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PubMed2001

Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia.

BACKGROUND: Cytokines demonstrate diverse actions in the brain and modulate systemic and central nervous system (CNS) responses to injury, infection, and inflammation. Cytokines in the CNS are elevated during infection and ischemia, two neurodevelopmental insults associated with increased schizophrenia risk. We hypothesize that cytokine-mediated neuronal injury during development may contribute to schizophrenia pathophysiology, causing subtle alterations in neuronal number and density. METHODS: We examined cytokine regulation of neuronal number in embryonic day 18 rat cortical cultures using MAP-2 immunohistochemistry. Mixed cultures derived from frontal cortex were fixed and stained after 48-hour exposure to the proinflammatory interleukin-1beta (IL-1beta), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha; 0, 10, 100, or 1000 units/mL). RESULTS: IL-1beta (maximum effect 35%) and IL-6 (maximum effect 29%) produced dose-dependent decreases in the number of cells (neurons) immunoreactive for MAP-2 antibody, suggesting decreased neuronal survival. TNF-alpha also tended to decrease MAP-2 immunostaining at the highest dose tested. CONCLUSIONS: Our data suggest a role for cytokines in the modulation of neuronal survival during neurodevelopment, a finding potentially relevant to schizophrenia pathophysiology. If cytokine-mediated neuronal injury proves to be a common response to gestational insults associated with increased schizophrenia risk, the pharmacologic modulation of these molecules may have clinical utility.

Animals↗

PubMed2002

Paracingulate morphologic differences in males with established schizophrenia: a magnetic resonance imaging morphometric study.

BACKGROUND: Our previous work on sulcal-gyral brain morphology in healthy volunteers revealed that males were characterized by greater cortical folding in the left versus right anterior cingulate cortex. Given the evidence showing an absence or reversal of normal anatomical asymmetries in patients with schizophrenia, the current study examined the anterior cingulate cortex sulcal-gyral patterns in patients with schizophrenia. METHODS: Using high-resolution magnetic resonance imaging, we examined anterior cingulate cortex surface morphology in a group of 55 patients with established schizophrenia and 75 healthy controls. All subjects were male and right-handed. Depending on the presence of a paracingulate sulcus and its antero-posterior extent, three types of anterior cingulate cortex sulcal patterns were identified: "prominent," "present," and "absent." Measures of overall cerebral hemispheric folding were used as independent variables and as covariates to ascertain the specificity of the findings to the anterior cingulate cortex. RESULTS: Examination of anterior cingulate cortex morphology showed that, compared with controls, patients with schizophrenia lacked the leftward anterior cingulate cortex sulcal asymmetry, which was explained by reduced folding in the left anterior cingulate cortex. These differences were over and above differences in cortical folding across the entire left hemisphere. CONCLUSIONS: These findings suggest that, in male patients with schizophrenia, there is a disturbance in the neurodevelopment of the left anterior cingulate cortex, as well as a more general aberration of left hemisphere development.

Adult↗

PubMed2003

Abnormal prefrontal cortex function during response inhibition in Turner syndrome: functional magnetic resonance imaging evidence.

BACKGROUND: Turner syndrome (TuS) arises from the partial or complete absence of one X chromosome. Although neuropsychological studies report impaired attentional function and response inhibition in TuS, the neural correlates of these cognitive problems are unknown. METHODS: Eleven female subjects with TuS and 11 individually matched normal control subjects were imaged using functional magnetic resonance imaging while performing a Go/NoGo task. RESULTS: Groups did not differ on accuracy or reaction time; however, the TuS group activated more in the bilateral superior and middle frontal gyri than control subjects. Control subjects did not activate more than the TuS group in any region. CONCLUSION: These findings suggest that female subjects with TuS compensate for executive dysfunction via recruitment of additional prefrontal cortex regions involved in inhibition, attention, and working memory, functions necessary for successful performance of Go/NoGo tasks. Elucidating brain function in TuS will advance our understanding of the influence of X-chromosome genes on neurodevelopment and brain function and contribute to planning future intervention strategies.

