Neurodevelopmental Anomalies Research Articles

54: Prevention of the alcohol-induced changes in brain-derived neurotrophic factor expression using neuroprotective peptides in a model of fetal alcohol syndrome

ObjectiveFetal alcohol syndrome (FAS) is the most common non genetic cause of mental retardation; prenatal alcohol exposure affects the development of the nervous system. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is essential in normal neuronal development and survival as well as synaptic plasticity, an important factor in learning and memory. Previously, we have shown that prenatal treatment with neuroprotective peptides, NAP+SAL, prevented alcohol induced fetal anomalies and learning deficits. Our objective was to evaluate if NAP+SAL′s neuroprotective effects are mediated by preventing alcohol-induced changes in BDNF expression during embryonic development.Study DesignA well-characterized FAS model was used (Webster, 1980). Timed, pregnant C57BL6/J mice were treated on gestational day 8 (E8) with alcohol (0.03 mL/g), placebo or alcohol+peptides (20g, 30 min before alcohol). Embryos were harvested at 6h(E8), 24h(E9) and day 10(E18). Each sample included at least 3 embryos, representing at least 3 litters per time point. Calibrator-normalized relative real-time PCR was performed to quantify BDNF with HPRT1 standardization. Statistics included ANOVA and Fisher PLSD.ResultsConclusionNAP+SAL prevented alcohol-induced changes in BDNF expression 24h and 10 days after alcohol exposure. This may explain, at least in part, the peptides prevention of neurodevelopmental anomalies and learning deficits in fetal alcohol syndrome. ObjectiveFetal alcohol syndrome (FAS) is the most common non genetic cause of mental retardation; prenatal alcohol exposure affects the development of the nervous system. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is essential in normal neuronal development and survival as well as synaptic plasticity, an important factor in learning and memory. Previously, we have shown that prenatal treatment with neuroprotective peptides, NAP+SAL, prevented alcohol induced fetal anomalies and learning deficits. Our objective was to evaluate if NAP+SAL′s neuroprotective effects are mediated by preventing alcohol-induced changes in BDNF expression during embryonic development. Fetal alcohol syndrome (FAS) is the most common non genetic cause of mental retardation; prenatal alcohol exposure affects the development of the nervous system. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is essential in normal neuronal development and survival as well as synaptic plasticity, an important factor in learning and memory. Previously, we have shown that prenatal treatment with neuroprotective peptides, NAP+SAL, prevented alcohol induced fetal anomalies and learning deficits. Our objective was to evaluate if NAP+SAL′s neuroprotective effects are mediated by preventing alcohol-induced changes in BDNF expression during embryonic development. Study DesignA well-characterized FAS model was used (Webster, 1980). Timed, pregnant C57BL6/J mice were treated on gestational day 8 (E8) with alcohol (0.03 mL/g), placebo or alcohol+peptides (20g, 30 min before alcohol). Embryos were harvested at 6h(E8), 24h(E9) and day 10(E18). Each sample included at least 3 embryos, representing at least 3 litters per time point. Calibrator-normalized relative real-time PCR was performed to quantify BDNF with HPRT1 standardization. Statistics included ANOVA and Fisher PLSD. A well-characterized FAS model was used (Webster, 1980). Timed, pregnant C57BL6/J mice were treated on gestational day 8 (E8) with alcohol (0.03 mL/g), placebo or alcohol+peptides (20g, 30 min before alcohol). Embryos were harvested at 6h(E8), 24h(E9) and day 10(E18). Each sample included at least 3 embryos, representing at least 3 litters per time point. Calibrator-normalized relative real-time PCR was performed to quantify BDNF with HPRT1 standardization. Statistics included ANOVA and Fisher PLSD. Results ConclusionNAP+SAL prevented alcohol-induced changes in BDNF expression 24h and 10 days after alcohol exposure. This may explain, at least in part, the peptides prevention of neurodevelopmental anomalies and learning deficits in fetal alcohol syndrome. NAP+SAL prevented alcohol-induced changes in BDNF expression 24h and 10 days after alcohol exposure. This may explain, at least in part, the peptides prevention of neurodevelopmental anomalies and learning deficits in fetal alcohol syndrome.

