoxic teratogen, MAM Ac, for understanding the mechanisms by which brain abnormalities in human micrencephaly are produced is discussed.     

Abnormal superior temporal connectivity during fear perception in schizophrenia

Patients with schizophrenia have difficulty in decoding facial affect. A study using event-related functional neuroimaging indicated that errors in fear detection in schizophrenia are associated with paradoxically higher activation in the amygdala and an associated network implicated in threat detection. Furthermore, this exaggerated activation to fearful faces correlated with severity of flat affect. These findings suggest that abnormal threat detection processing may reflect disruptions between nodes that comprise the affective appraisal circuit. Here we examined connectivity within this network by determining the pattern of intercorrelations among brain regions (regions of interest) significantly activated during fear identification in both healthy controls and patients using a novel procedure CORANOVA. This analysis tests differences in the interregional correlation strength between schizophrenia and healthy controls. Healthy subjects' task activation was principally characterized by robust correlations between medial structures like thalamus (THA) and amygdala (AMY) and middle frontal (MF), inferior frontal (IF), and prefrontal cortical (PFC) regions. In contrast, schizophrenia patients displayed no significant correlations between the medial regions and either MF or IF. Further, patients had significantly higher correlations between occipital lingual gyrus and superior temporal gyrus than healthy subjects. These between-group connectivity differences suggest that schizophrenia threat detection impairment may stem from abnormal stimulus integration. Such abnormal integration may disrupt the evaluation of threat within fronto-cortical regions.     

Projections of the medial orbital and ventral orbital cortex in the rat

The medial orbital (MO) and ventral orbital (VO) cortices are prominent divisions of the orbitomedial prefrontal cortex. To our knowledge, no previous report in the rat has comprehensively described the projections of MO and VO. By using the anterograde tracer Phaseolus vulgaris leucoagglutinin and the retrograde tracer Fluoro-Gold, we examined the efferent projections of MO and VO in the rat. Although MO and VO projections overlap, MO distributes more widely throughout the brain, particularly to limbic structures, than does VO. The main cortical targets of MO were the orbital, ventral medial prefrontal (mPFC), agranular insular, piriform, retrosplenial, and parahippocampal cortices. The main subcortical targets of MO were the medial striatum, olfactory tubercle, claustrum, nucleus accumbens, septum, substantia innominata, lateral preoptic area, and diagonal band nuclei of the basal forebrain; central, medial, cortical, and basal nuclei of amygdala; paratenial, mediodorsal, and reuniens nuclei of the thalamus; posterior, supramammillary, and lateral nuclei of the hypothalamus; and periaqueductal gray, ventral tegmental area, substantia nigra, dorsal and median raphe, laterodorsal tegmental, and incertus nuclei of the brainstem. By comparison, VO distributes to some of these same sites, notably to the striatum, but lacks projections to parts of limbic cortex, to nucleus accumbens, and to the amygdala. VO distributes much more strongly, however, than MO to the medial (frontal) agranular, anterior cingulate, sensorimotor, posterior parietal, lateral agranular retrosplenial, and temporal association cortices. The patterns of MO projections are similar to those of the mPFC, whereas the projections of VO overlap with those of the ventrolateral orbital cortex (VLO). This suggests that MO serves functions comparable to those of the mPFC, such as goal-directed behavior, and VO performs functions similar to VLO such as directed attention. MO/VO may also serve as a link between lateral orbital and medial prefrontal cortices.     

Lack of normal pattern of cerebral asymmetry in familial schizophrenic patients and their relatives--The Maudsley Family Study

Lack of the normal cerebral asymmetry has been reported in schizophrenia. We wished to test the hypothesis that this lack of the normal pattern of asymmetry is familial and that it can be found in both schizophrenic and non-schizophrenic family members. In particular, we wanted to know whether those relatives who appear to be transmitting liability to the illness also demonstrate the loss of normal asymmetry. We studied families with several members affected with schizophrenia. We carried out volumetric measurements of prefrontal, premotor, sensorimotor and occipitoparietal regions in each hemisphere using 3D reconstructed MRI images in 29 schizophrenic patients, 55 of their first degree relatives, and 39 unrelated control subjects on contiguous thin slices of the brain. Nine of the unaffected relatives appeared to be transmitting the liability for schizophrenia (e.g. the mother of a schizophrenic patient who, although not psychotic herself, had a schizophrenic parent or sibling). We termed them presumed obligate carriers and the remaining 46 relatives presumed non-obligate carriers. The healthy control subjects showed larger right than left prefrontal regions and larger left than right sensorimotor and occipitoparietal regions. The schizophrenic patients showed lack of this normal brain asymmetry in the prefrontal, sensorimotor and occipitoparietal cortical regions. The presumed obligate carriers were similar to the schizophrenic patients in exhibiting lack of asymmetries in these cortical regions, while the presumed non-obligate relatives showed lack of asymmetry only in the occipitoparietal region. There was no overall reduction in total or regional brain volumes among the groups. Our findings indicate that lack of the normal pattern of frontal and occipital asymmetry is a marker for genetic liability to schizophrenia in families multiply affected with schizophrenia.