Adolescent↗

PubMed2003

Developmental abnormalities of the hippocampus in first-episode schizophrenia.

BACKGROUND: The human hippocampus becomes visible during the first trimester and folds to form the hippocampal fissure (HF) in the second trimester. The walls of this fissure fuse by 30 weeks, although small residual cavities can occur if development is disrupted. The primary purpose of this study was to determine if hippocampal fissures are evident in schizophrenia. A second goal was to assess the association between HF size and premorbid and clinical features of the illness. METHODS: Magnetic resonance imaging scans were obtained on 33 patients with first-episode schizophrenia and 19 healthy volunteers. Hippocampal fissures were measured using semi-automated procedures, and hippocampi were manually traced. Birth history and premorbid functioning were assessed using maternal report. RESULTS: Patients had a significantly larger mean HF volume and a nonsignificantly smaller hippocampal volume. Hippocampal fissure size was significantly associated with poor educational achievement and with anxiety-depression symptoms during the onset of illness. Smaller hippocampal size was associated with poor premorbid adjustment. CONCLUSIONS: Larger HF size and an association between low educational achievement and enlarged HFs suggest abnormal neurodevelopment in schizophrenia. The association between HF size and anxiety-depression symptoms suggests that hippocampal abnormalities underlying HF dilatation may be a predisposing factor for increased stress sensitivity.

Adult↗

PubMed1998

Further studies of elevated cerebrospinal fluid neuronal cell adhesion molecule in schizophrenia.

BACKGROUND: The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures. METHODS: CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects. RESULTS: CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found. CONCLUSIONS: Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment.

Adult↗

PubMed1998

Serotonergic basis of antipsychotic drug effects in schizophrenia.

Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. There are two reasons for the new emphasis: the tremendous success of the so-called "atypical" antipsychotic drugs (a common feature of which is their high affinity for specific 5-HT receptor subtypes); and the elucidation of a complex family of 5-HT receptors whose function and pharmacology is only beginning to be understood. This paper will review the evidence that pertains to the role of 5-HT in mediating antipsychotic drug effects. The interaction of dopamine and 5-HT systems will be reviewed, and the mechanisms of action of atypical antipsychotic drugs will be evaluated in this context. The impact of serotonin on neurodevelopment, and the involvement of serotonin in the psychotomimetic and psychotogenic properties of hallucinogens, will be discussed. Together, these facts will be placed into the context of changes in serotonergic function in schizophrenia.

Antipsychotic Agents↗

PubMed1999

Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective.

The history of psychiatric research is filled with widely accepted etiologic and pathophysiologic theories that eventually were proven wrong. The prevailing pathophysiologic theories of schizophrenia have emphasized the role of abnormal neurodevelopment in determining the onset and course of the illness. Relatively little attention has been paid to the role of neurodegenerative processes despite the clinical course of the illness and the fact that most patients experience varying degrees of behavioral and cognitive deterioration. This is partially due to the absence of clear histologic evidence of neurodegeneration, but may also be due to the narrow traditional conception of neurodegeneration that is generally employed. This article suggests that the rejection of a role for neurodegeneration in the pathophysiology of schizophrenia is unproven and may be premature. A wholly neurodevelopmental perspective of the illness imbues the illness with a pessimistic inevitability and therapeutic nihilism that may be unwarranted. This article reviews selectively a diverse body of evidence that is consistent with the hypothesis that schizophrenia involves a limited neurodegenerative process reflected by the psychotic symptoms and that is most active in the early stages of the illness. The evidence for this hypothesis comes from studies of premorbid status, illness course, symptomatology and treatment effects as well as neuroimaging and postmortem findings. Recent results from the latter interpreted in the context of molecular neurobiology suggest new pathophysiologic models.

Brain Diseases↗

PubMed2000

Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice.