MRI study of the cavum septum pellucidum in obsessive–compulsive disorder

The cavum septum pellucidum (CSP), a putative marker of neurodevelopmental anomaly, has been associated with an increased risk of several psychiatric disorders. The purpose of this study was to evaluate the CSP in patients with obsessive-compulsive disorder (OCD) compared with healthy control subjects. Seventy-one patients with OCD and 71 healthy volunteers matched for age and sex were evaluated with magnetic resonance imaging. We evaluated the CSP using criteria employed in previous studies: presence of the CSP, length of the CSP, and overall size of the CSP, measured in five grades, ranging from grades 0 (no CSP) to 4 (severe CSP). We evaluated OCD symptom severity using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The CSP presence was significantly greater in the OCD group (60.6%) than in control subjects (29.6%), and CSP size grade was significantly larger in the OCD group (chi(2) = 15.609, P = 0.004). CSP length showed no significant group difference. Among patients with OCD, those with a CSP had higher scores on the obsession subscale of the Y-BOCS than those without a CSP (Z = -2.358, P = 0.018), while they did not show significant difference from those without a CSP in the compulsion subscale of the Y-BOCS, age, duration of illness, or age at onset. These results indicate that neurodevelopmental alterations in midline structures might contribute to the pathogenesis of OCD.

Mechanistic Approach to Understanding Psychosis Risk in Velocardiofacial Syndrome

Velocardiofacial syndrome (VCFS), the most common chromosomal microdeletion syndrome in humans, is caused by a heterozygous deletion of chromosome 22q11.2. With an incidence of 1/2000-1/6000, it is associated with a vast array of abnormalities such as congenital heart disease, palatal dysfunction, immune deficiency, hypoparathyroidism and cognitive impairment. In addition to the numerous medical and developmental problems, retrospective studies in the last decade have reported a markedly high incidence (∼ 40%) of schizophrenia, bipolar disorder and depression in late adolescence and adulthood in individuals with the deletion. This risk of schizophrenia spectrum disorders in VCFS approaches that of a monozygotic twin of a patient with schizophrenia, or that of an individual with both parents with schizophrenia. These observations provide the strongest known link between psychosis and an identified genetic condition. In recent years, schizophrenia has been viewed as a neurodevelopmental disorder. This neurodevelopmental theory suggests that neurocognitive and neuroanatomical abnormalities often precede the development of overt psychosis. Genetic factors are thought to be contributory to these neurodevelopmental anomalies that are thought to ultimately culminate in schizophrenia spectrum disorders. However, gene identification has largely been unsuccessful, due to the complex nature of the inheritance of the genes and the probability that multiple genes of individual modest effect are involved. Identification of predisposing genetic markers would enable identification of a high-risk group that would enable the prospective study of the factors contributing to psychosis. The presence of a known genetic abnormality that causes neurodevelopmental deficits, confers a high-risk of psychosis and since the signs, symptoms and response to treatment of schizophrenia secondary to VCFS are thought to be no different to that in primary schizophrenic illness, it has been suggested that VCFS represents an ideal model for the study of the factors contributing to schizophrenia. This article delineates the current understanding of the psychological and psychiatric findings, brain morphometric abnormalities and genetic studies in VCFS and their relevance to schizophrenia spectrum disorders.

