Parahippocampal epilepsy with subtle dysplasia: A cause of "imaging negative" partial epilepsy.

PURPOSE: Lesion-negative refractory partial epilepsy is a major challenge in the assessment of patients for potential surgery. Finding a potential epileptogenic lesion simplifies assessment and is associated with good outcome. Here we describe imaging features of subtle parahippocampal dysplasia in five cases that were initially assessed as having imaging-negative frontal or temporal lobe epilepsy. METHODS: We analyzed the clinical and imaging features of five patients with seizures from the parahippocampal region. RESULTS: Five patients had subtle but distinctive magnetic resonance imaging (MRI) abnormalities in the parahippocampal gyrus. This was a unilateral signal abnormality in the parahippocampal white matter extending into gray matter on heavily T(1)- and T(2)-weighted images with relative preservation of the gray-white matter boundary on T(1)-weighted volume sequences. Only one of these patients had typical electroclinical unilateral temporal lobe epilepsy (TLE); one mimicked frontal lobe epilepsy, two showed bitemporal seizures, and one had unlocalized partial seizures. All have had surgery; four are seizure-free (one has occasional auras only, follow-up 6 months to 10 years), and one has a >50% seizure reduction. Histopathologic evaluation suggested dysplastic features in the surgical specimens in all. DISCUSSION: In patients with lesion-negative partial epilepsy with frontal or temporal semiology, or in cases with apparent bitemporal seizures, subtle parahippocampal abnormalities should be carefully excluded. Recognizing the MRI findings of an abnormal parahippocampal gyrus can lead to successful surgery without invasive monitoring, despite apparently incongruent electroclinical features.

Clozapine or Haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins' concentrations.

SUMMARY: Rats exposed during prenatal life to methylazoxymethanol (MAM) display in postnatal age structural and behavioral deficits resembling those observed in schizophrenic patients. These deficits are associated with significant changes in brain nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), particularly in the hippocampus and entorhinal cortex. In the present study, we used the MAM model to investigate in young rats the effect of antipsychotics, Clozapine and Haloperidol, on brain and blood NGF and BDNF presence. Young animals were used because administration of antipsychotics during adolescence is a common feature of intervention. The results showed that administration of Clozapine and Haloperidol causes significant changes in the concentration of NGF and BDNF in the brain and bloodstream of MAM-treated rats. These findings indicate that these drugs may affect the synthesis and release of neurotrophins in the central nervous system and in the blood circulation. In addition, the MAM model can be a useful tool to investigate the biochemical and molecular mechanisms regarding the effects of antipsychotics.

[Structural and functional brain changes in schizophrenic disorders. Indications of early neuronal developmental disturbances?]. / Strukturelle und funktionelle Hirnveränderungen bei schizophrenen Psychosen. Hinweis auf eine frühe neuronale Entwicklungsstörung?

The neurodevelopmental hypothesis of schizophrenia, which was established 30 years ago and discussed controversially for a long time, postulates that pre- and perinatally acting cerebral noxae cause disturbances of corticogenesis in the developing neuronal fibre systems which are essential for later onset of the disease. During recent years the cerebral alterations of schizophrenic patients could be further characterized as area-, layer-, and cell type-specific changes in temporolimbic and frontal regions leading to specific abnormalities of intrinsic and extrinsic connectivity. Animal models allowed for realistic imitations of these structural lesions and for elucidating their functional consequences concerning transmitter systems and behaviour. With modern neuroimaging techniques microstructural changes and alterations in cerebral activation can be exactly demonstrated and related to the specific psychopathologic features of schizophrenia.

Postnatal development of entorhinodentate projection of the Reeler mutant mouse.