Neural activity is crucial for cell survival and fine patterning of neuronal connectivity during neurodevelopment. To investigate the role in vivo of sodium channels (NaCh) in these processes, we generated knockout mice deficient in brain NaChalpha(II). NaChalpha(II)(-/-) mice were morphologically and organogenically indistinguishable from their NaChalpha(+/-) littermates. Notwithstanding, NaChalpha(II)(-/-) mice died perinatally with severe hypoxia and massive neuronal apoptosis, notably in the brainstem. Sodium channel currents recorded from cultured neurons of NaChalpha(II)(-/-) mice were sharply attenuated. Death appears to arise from severe hypoxia consequent to the brainstem deficiency of NaChalpha(II). NaChalpha(II) expression is, therefore, redundant for embryonic development but essential for postnatal survival.

Animals↗

PubMed2002

Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus.

Increasing evidence suggests that schizophrenia is a neurodevelopmental disorder with a progressive course characterized by worsening of symptoms and morphological alterations within the brain. This suggests that a neurodegenerative component may exist in schizophrenia. The role of brain-derived neurotrophic factor (BDNF) in neurodevelopment, cell viability and synaptic plasticity led to the investigation of BDNF as a potential candidate molecule in the pathophysiology of schizophrenia. BDNF mRNA was examined by in situ hybridization in the prefrontal cortex and hippocampus of animals with neonatal ibotenic acid lesions of the ventral hippocampus, a putative neurodevelopmental animal model of schizophrenia. Results demonstrate that animals with neonatal ibotenic acid lesions of the ventral hippocampus have reduced basal levels of BDNF mRNA. It is possible that alterations in this trophic factor render animals more susceptible to neurodegenerative insults.

Animals↗

PubMed2002

Alterations in septohippocampal cholinergic neurons resulting from interleukin-2 gene knockout.

Interleukin-2 (IL-2) has potent effects on acetylcholine (ACh) release from septohippocampal cholinergic neurons and trophic effects on fetal septal and hippocampal neuronal cultures. Previous work from our lab showed that the absence of endogenous IL-2 leads to impaired hippocampal neurodevelopment and related behaviors. We sought to extend this work by testing the hypotheses that the loss of IL-2 would result in reductions in cholinergic septohippocampal neuron cell number and the density of cholinergic axons found in the hippocampus of IL-2 knockout mice. Stereological cell counting and imaging techniques were used to compare C57BL/6-IL-2(-/-) knockout and C57BL/6-IL-2(+/+) wild-type mice for differences in choline acetyltransferase (ChAT)-positive somata in the medial septum and vertical limb of the diagonal band of Broca (MS/vDB) and acetylcholine esterase (AChE)-labeled cholinergic axons in hippocampal projection fields. IL-2 knockout mice had significantly lower numbers (26%) of MS/vDB ChAT-positive cell bodies than wild-type mice; however, there were no differences in striatal ChAT-positive neurons. Although AChE-positive axon density in CA1, CA3b, the internal, and external blades of the dentate gyrus did not differ between the knockout and wild-type mice, the distance across the granular cell layer of the external blade of the dentate gyrus was reduced significantly in IL-2 knockout mice. Further research is needed to determine whether these outcomes in IL-2 knockout mice may be due to the absence of central and/or peripheral IL-2 during brain development or neurodegeneration secondary to autoimmunity.

Animals↗

PubMed1998

Methylazoxymethanol acetate-induced abnormalities in the entorhinal cortex of the rat; parallels with morphological findings in schizophrenia.