Not for the eyes only: PAX6 and glucose metabolism

Paired box 6 (PAX6) is a member of the PAX multigene family of transcription factors: this family regulates embryonic differentiation. Nine unlinked PAX genes dispersed throughout the genome encode proteins that each include a 128-amino-acid sequence-specific highly conserved DNA-binding domain, the Paired box, which can regulate the expression of other genes [1]. PAX6 also contains another common DNA-binding element: the homeobox that encodes a 60-amino-acid homeodomain responsible for target sequence recognition [2]. The paired domain and homeodomain interact cooperatively to recognise multiple DNA binding sites [3]. Pax6 is expressed in the developing nervous system and in developing eyes [4], and also has important functions in the development of the endocrine pancreas. Genetic studies indicate that all eyes share a similar developmental cascade: mutations in Pax6 disrupt eye development in both mammals and insects [4]. Pax6 appears to be necessary for the correct execution of beta cell differentiation [5] and is essential for the normal expression of insulin [6]. PAX6 is required for the differentiation of pancreatic islet alpha cells, and competes with PAX4 in binding to a common element in the glucagon, insulin and somatostatin promoters [7]. Mice lacking both Pax4 and Pax6 fail to develop any mature endocrine cells, suggesting that both genes are required for endocrine development of the pancreas [8]. As well as binding to a common element in the glucagon, insulin and somatostatin promoters, Pax6 also transactivates the glucagon and insulin promoters [6]. Pax6-deficient mice have reductions in both insulinand glucagon-expressing cells. Human PAX6 is transcribed as a 2.7 kb mRNA and encodes a 422-amino-acid protein. PAX6 extends to over 22 kb: it contains 14 exons and intron sequences and is highly conserved among vertebrates and lower animals. Mutations in PAX6 in humans cause aniridia type II, a bilateral panocular disorder characterised by a complete or partial absence of the iris and fovea, and malformations of the lens and anterior chamber [2]. About one-third of the cases are sporadic and two-thirds are familial, with autosomal dominant inheritance and high penetrance. There is a PAX6 dosage effect in aniridia, ranging from mild loss of visual acuity and cataracts, to severe nervous system defects and anophthalmia [7]. Using magnetic resonance imaging techniques and smell testing, Sisodiya et al. [9] showed with that reduced olfaction was present in a large proportion of aniridia patients, indicating that PAX6 haploinsufficiency causes more widespread human neurodevelopmental anomalies. Yasuda et al. [10] were the first to demonstrate that carriers of the PAX6 mutation might have abnormal glucose Diabetologia (2009) 52:381–384 DOI 10.1007/s00125-008-1251-1

Oxoguanine Glycosylase 1 Protects Against Methamphetamine-Enhanced Fetal Brain Oxidative DNA Damage and Neurodevelopmental Deficits

In utero methamphetamine (METH) exposure enhances the oxidative DNA lesion 7,8-dihydro-8-oxoguanine (8-oxoG) in CD-1 fetal mouse brain, and causes long-term postnatal motor coordination deficits. Herein we used oxoguanine glycosylase 1 (ogg1) knock-out mice to determine the pathogenic roles of 8-oxoG and OGG1, which repairs 8-oxoG, in METH-initiated neurodevelopmental anomalies. Administration of METH (20 or 40 mg/kg) on gestational day 17 to pregnant +/- OGG1-deficient females caused a drug dose- and gene dose-dependent increase in 8-oxoG levels in OGG1-deficient fetal brains (p < 0.05). Female ogg1 knock-out offspring exposed in utero to high-dose METH exhibited gene dose-dependent enhanced motor coordination deficits for at least 12 weeks postnatally (p < 0.05). Contrary to METH-treated adult mice, METH-exposed CD-1 fetal brains did not exhibit altered apoptosis or DNA synthesis, and OGG1-deficient offspring exposed in utero to METH did not exhibit postnatal dopaminergic nerve terminal degeneration, suggesting different mechanisms. Enhanced 8-oxoG repair activity in fetal relative to adult organs suggests an important developmental protective role of OGG1 against in utero genotoxic stress. These observations provide the most direct evidence to date that 8-oxoG constitutes an embryopathic molecular lesion, and that functional fetal DNA repair protects against METH teratogenicity.