We anterogradely labeled entorhinodentate axons by the injection of biotin dextran amine into the entorhinal cortex of adult wildtype and reeler mice to clarify whether the course and terminal endings of the reeler entorhinal projection are normal or not. We found that in the reeler mouse, biotin dextran amine-labeled entorhinodentate fibers arising from the entorhinal cortex curved around the hippocampal fissure instead of crossing it, whereas in the wildtype mouse, they crossed the fissure as a perforant pathway. Next, we examined carbocyanine dye (DiI) labeling of the immature entorhinodentate projection and the developmental changes of the hippocampal fissure during early postnatal days based on the laminin and glial fibrillary acidic protein (GFAP) immunohistochemistry. Injection of DiI into the entorhinal area of the wildtype and reeler mice at postnatal day 1 resulted in anterograde labeling of pioneer axons passing through the hippocampal fissure. However, follower axons could not penetrate through the hippocampal fissure in reeler mice, whereas in the normal controls, many DiI-labeled axons continued to pass through the fissure. GFAP immunohistochemistry demonstrated that GFAP-immunopositive astrocytes were abundant along the hippocampal fissure both in the wildtype and reeler mice at birth. In the wildtype mouse, GFAP-positive neurons nearby the fissure were decreasing in number during the early postnatal days, whereas in the reeler mouse, many GFAP-positive astrocytes were continuing to accumulate there. This barrier made of astrocytes in the reeler mouse may obstruct the ingrowth of the follower axons arising from the entorhinal cortex through the hippocampal fissure, resulting in the abnormal course of the entorhinodentate axons in this mutant.

The development concept of "endogenous psychoses".

Several structural deviances in the brain in "endogenous psychoses" have been described over the last decades. The enlargement of the lateral ventricles and the subtle structural deficits in temporobasal and orbital frontal structures (hypofrontality) are reasonably well established in the majority of schizophrenic patients. We examined the cytoarchitecture of these important central structures, namely the entorhinal region and the orbitofrontal cortex (Brodmann area 11), which have been under meticulous investigation in our laboratories over the last few decades. In a new series of schizophrenic patients and normal controls, we made serial cuts of the whole rostral entorhinal cortex on both sides. For this report, we selected two cases with very different psychopathologies, and present the serial cuts through both hemispheres and the malformations found. We report on the differing magnitude of the heterotopic malformations (for definition see page 103), either bilaterally or unilaterally.

Gray matter features of schizotypal disorder patients exhibiting the schizophrenia-related code types of the Minnesota Multiphasic Personality Inventory.

OBJECTIVE: Previous studies have suggested that several code types of the Minnesota Multiphasic Personality Inventory (MMPI) are useful markers for identifying schizophrenia. We hypothesized that schizotypal disorder (STD) patients with such schizophrenia-related code types have the morphological brain abnormalities associated with schizophrenia. METHOD: Voxel-based morphometric analysis with statistical parametric mapping (SPM) 99 software was used to investigate the differences in brain morphology between 14 STD patients with the schizophrenia-related code types of the MMPI and 28 normal individuals. RESULTS: The STD patients showed significantly decreased gray matter volume in the insular regions bilaterally and in the left entorhinal cortex, compared with the controls. CONCLUSION: Our findings suggest that STD patients with the schizophrenia-related code types have volume reductions in these regions as an endophenotype that overlaps with schizophrenia.

Increased frequency of dentate granule cells with basal dendrites in the hippocampal formation of schizophrenics.

In the hippocampal formation of schizophrenics, the detailed morphology of Golgi-impregnated granule cells was examined. These granule cells of the dentate gyrus are interposed between the rostral entorhinal cortex and the hippocampus proper. In these limbic regions significant cytoarchitectural alterations in schizophrenics are reported, giving rise to the concept of a prenatal limbic maldevelopment in schizophrenia. Compared to controls, the frequency of dentate granule cells with basal dendrites was significantly increased in schizophrenics [43% (+/-3)] vs. [22% (+/-2) in the control group]. In epilepsy, dentate granule cells of epileptic patients also develop basal dendrites, which is explained as an adaptive process of plasticity. Similarly, the hippocampal alterations described in schizophrenics could be the sequela of primary entorhinal cytoarchitectural alterations. Since the increase in basal dendrites seems to reflect a process of continuous plasticity, suggesting an increased rate of postnatal granule cell generation, the synthesis of a prenatal limbic maldevelopment with an ongoing process of plasticity might, therefore, supersede the hypothesis of a neurodegeneration in schizophrenia.

Impaired postnatal development of hippocampal neurons and axon projections in the Emx2-/- mutants.