It has been suggested repeatedly that the non-heritable factors in the pathogenesis of schizophrenia involve abnormalities of prenatal neurodevelopment. Furthermore, post-mortem studies show neuropathology of apparently developmental origin in the entorhinal cortex and other brain regions of schizophrenic subjects. In an attempt to model a developmental defect of the entorhinal region in the rat, cerebrocortical proliferation was briefly interrupted during its earliest stages, when the entorhinal area is thought to undergo major cell division. Specifically, the experimental set-up involved the administration of methylazoxymethanol acetate (MAM) on 1 of 4 consecutive days of embryonal development, from E9 to E12. Analysis of the forebrain in adult animals shows reduction of the entorhinal cortex in rats treated on each of these days. This effect shifts from lateral to medial divisions of the entorhinal cortex with later administration of MAM, following a known developmental gradient. Morphological consequences of MAM administration appear to be largely confined to the entorhinal cortex in the groups treated on E9 to E11, although slight reductions of the frontal and occipital neocortex were also observed in these animals. MAM treatment on E12 produces relatively more widespread damage, as reflected among other in a small reduction of brain weight. The described brain abnormalities are not accompanied by obvious phenotypical changes in any, but the E12-treated group. They, moreover, involve cortical thinning, disorganised cortical layering, and abnormal temporal asymmetries. These finding bare some similarity to observations in brains of schizophrenic subjects. The possible relevance of this approach in modeling neurodevelopmental aspects of schizophrenia is discussed.

Animals↗

PubMed1999

Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity.

Brain dysmorphogenesis and persistent psychomotor disturbances are hallmarks of developmental methylmercury (MeHg) exposure, but the molecular mechanisms underlying these effects are poorly understood. Targets of developmental MeHg exposure include neural cell adhesion molecules (NCAMs), sialoglycoconjugate molecules whose proper temporal and spatial expression is important at all stages of neurodevelopment and especially during synaptic structuring. To investigate the effects of MeHg on the temporal expression of NCAM during development, rat pups were dosed with 7.0 mg/kg MeHgCl (s.c.) on alternate days from postnatal days (PNDs) 3-13 and killed on PNDs 15, 30 and 60. Brain MeHg concentrations were determined in a subset of litters injected with CH(3)203Hg. Expression of NCAM180 protein and of NCAM180 polysialylation was examined in whole cerebellum homogenates, cerebellar synaptosomes and isolated cerebellar growth cones by Western blotting and immunocytochemical staining. NCAM sialyltransferase activity was assayed in preparations of purified Golgi apparatus from the cerebelli of rats treated in vivo, or following in vitro incubation with 0, 1, 2.5, or 7.5 microM MeHg for 2 h. At PND15, no change in NCAM180 protein expression was observed in any cerebellar preparations, but decreased polysialylation of NCAM180 was observed in cerebellar whole homogenates, synaptosomes and isolated growth cones. At PND30, both NCAM180 protein expression and NCAM180 polysialylation were elevated in whole homogenate preparations but not in synaptosomes. NCAM180 expression in MeHg-treated rats was similar to controls at PND60, 47 days after the last methylmercury administration. In vivo studies of cerebellar Golgi sialyltransferase activity revealed significant reductions in PND15 MeHg-treated rats as compared to controls, but no changes in sialyltransferase activity in PND30 and PND60 animals. In vitro experiments revealed decreasing sensitivity of cerebellar sialyltransferases to MeHg as the developmental age of the rat increased. Toxic perturbation of the developmentally-regulated expression of polysialylated NCAM during brain formation may disturb the stereotypic formation of neuronal contacts and could contribute to the behavioral and morphological disturbances observed following MeHg poisoning.

Animals↗

PubMed2005

SPECT findings in children with specific language impairment.

Findings from 99mTc-HMPAO SPECT measurements at rest in a group of 19 school-age children with specific language impairment (SLI) were compared to a group of 12 children with attention-deficit hyperactivity disorder (ADHD). The regional cerebral blood flow (CBF) distributions were different in the two groups. Children with SLI showed significantly lower CBF values in the right parietal region and in the subcortical region compared to the ADHD group. In addition, the SLI group had symmetric CBF distributions in the left and right temporal regions, whereas the ADHD group showed the usual asymmetry with left-sided hemispheric predominance in the temporal regions. The findings give further evidence for anomalous neurodevelopment with deviant hemispheric lateralization as an important factor in the aetiology of SLI. They also point to the role of subcortical structures in language impairment in childhood. Earlier focus on cortical structures in SLI research needs to be widened to include subcortical regions as well.