Recognition and Prevention of Major Mental and Substance Use Disorders

Back to table of contents Previous article Next article Book ReviewFull AccessRecognition and Prevention of Major Mental and Substance Use DisordersTimothy B. Sullivan M.D.Timothy B. Sullivan M.D.Search for more papers by this authorPublished Online:1 Oct 2007https://doi.org/10.1176/ps.2007.58.10.1379aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Ming Tsuang has been a luminary in the field of psychiatric research for more than 35 years. He has contributed greatly to our knowledge of psychiatric epidemiology, nosology, genetics, and etiology. In this text he has concentrated the work of research teams focused on a goal that clinicians must imagine to be unreachable: the possibility of intervening to prevent the development of major psychiatric disorders.The title of this work is provided by a pivotal research project—detailed in the critical central section on schizophrenia research—the Hillside Recognition and Prevention Program. Data from this series of studies has identified the presence and importance of prodromal neurocognitive deficits among persons with schizophrenia and the possibility of early treatment in selected populations. This program has also challenged preconceptions, for example, by demonstrating that antidepressants may be as effective as antipsychotics in ameliorating the course of schizophrenia among at-risk individuals.In one chapter, Barbara Cornblatt and her coauthors discuss the ethics of the Hillside research design, its limitations, and why they and others think that prevention of schizophrenia is possible. This latter issue engenders a review of a changing perspective in schizophrenia research, which accords less importance to Kraepelin's century-old postulate that schizophrenia is primarily a neurodegenerative disorder, instead viewing the illness as neurodevelopmental with multiple variables and markers of risk. It is the presence of those markers, and the possibility of intervention to influence susceptibility to "triggers" among persons at risk because of neurodevelopmental anomalies, that has excited interest in this topic.Tsuang's group adds a chapter on this subject in which they review more than 20 years of their research. In addition to discussing their family studies that describe characteristic neurocognitive and behavioral abnormalities or markers, Tsuang and his colleagues detail the molecular genetics and neurophysiology of schizophrenia. This fascinating research is the underpinning of our clinical psychopharmacology and adumbrates the direction of future clinical practice.Introductory chapters review etiological risk factors, including genetic determinants and general environmental influences, and a thought-provoking chapter focuses on the role of the social environment in the development of major mental illnesses. Other chapters review the work of various authors, focusing on important contributors in matters relating to the themes of vulnerability and prevention.The term "recognition" in the title does not imply a review of research on diagnostic tools or strategies, which I had mistakenly anticipated. The contributors here are principally concerned with identifying vulnerability markers, which may then suggest therapeutic targets, especially in the prodromal context.I found this to be an intriguing book, helpfully focusing a large body of work that I would not likely otherwise have been able to digest. The articles are clearly written, in the main, and with mindfulness of the audience, which includes clinicians not familiar with the details of much of the basic science recounted here. It is a commendably useful text, to be read for its evident importance to our understanding of a critical and expanding area of investigation.Dr. Sullivan is chief of services for the seriously mentally ill at Saint Vincent's Catholic Medical Center in Westchester, New York, and assistant professor of psychiatry at New York Medical College in Valhalla. FiguresReferencesCited byDetailsCited byNone Volume 58Issue 10 October, 2007Pages 1379-1380PSYCHIATRIC SERVICES October 2007 Volume 58 Number 10 Metrics PDF download History Published online 1 October 2007 Published in print 1 October 2007

In vivo evidence for early neurodevelopmental anomaly of the anterior cingulate cortex in bipolar disorder

Anterior cingulate cortex (ACC) abnormalities are commonly reported in studies of patients with bipolar disorder (BD), but it is unclear whether these precede or follow illness onset. We investigated the evidence for early neurodevelopmental anomalies in the ACC and adjacent paracingulate cortex (PaC) of BD patients by studying cortical folding patterns of the region. Magnetic resonance images were acquired from 54 BD patients and 116 healthy controls. Cortical folding patterns were assessed by classifying the incidence of the paracingulate sulcus (PCS) and interruptions in the course of the cingulate sulcus (CS). Patients were significantly less likely to show a PCS bilaterally. There were no differences in the frequency of CS interruptions. The bilateral reduction observed in our patient sample implicates aberrant pre- or peri-natal developmental processes. To our knowledge, this is the first in vivo evidence for early neurodevelopmental anomaly of the ACC/PaC region in BD.