The specification and innervation of cerebral subregions is a complex layer-specific process, primed by region-specific transcription factor expression and axonal guidance cues. In Emx2-/- mice, the hippocampus fails to form a normal dentate gyrus as well as the normal layering of principal neurons in the hippocampus proper. Here, we analyzed the late embryonic and postnatal development of the hippocampal formation and its axonal projections in mice lacking Emx2 expression in vitro. As these mutants die perinatally, we used slice cultures of Emx2 mutant hippocampus to circumvent this problem. In late embryonic Emx2-/- cultivated hippocampi, both the perforant path as well as the distribution of calretinin-positive cells are affected. Traced entorhinal afferents in co-cultures with hippocampus from embryonic Emx2-/- mice terminate diffusely in the prospective dentate gyrus in contrast to the layer-specific termination of co-cultures from wild-type littermates. In addition, in brain slice cultures from null mutants the presumptive dentate gyrus failed to develop its normal cytoarchitecture and mature dentate granule cells, including the lack of their mossy fiber projection. Our data indicate that Emx2 is essential for the terminal differentiation of granular cells and the correct formation of extrinsic and intrinsic hippocampal connections.

Developmental malformations in cerebral structures in "endogenous psychoses".

The last decades have revealed several structural deviances in patients with so called "endogenous psychoses". Reasonably well established are the enlargement of the lateral ventricles and subtle structural deficits in temporobasal and orbital frontal structures (hypofrontality) in a majority of schizophrenic patients. It is the aim of this investigation to examine the cytoarchitecture of these important central structures, namely the entorhinal region and the orbitofrontal cortex (Brodmann area 11) which have been under meticulous investigation in our laboratories over decades (for review: Beckmann, 2000).

Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality.

BACKGROUND: Previous studies using semiquantitative or qualitative techniques demonstrated abnormalities of positioning of clusters of neurons (pre-alpha cells) in the entorhinal cortex in schizophrenia, suggesting a developmental mechanism could contribute to the illness. Recent quantitative studies of laminar thickness and laminar cell counts have been less consistent, and several failed to replicate the finding. However, none of the quantitative studies focused on the position of the pre-alpha cell clusters. METHODS: To study pre-alpha cell position in detail, we examined the entorhinal cortex in serial sections from 21 control and 19 schizophrenic brains. Cluster position relative to the gray-white matter junction and cluster size were measured. RESULTS: Quantitative assessment of 1991 clusters indicated clusters were positioned relatively closer to the gray-white matter junction in the anterior half of schizophrenic entorhinal cortices. In addition, the size of clusters in males with schizophrenia was reduced. CONCLUSIONS: These results support the model of schizophrenia as an illness in which brain development is impaired. The findings in males with schizophrenia may indicate the presence of more severe pathology, or an additional pathogenic mechanism.

Interruptions of early cortical development affect limbic association areas and social behaviour in rats; possible relevance for neurodevelopmental disorders.

Deficits in social behaviour are found in several neuropsychiatric disorders with a presumed developmental origin. Adequate social behaviour may rely importantly on the associative integration of new stimuli with previously stored, related information. The limbic allocortex, in particular the entorhinal region, is thought to support this kind of processing. Therefore, in the present study, gestating dams were treated with methylazoxymethanol acetate (MAM) on one of gestational days nine to twelve, to interrupt neuronal proliferation in the entorhinal region of the developing foetuses. Effects of prenatal MAM administration on social behaviour were evaluated in adult animals. As the entorhinal cortex has been implicated by some studies in spatial memory, effects on this function were also investigated. Following the behavioural studies, brain morphology was screened for effects of MAM. Our results show moderate to severe social impairment in MAM-treated animals, depending on the exact timing of prenatal exposure. By contrast, spatial reference and working memory were not importantly affected in any group. Analysis of brain morphology in the MAM-treated offspring supported maldevelopment of the entorhinal cortex and revealed mild abnormalities also in some connected limbic and limbic affiliated structures, such as the perirhinal and ectorhinal cortex, the anterior cingulate cortex and the medial septum-diagonal band region. Findings are discussed with respect to entorhinal cortex function, and with regard to their relevance for psychiatric disorders with a putatively neurodevelopmental pathogenesis, such as schizophrenia.

Cytoarchitecture of the entorhinal cortex in schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether schizophrenia is associated with abnormalities in neuronal migration in the entorhinal cortex. METHOD: Nissl-stained sections through three cytoarchitectonic subdivisions of the entorhinal cortex were examined in postmortem brain specimens from 10 schizophrenic subjects and 10 matched normal comparison subjects. RESULTS: No qualitative differences in cytoarchitecture were observed between the schizophrenic and comparison subjects. CONCLUSIONS: These findings do not replicate previous reports of cytoarchitectural disturbances in the entorhinal cortex of schizophrenic subjects and thus fail to support the hypothesis of abnormal neuronal migration in schizophrenia.