The Neurodevelopmental Hypothesis of Schizophrenia, Revisited

While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.     

Integrated Care Pathways for Schizophrenia: A Scoping Review

This paper summarizes the existing evidence for integrated care pathways (ICPs) for the treatment of schizophrenia. Scoping review methods following PRISMA guidelines were employed due to the variable nature of the evidence in this area. The review identified 13 papers. Of these papers, 7 focused on describing ICP content and process-related data and 6 examined clinical outcomes. Of the 6 studies providing outcome data, 2 reported improved outcomes associated with ICPs. Conceptually, ICPs hold great promise for improving the quality of schizophrenia care. However, in contrast with other specialty healthcare domains, the schizophrenia ICP evidence base is very limited and has not fulsomely begun to address ICPs for effectiveness.     

Neurodevelopmental and Neurodegenerative Models of Schizophrenia: White Matter at the Center Stage

Schizophrenia is a disorder of cerebral disconnectivity whose lifetime course is modeled as both neurodevelopmental and neurodegenerative. The neurodevelopmental models attribute schizophrenia to alterations in the prenatal-to-early adolescent development. The neurodegenerative models identify progressive neurodegeneration as its core attribute. Historically, the physiology, pharmacology, and treatment targets in schizophrenia were conceptualized in terms of neurons, neurotransmitter levels, and synaptic receptors. Much of the evidence for both models was derived from studies of cortical and subcortical gray matter. We argue that the dynamics of the lifetime trajectory of white matter, and the consistency of connectivity deficits in schizophrenia, support white matter integrity as a promising phenotype to evaluate the competing evidence for and against neurodevelopmental and neurodegenerative heuristics. We develop this perspective by reviewing normal lifetime trajectories of white and gray matter changes. We highlighted the overlap between the age of peak of white matter development and the age of onset of schizophrenia and reviewed findings of white matter abnormalities prior to, at the onset, and at chronic stages of schizophrenia. We emphasized the findings of reduced white matter integrity at the onset and findings of accelerated decline in chronic stages, but the developmental trajectory that precedes the onset is largely unknown. We propose 4 probable lifetime white matter trajectory models that can be used as the basis for separation between the neurodevelopmental and neurodegenerative etiologies. We argue that a combination of the cross-sectional and longitudinal studies of white matter integrity in patients may be used to bridge the neurodevelopment and degeneration heuristics to advance schizophrenia researchKey words: white matter integrity, etiology of schizophrenia, diffusion tensor imaging     

Endogenous Cell Type–Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders

Background

Disrupted in schizophrenia 1 (DISC1) has been implicated in a number of psychiatric diseases along with neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed toward understanding the function of DISC1 through the determination of its protein-protein interactions within an in vitro setting, endogenous interactions involving DISC1 within a cell type–specific setting relevant to neural development remain unclear.

Hierarchical Pathways from Sensory Processing to Cognitive,Clinical, and Functional Impairments in Schizophrenia

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.     

Neurodevelopmental toxicology

The fields of neurotoxicology and developmental toxicology are exploding in research and interest. Much of the data currently known are from epidemiologic human studies or studies of animal models. Each of these modes is difficult to translate to individual clinical encounters. It is often difficult to state with certainty which of the numerous chemical or physical agents in our environment are neurotoxic. Basic scientists will help with advances in molecular biology and toxicology. Improved clinical understanding of these issues may help patients to understand the medical issues; allay feelings of anxiety, guilt, or fear; and avoid unnecessary testing. For exposures that manifest as threshold phenomena, such as lead, the risk to society is even greater than to an individual. Individual risk may be less of a concern than the population's risk because small elevations in the average BLL can cause profound shifts in the normative curve of intelligence, increasing the burden on our institutions and bankrupting the brain trust. Good scholarship and interpersonal judgement are vital when counseling patients on the potential consequences of chemical exposures and are no less important when making policy. The challenge for the clinician reading the research is to remain aware of the limitations and biases of our science.     

Neurodevelopmental liabilities in epilepsy

The epilepsies are a heterogenous group of cortical disorders characterized by recurrent excessive neuronal activity. In the pathophysiology of these disorders are included mechanisms of abnormal neuronal potential generation secondary to channelopathies, excitotoxic mechanisms secondary to imbalance in neuronal excitation and inhibition, and abnormalities of neuronal organization. In this article the mechanisms of the epilepsies are reviewed, in the setting of three examples: autosomal dominant nocturnal frontal lobe epilepsy, mesial temporal sclerosis and malformations of cortical development.     

Neurodevelopmental hypothesis in schizophrenia

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.     