Heterotaxia, Congenital Heart Disease, and Primary Ciliary Dyskinesia

The human heart is strikingly asymmetrical along the left-right body axis. If one begins with the position of the heart in the left chest, continues through asymmetrical venous drainage into the atria and asymmetrical orientation of the 2 anatomically and functionally distinct ventricles, and finally proceeds through the highly asymmetrical coil of semilunar valves and great vessels, the structure and function of the human heart are precisely aligned to the left-right axis. When cardiac asymmetries either fail to develop or align incorrectly relative to each other or relative to other organs, a plethora of congenital heart disease results. This group of heart diseases is called heterotaxy syndrome and represents both a difficult clinical challenge and a fascinating window into the biology underlying one of the most fundamental embryological processes, namely, the mechanism by which an organism establishes the 3 body axes. Positioning of organs along the left-right axis can be divided into 3 broad classes: situs solitus, in which all organs are positioned normally; situs inversus, in which there is mirror image reversal of all organs; and heterotaxy, in which there is any positioning of organs along the left-right axis differing from situs solitus and situs inversus (Figure). Pure situs inversus is found in 1 of 8500 in the general population and is usually not associated with intracardiac defects. In contrast, heterotaxy has a high degree of association with intracardiac defects. It has a reported incidence of 1 of 10 000 and is associated with at least 3% of cases of congenital heart disease.1 The anatomic spectrum of organ laterality. A, Situs solitus. B, Right atrial isomerism. The liver is midline, there are 2 eparterial bronchi, the position of the stomach and cardiac apex is indeterminate, and there is asplenia. C, Left atrial isomerism. The liver is midline, there …

Neuroimaging and emerging psychotic disorders: The Melbourne ultra-high risk studies

Although the underlying neurobiology of emerging psychotic disorders is not well understood, evidence from structural imaging and other studies support the notion that schizophrenia arises as a consequence of both an ‘early neurodevelopmental’ disturbance, as well as ‘late neurodevelopmental’ changes occurring during the initial stages of a psychotic illness, including around the time of transition to illness. In line with this, our longitudinal MRI findings in individuals at ultra-high risk for developing a psychotic illness show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal lobe regions. In a further series of longitudinal studies in first-episode psychosis, we have identified changes in prefrontal regions that indicate an accelerated loss of grey matter in patients compared to healthy control subjects. We suggest that the available evidence is consistent with the presence of subtle regionally and temporally specific neurobiological changes through the course of psychosis (Pantelis et al., ), including: (1) evidence for early (pre- and peri-natal) neurodevelopmental anomalies, (2) evidence for progressive grey matter loss involving medial temporal and orbital prefrontal regions around the time of transition to illness, and (3) evidence of late (post-pubertal) neurodevelopmental changes soon after the onset of psychosis, involving an acceleration of normal brain maturational processes, associated with significant loss of grey matter in dorsal prefrontal regions. The pathological processes underlying such changes remain unclear and may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. These findings suggest that early markers of impending illness may prove difficult to define, and that brain changes in psychosis may better be conceptualized as anomalous trajectories of brain development. Further, active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.

Alcohol-induced learning deficits are not prevented through GABA-A3

Fetal Alcohol Syndrome (FAS) is characterized by neurodevelopmental anomalies and life-long learning impairment. In a model for FAS we showed that prenatal treatment with neuroprotective peptides (NAP+SAL) prevented alcohol-induced learning deficits. We evaluated the role of GABA receptor as a potential mechanism for the peptide neuroprotection. The GABA-Aβ3 subunit is important for learning and is increased after alcohol exposure in the adult. We were interested in evaluating whether prenatal alcohol exposure affects GABA-Aβ3 and if the peptides mechanism of action for preventing alcohol-induced learning deficits includes the subunit.