Adolescent↗

PubMedDate not supplied

[Biological models of schizophrenia: an update].

This paper is a review of the principal, currently proposed, biological models of schizophrenia. The convergence of recent neurobiological studies indicates that schizophrenia may be a neurodevelopmental and progressive disorder with multiple biochemical abnormalities involving dopamine, serotonin, glutamate and gamma-aminobutyric acidergic systems. In post-mortem tissue, structural abnormalities and alterations in synaptic connectivity have been observed in the intracortical circuitry of the prefrontal dorsal cortex. These morphological modifications could be sequelae of earlier environmental insults and genetic processes. There are probably multiple susceptibility genes, each of small effect, which act in conjunction with environmental factors: obstetric abnormalities, intra-uterine infection and abnormal nutrition. Candidate identified genes could influence neurodevelopment, synaptic plasticity and neurotransmission. If schizophrenia is clearly related to an abnormality of early brain development, the clinical expression of the illness itself is delayed typically for about two decades after birth. A similar delayed onset is also observed in the secondary psychosis associated with metachromatic leukodystrophy, a genetic disease affecting myelin. Schizophrenia is a term reserved for idiopathic cases of chronic psychosis. Strictly speaking, schizophrenia is a syndrome. There are no established laboratory tests, neuro-imaging studies, electrophysiological paradigms or neuropsychological testing batteries that can explicitly confirm this behavioural disorder to the exclusion of symptomatology: what physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms. The diagnosis criteria of the various DSM reflect the American psychiatrists' concern for establishing a consensus classification preserving a wider definition of schizophrenia or more precisely of the schizophrenic disorder. One can presume that research work established from too numerous and insufficiently specific variables doesn't permit the definition of one or several aetiologies. We hope that one day all schizophrenia will be correlated to one precise causal factor permitting the optimal targeting of interesting therapeutic approaches. The multiplicity of concepts and models reflects our questioning.

Dopamine↗

PubMed2002

In vitro vs in vivo Pb effects on brain protein kinase C activity.

Alteration of normal protein kinase C (PKC) function by environmental Pb exposure during neurodevelopment is hypothesized to be an important mechanism of toxicity underlying neurologic impairment. Previous studies have reported widely varying effects of Pb on PKC, possibly in part because of differences in in vitro and in vivo models used in those studies. Therefore, we tested the hypothesis that, with comparable tissue Pb levels, the effects of in vitro Pb exposure on brain PKC are the same as the effects caused by in vivo Pb exposure of intact animals. For chronic in vivo Pb exposure, female Long-Evans rats were exposed to Pb or vehicle from postnatal days 1 to 34-36 (n=10/treatment). For in vitro Pb exposure, homogenate of the frontal cortex region was exposed directly to Pb in an amount comparable to that accumulated in brain during chronic in vivo Pb exposure. Brain Pb levels were measured using ultraclean techniques and inductively coupled plasma mass spectrometry. PKC activity was subsequently determined in cytosolic and membrane subcellular fractions in the frontal cortex, hippocampus, and remaining brain regions. Results indicate that brain Pb levels following in vivo Pb exposure were increased approximately 20-fold above those of nonexposed animals (vehicle group [Pb] approximately 130ng Pb/g dry wt.). However, in vivo Pb exposure did not measurably alter brain PKC activity in the regions tested. In contrast, in vitro Pb exposure significantly increased PKC activity by approximately 20% in the frontal cortex homogenate membrane subcellular fraction. These results indicate that Pb added in vitro caused more dramatic effects than those produced by a comparable amount of Pb in the tissue from in vivo exposure. While the mechanisms underlying these outcomes are not clear, they suggest that in vitro models might not accurately reflect effects of chronic low-level in vivo Pb exposure.

Animals↗

PubMed2003

A retrospective case-control study of developmental and other outcomes in a cohort of Australian children conceived by intracytoplasmic sperm injection compared with a similar group in the United Kingdom.