Identification of Subgroups of Schizophrenia Patients With Changes in Either Immune or Growth Factor and Hormonal Pathways

Schizophrenia is a heterogeneous disorder normally diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria. However, these criteria do not necessarily reflect differences in underlying molecular abnormalities of the disorder. Here, we have used multiplexed immunoassay analyses to measure immune molecules, growth factors, and hormones important to schizophrenia in acutely ill antipsychotic-naive patients (n = 180) and matched controls (n = 398). We found that using the resulting molecular profiles, we were capable of separating schizophrenia patients into 2 significantly distinct subgroups with predominant molecular abnormalities in either immune molecules or growth factors and hormones. These molecular profiles were tested using an independent cohort, and this showed the same separation into 2 subgroups. This suggests that distinct abnormalities occur in specific molecular pathways in schizophrenia patients. This may be of relevance for intervention studies that specifically target particular molecular mechanisms and could be a first step to further define the complex schizophrenia syndrome based on molecular profiles.Key words: schizophrenia, subtypes, diagnosis, molecular profiling, immune factors, growth factors     

Epigenetic Mistakes in Neurodevelopmental Disorders

Epigenetics is the array of the chromatin modifications that customize in cell-, stage-, or condition-specific manner the information encloses in plain DNA molecules. Increasing evidences suggest the importance of epigenetic mechanisms for development and maintenance of central nervous system. In fact, a large number of newly discovered genetic causes of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and many other syndromes are mutations within genes encoding for chromatin remodeling enzymes. Here, we review recent findings on the epigenetic origin of human diseases, with emphasis on disorders that affect development of the nervous system, and discuss novel therapeutic avenues that target epigenetic mechanisms.     

Comparative Analysis of Gene Expression Profiles Involved in Calcium Signaling Pathways Using the NLVH Animal Model of Schizophrenia

In this study, we evaluated the expression profile changes of genes that intervene in the calcium signaling pathway, in young and adult Wistar rats, using the animal model of neonatal lesion in ventral hippocampus (NLVH) (a recognized animal model for schizophrenia) and compared to the group of control animals (Sham). Through microarray technology, gene expression profiles were obtained from the three brain areas (nucleus accumbens, prefrontal cortex, and hippocampus) of young male Wistar rats (45 days) and adults (90 days) whether or not subjected to NLVH. The calcium signaling pathway reported a greater number of differentially expressed genes with z-score two values, >?2 (over-expression) and <???2 (under-expression), in the three evaluated areas. The comparative analyses of this approach were performed in juvenile and adult rats with ventral hippocampal lesion in neonate rats (NLVH). NLVH influenced change expressions in various genes involved in Ca²⁺ homeostasis, including Cacna1d, Atp2a2, Adcy2, Ppp3cb, and Ptk2b. The expression of Adcy2, Ppp3cb, and Ptk2b genes changed in both age groups; therefore, the study of gene expression profiles between juvenile and adult rats may help to understand the molecular mechanisms of schizophrenia.     

Neurodevelopmental hypothesis of schizophrenia

Studies examining comparative outcomes of schizophrenia in high-income countries with those in low- and middle-income countries remain of interest to researchers and may be of value in understanding some environmental factors that influence the course and outcome of the disorder. The view that the disorder has a better outcome in low- and middle-income countries compared with high-income countries, even though widespread and supported by a set of World Health Organization (WHO) studies, requires further testing and exploration. Unfortunately, although not insurmountable, the obstacles for such studies both in terms of implementation and interpretation are considerable.     

Neurodevelopmental outcome in children with posthemorrhagic hydrocephalus

To determine the factors affecting the neurodevelopmental outcome in children with posthemorrhagic hydrocephalus, 78 children with intraventricular hemorrhage grade 3 or 4 were analyzed concerning the outcome in relation to the grade of intraventricular hemorrhage and intervention (surgical, medical, or no intervention) by means of a follow-up study. The mean age of the subjects at the last follow-up was 9.8 years. In children with intraventricular hemorrhage grade 4 with parenchymal hemorrhage, the outcomes in the group not requiring intervention were better than those in the groups requiring intervention, whereas in children with intraventricular hemorrhage grade 3 without parenchymal hemorrhage, there were no differences in the outcomes among the three groups with and without intervention. For the subjects who had undergone the same intervention, the outcomes in children with intraventricular hemorrhage grade 4 were worse than those in children with intraventricular hemorrhage grade 3. The outcomes in the children with surgical intervention only correlated with the grade of intraventricular hemorrhage. From these findings, we concluded that the outcomes in children with posthemorrhagic hydrocephalus were far more affected by the existence or extent of parenchymal hemorrhage than by the hydrocephalic process, which was suggested to be effectively controlled by the intervention.