La schizophrénie à début précoce : caractéristiques cliniques et endophénotypiques

Early onset schizophrenia is commonly considered as severe, resistant to treatment, and associated with a poor prognosis. It offers an interesting field of research for the neuro-developmental theory of schizophrenia, which hypothesises a link between some neuro-developmental markers such as physical and neurological anomalies, morphological brain abnormalities, and specific cognitive disturbances, with the existence of a vulnerability to a further occurrence of schizophrenic disorders. These markers, proved to be more common in schizophrenic patients, are considered by some authors as endophenotypes of schizophrenia. The objective of this study was to specify the clinical and endophenotypical features of early-onset schizophrenia. A comparative study was carried out on two groups of patients with schizophrenia according to DSM-IV criteria, who were systematically recruited from the outpatient clinic of psychiatry of the University Hospital of Monastir during the second semester of 2003. Patients who did not meet exclusion criteria (age over 50 years at study time, age of onset between 15 and 20, medical history of cranial trauma, evidence of cerebral disorders or mental retardation, addiction to alcohol or to psychoactive substances) were divided into 2 groups: Group I : onset before the age of 14 (N = 15). With a mean age at the time of the study of 20.8 ± 8.1 years and a gender distribution of 8 male vs 7 female patients; and Group II : onset after the age of 20 ( N = 35), with a mean age at the time of the study of 34.6 ± 6.2 years and a predominance of male patients (80 %). The following tests were administered to both groups: Positive and Negative Syndrome Scale (PANSS), Evaluation of Global Functioning (EGF), Clinical Global Impressions (CGI), Minor Physical Anomalies Scale (MPAS) and Neurological Soft Signs (NSS). In the early-onset schizophrenia group, the disorganised subtype was predominant (60 %), in the second group the paranoid subtype was the most frequent (43 %) ( P = 0.2). The severity of the disorder and of psychotic symptoms were more important in the early-onset schizophrenia group. Negative symptoms were predominant in group I (PANSS negative score = 30.6 ± 10.1 vs 24.9 ± 8.4 in group II) ( P = 0.04). The physical and the neurological anomalies were more frequent in the early-onset group, with a total score of MPAS of 5.8 ± 2.8 vs 4.2 ± 2.4 ( P = 0.04), and a score of NSS at 24.5 ± 6.1 vs 19.6 ± 5.4 ( P = 0.006) respectively. These results show neurodevelopmental anomalies to be more common in early-onset schizophrenia, which could be interpreted as an association between early damages to the brain and occurrence of severe and early forms of schizophrenia. These findings highlight the probability of neurodevelopmental determinism in schizophrenia.

Schizophrenia and diabetes: Epidemiological data

The association of diabetes mellitus and mental illness, in particular, schizophrenia, has been remarked upon for over a century. Recentepidemiological studies have shown the age- and sex-matched prevalence of diabetes in patients with schizophrenia to be 1.5–2 times those in the general population. This difference is particularly noticeable in younger patients. The explanation for this finding probably resides in both environmental and biological factors. Patients with schizophrenia tend to be sedentary and have a poor diet, which are both known risk factors for diabetes. However, familial studies have indicated a heritable component to the risk of diabetes in patients with schizophrenia. A number of biological mechanisms have been proposed to explain this, including neuroendocrine changes and neurodevelopmental anomalies, but none are entirely satisfactory. In addition, it has been suggested that treatment with antipsychotic medication may potentially increase the risk of diabetes and account for some of the increased prevalence seen in patients with schizophrenia. It has been suggested that different antipsychotic drugs may differ in their ability to facilitate the emergence of poor glycaemic control in patients with schizophrenia. However, the situation is far from clear and more work is required to accurately assess the potential risk associated with different antipsychotic drugs.