OBJECTIVE: To investigate the possibility that children born after ICSI were at increased risk for neurodevelopmental delay. DESIGN: Retrospective case-control study. SETTING: IVF clinic. PATIENT(S): Fifty-eight singleton children born after ICSI and 38 normally conceived singleton children (controls), matched for relevant sociodemographic characteristics, from Australia and 208 case-patients and 221 controls from the United Kingdom. MAIN OUTCOME MEASURE(S): Antenatal and perinatal, and sociodemographic characteristics; physical health, including congenital abnormalities; and neurodevelopment by using the Griffiths scales of mental development. RESULT(S): Eighty-five percent of case-patients and 96% controls were assessed at a mean age of 13 months. Neurodevelopmental scores were similar in all children. Perinatal outcome was similar, apart from more caesarean sections in the case-patients. Rates of congenital anomalies were similar (5.6% among case-patients vs. 5.7% among controls). Children from fathers with oligozoospermia showed no extra problems. Children born after ICSI in the United Kingdom and Australia were similar. CONCLUSION(S): Children conceived after ICSI did not differ from their naturally conceived peers in physical health or development at ages up to 15 months.

Adult↗

PubMedDate not supplied

Anatomical risk factors that distinguish dyslexia from SLI predict reading skill in normal children.

UNLABELLED: These studies investigated whether anatomical measures could separate phonologically-based reading disability (PD) from nonphonologically-based learning disabilities such as specific language impairment (SLI). In a previous study. four brain measures (cerebral asymmetry. summed planum temporale and parietale asymmetry, anterior cerebellar asymmetry, and a duplicated left Heschl's gyrus) distinguished a group of PD adults from reading disabled adults without specific phonological deficits (URD). Study 1 found that these measures did not distinguish 14 reading disabled children from 21 children with SLI. Instead, differences were found in cerebral volume, planum temporale asymmetry, and the size of a single left Heschl's gyrus. Study 2 demonstrated that including all seven measures in a discriminant analysis separated the adults and children into two groups: one with 100% of the PD adults and 75% of the reading disabled children and the other with 72% of the SLI children and 75% of the URD adults. Study 3 demonstrated that an anatomical risk factor index (ARF7) generated from the discriminant function with seven brain measures predicted reading in normal children. Children with ARF7 near 0 (normal anatomy) had superior verbal ability and phonological decoding scores that improved with age. Normal children with negative ARF7 the relatively s mall symmetrical structures that characterize SLI)had deficits in verbal ability. Children with positive ARF7 (the asymmetrical structures that characterize PD) had phonological decoding scores that decreased with age. These results suggest that PD and SLI are qualitatively different disorders associated with anatomical deviations in opposite directions from the population mean. LEARNING OUTCOMES: As a result of this activity, the participant will be able to: (1) distinguish the neuroanatomical features that characterize PD and SLI; (2) recognize that PD is associated with large asymmetrical brain structures while SLI is associated with smaller symmetrical brain structures; (3) understand that children with moderate sized brains and whose anatomy is intermediate between symmetry and extreme asymmetry have an enhanced probability of developing good verbal ability; (4) understand that reading disabilities depend on the interaction of neurodevelopment and the environment.

Brain↗

PubMed1991

Is it correct to correct? Developmental milestones in 555 "normal" preterm infants compared with term infants.

To determine whether correction for preterm birth should be applied during developmental assessment, we conducted a prospective national survey of very premature infants (born at less than 32 weeks of gestation); neurodevelopment in the first 2 years was studied with the Dutch child health care developmental assessment. In 555 preterm children who had no evidence of handicap at 2 years of age, the age at which developmental milestones were reached was established. The results were compared with the results of the same assessment in Dutch children born at term. During the first year, the development of the very premature children equaled the development of normal children when full correction was applied. At 2 years of age, development was equal to or better than normal children's development without correction. We conclude that full correction for prematurity should be applied in the first year to avoid overreferral for developmental stimulation, whereas at 2 years of age correction is not necessary.

Age Factors↗