Developing Therapeutics for Schizophrenia and Other Psychotic Disorders

Although the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the disease and target the same for revolutionary disease modifying therapy. This postulate is based on recent studies that have begun to provide a testable etiopathology model that integrates interactions between genetic vulnerability factors, neurodevelopmental anomalies, and neurotransmitter systems. This review begins with a brief overview of the nosology and etiopathology of schizophrenia and related psychotic disorders to establish a context for subsequent detailed discussions on drug discovery and development for psychotic disorders. Particular emphasis is placed on recent advances in genetic association studies of schizophrenia and how this can be integrated with evidence supporting neurodevelopmental abnormalities associated with the disease to generate a testable model of the disease etiopathology. An in-depth review of the plethora of new targets and approaches targeting the unmet medical need in the treatment of schizophrenia exemplify the challenges and opportunities in this area. We end the review by offering an approach based on emerging genetic, clinical, and neurobiological studies to discover and validate novel drug targets that could be classified as disease modifying approaches.

Morphological differences among cavum septi pellucidi obtained in patients with schizophrenia and healthy individuals: Forensic implications. A post‐mortem study

Cavum septi pellucidi (CSP), especially when longer than 6 mm, has been recognized as a neurodevelopmental anomaly associated with schizophrenia. The present post-mortem study was designed to determine the importance of linear parameters of CSP and to evaluate the possible differences of CSP in schizophrenic patients (n=25 out of 110 CSP+ brains) and normal persons (n=40 out of 110 CSP+ brains). According to our results, schizophrenia patients had significantly longer and wider CSP than normal individuals. Also, statistical analysis revealed a higher suicide rate in CSP-positive patients with schizophrenia.

L’hypothèse neurodéveloppementale dans la schizophrénie

The hypothesis for a neurodevelopmental basis to the underlying physiopathological disorder leading to schizophrenia has been proposed by many investigators for more than two decades. This hypothesis is supported by -several lines of evidence. Pregnancy and delivery complications, particularly those with known or presumed impact on fetal neurologic development, result in increased risk for psychotic disorders. Other possible etiologic candidates include viral infections. Minor physical anomalies, manifesting as slight anatomical defects of the head, hair, eyes, mouth, hands and feet, as dematoglyphic fluctuating asymmetries, are due to some injury occurring during the first or second trimester of fetal life, and are more common among patients with schizophrenia and in their unaffected siblings than in the general population. But a major Issue in a such neurodevelopmental model theory is the delayed onset of the schizophrenic disorder. Although early signs and prodromal symptoms can be defined retrospectively in patients who have developed schizophrenia, they do have to be confirmed as early predictors in prospective and longitudinal studies. Abnormalities in brain development and maturation seem to begin prenatally, but may continue throughout childhood and the observed changes during these periods must have -consequences for the neuronal circuitry and connectivity. Advances in brain imaging have now led to the identification of a great number of brain abnormalities in schizophrenia. The most consistently replicated structural anomaly present in the brains of patients with chronic schizophrenia is ventricular enlargement. These findings also include medial temporal lobe structures (which include the amygdala, hippocampus, and parahippocampal gyrus), and neocortical temporal lobe regions (superior temporal gyrus). There is also some evidence for frontal lobe abnormalities, particularly prefrontal gray matter and orbitofrontal regions. Similarly, there are findings for parietal lobe abnormalities (particularly of the inferior parietal lobule which includes both supramarginal and angular gyri) and subcortical abnormalities (basal ganglia, corpus callosum, and thalamus) but more equivocal evidence for cerebellar abnormalities. However, it is possible that the brain structural abnormalities observed in schizophrenia are not only due to neurodevelopmental anomalies, but also to an alteration in cortical plasticity and maturation processes that occurs over the long course of the disease. The genetic predisposition for schizophrenia has been confirmed in many studies. It is utterly disappointing that molecular genetic approaches have so far not yielded conclusive evidence for vulnerability or protection genes in schizophrenia. Future studies will likely benefit from: 1) studying more homogeneous patient groups, 2) studying high risk populations such as biological relatives of patients with schizophrenia, 3) using longitudinal and prospective methodological design in order to confirm the predictive validity of neurodevelopmental clues found in patients with schizophrenia, 4) applying newer strategies such as composite phenotypes of developmental origin, in combination with new genetic methods.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review.

Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 2001: 3: 106 150. C Munksgaard, 2001 To present a comprehensive review of the existing neuropsychological and neuroimaging literature on bipolar affective disorder. This review critically evaluates two common conceptions regarding the neuropsychology of bipolar disorder: 1) that, in contrast to schizophrenia, bipolar affective disorder is not associated with general cognitive impairment independent of illness episodes, and 2) relative right hemisphere (RH) dysfunction is implicated in bipolar illness patients, supported by reports of relatively greater impairment in visuospatial functioning, lateralization abnormalities, and mania secondary to RH lesions. The major computerized databases (Medline and PSYCInfo) were consulted in order to conduct a comprehensive, integrated review of the literature on the neuropsychology and neuroanatomy of bipolar disorder. Articles meeting specified criteria were included in this review. In a critical evaluation of the above notions, this paper determines that: 1) while there is little evidence for selective RH dysfunction, significant cognitive impairment may be present in bipolar illness, particularly in a subgroup of chronic, elderly or multiple-episode patients, suggesting a possible toxic disease process, and 2) the underlying functional correlate of these cognitive deficits may be white matter lesions ('signal hyperintensities') in the frontal lobes and basal ganglia, regions critical for executive function, attention, speeded information processing, learning and memory, and affect regulation. While this hypothesized neural correlate of cognitive impairment in bipolar disorder is speculative, preliminary functional neuroimaging evidence supports the notion of frontal and subcortical hypometabolism in bipolar illness. The etiology of the structural brain abnormalities commonly seen in bipolar illness, and their corresponding functional deficits, remains unknown. It is possible that neurodevelopmental anomalies may play a role, and it remains to be determined whether there is also some pathophysiological progression that occurs with repeated illness episodes. More research is needed on first-episode patients, relatives of bipolar probands, and within prospective longitudinal paradigms in order to isolate disease-specific impairments and genetic markers of neurocognitive function in bipolar disorder.

Perspectives in pediatric neurosurgery.

The new millennium beckons for novel advances in the diagnosis and treatment of pediatric neurosurgical conditions. Almost every aspect of pediatric neurosurgery has changed over the last decade. Undoubtedly with the application of knowledge in molecular biology to human disease many aspects of neurosurgery, especially neuro-oncology and the field of neuro-developmental anomalies, will change appreciably over the next decade. Overall, the trend in surgery in general and neurosurgery in particular is toward less invasive procedures and possibly non-surgical interventions. This review will briefly cover many of the important areas of pediatric neurosurgery. We will describe the state-of-the-art of our subspecialty and discuss possible future directions.

Enlarged Cavum Septi Pellucidi in Patients With Schizophrenia: Clinical and Cognitive Correlates

Enlarged cavum septi pellucidi (CSP) is a neurodevelopmental anomaly that has been associated with schizophrenia. This study was designed to evaluate, in patients with schizophrenia, the relationship between the severity of this anomaly and measures of symptom and cognitive skills. Three groups were used: patients with large CSP (n=14), patients without large CSP (n=14), and healthy control subjects (n=14). In patients with large CSP, a significant, inverse relationship was found between size of CSP and measures of cognitive deficit. Thus, the greater the size of the anomaly, the greater the cognitive deficit. No relationship was found between severity of CSP and symptom measures.

Enlarged cavum septi pellucidi in patients with schizophrenia: clinical and cognitive correlates.

Enlarged cavum septi pellucidi (CSP) is a neurodevelopmental anomaly that has been associated with schizophrenia. This study was designed to evaluate, in patients with schizophrenia, the relationship between the severity of this anomaly and measures of symptom and cognitive skills. Three groups were used: patients with large CSP (n=14), patients without large CSP (n=14), and healthy control subjects (n=14). In patients with large CSP, a significant, inverse relationship was found between size of CSP and measures of cognitive deficit. Thus, the greater the size of the anomaly, the greater the cognitive deficit. No relationship was found between severity of CSP and symptom measures.