Schizophrenia Begins During Pregnancy New Evidence Suggests
A new study has found that schizophrenia could originate as early as the first 12 weeks of pregnancy, which means we might be able to eventually treat it in utero before birth.
By growing “mini brains” in lab conditions, scientists have been able to identify disruptions in stem cells surrounding the ventricles, or brain cavities, as early as two weeks into the growth the equivalent of the first trimester of pregnancy.
According to the team of researchers, this is a major step forward in understanding the biological origins of the brain disorder, which was first described in an ancient Egyptian medical text called the Ebers Papyrus back in 1550 BCE.
“This disease has been mischaracterised for 4,000 years,” says one of the researchers, Michal K. Stachowiak from the State University of New York at Buffalo.
“We finally now have evidence that schizophrenia is a disorder that results from a fundamental alteration in the formation and structure of the brain.”
Disrupted stem cells in schizophrenia samples .
The team grew what are known as cerebral organoids, miniature organs resembling the brain, using reprogrammed skin cells from three people with schizophrenia and four people without that were acting as a control group.
Fed with the right nutrients, acids, and glucose, these mini brains can grow to create neuroectoderm, the tissue that forms our brains. Eventually, brain ventricles, a cortex, and a region similar to the brain stem appear.
Activated Microglia Astrocytes And Oligodendrocytes
Perinatal inflammation can activate fetal microglia and astrocytes to trigger cytokine release, which can injure neurons and oligodendrocytes.114 Histopathological studies of the brains of individuals with ASD have found microglial activation and an abnormal morphology and distribution of microglia.99,115118 Further, in vivo imaging has demonstrated increased microglial activity in patients with ASD119 and other work has demonstrated possible abnormal microglia-neuron interactions.118 In numerous animal studies, maternal inflammation induces microglial activation113,120122in the fetal brain, although these findings have not been universally replicated.123125 In vitro studies have demonstrated increased neurotoxic cytokine release from activated microglia, which may damage or kill neurons and glia.113 There have been findings of microglial activation in schizophrenia126132, though again with substantial inconsistencies, and some work has examined the role of microglia in bipolar disorder and depression.133135
What Role Do Epigenetic Factors Play In Schizophrenia And Could This Affect Brain Development
As previously mentioned most genetic variance in schizophrenia is in non-coding, potentially regulatory areas of the genome. In general, during development the more well-studied epigenetic processes such as DNA methylation and histone acetylation control the availability of the local chromatin environment for transcription and along with small non-coding RNA species help cells to maintain a differentiated state,. Here, I will discuss the epigenetic factors implicated in schizophrenia which may also have implications for developing brains.
In general, the genome becomes progressively more methylated with age. This has been recently confirmed for genes related to brain development, i.e. neuron differentiation and axonogenesis in the human prefrontal cortex . However more importantly when these authors examined CpG sites within schizophrenia GWAS-implicated variants, this CpGs were more highly methylated and this finding was driven by sites that were more heavily methylated in foetal compared with adult life. Importantly, reanalysis of such methylation patterns in adult PFC from patients with schizophrenia showed no such association. This work was largely replicated by a separate group that found the GWAS-significant loci were more than four times likely to be methylated in the foetal brain compared to regions unrelated to schizophrenia.
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Prenatal Lead Exposure And Neurodevelopment
For centuries lead has been known as a toxic agent but only recently has been recognized as having subtle but significant developmental effects. McKhann stated in 1926 that the manifestations of Pb poisoning usually subside without serious consequences. In 1943 disproved this statement in a follow-up study of 20 children with documented Pb poisoning. They examined not only gross neurologic signs but also IQ scores and academic performance. Although based on a small sample of convenience, 19 of the children later exhibited serious difficulties in school. Since these initial studies, prenatal Pb exposure has been measured using maternal blood Pb during pregnancy, neonatal BPb, amniotic fluid, and umbilical cord BPb . Comparisons of maternal and umbilical BPb indicate that transfer of Pb from maternal to fetal blood during pregnancy is unimpeded by the placenta. Prospective approaches to Pb exposure and development have been used in a number of instances. They have focused primarily on developmental outcomes such as attention, academic achievement, and cognition, and have used maternal blood draws or postnatal measures in a variety of biologic media . These studies and others generally have provided strong support for the role of Pb as a developmental neurotoxin . However, because they mostly have followed subjects into or through childhood, they are not informative regarding adult-onset disorders such as schizophrenia.
Funding Priorities And Training
In light of the morbidity and stigma associated with psychosis and schizophrenia specifically, a strong federally funded research program designed to provide reliable psychosis incidence estimates across racial and ethnic groups in the United States that systematically account for misdiagnosis is urgently needed. Relatedly, funding intervention development efforts that include multilevel targets, including those at the neighborhood level, such as those connected to collective racial trauma, may better capture an important area of risk that our review suggests contributes to psychosis outcomes. Definitive causal evidence is lacking because the critical studies have not yet been carried out, but the available evidence points to a social system of contributory causes for psychosis in the United States that may require multilevel interventions. Such interventions require equitable community partnerships that target the health of the community and include the perspective of institutions and organizations within communities . As an example, Hankerson et al. are using community-partnered participatory research principles to develop and implement a depression intervention that incorporates the neighborhood-level perspective of African American churches in the local community. More funding for these approaches is needed, as they provide an opportunity to include community-level targets in interventions that would not otherwise be revealed.
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Infections And Immune System
A number of viral exposures during prenatal development, have been associated with an increased risk of schizophrenia. Schizophrenia is somewhat more common in those born in winter to early spring, when such infections are more common.
Influenza has long been studied as a possible factor. A 1988 study found that individuals who were exposed to the Asian flu in the second trimester were at increased risk of later developing schizophrenia. This result was corroborated by a later British study of the same pandemic, but not by a 1994 study of the pandemic in Croatia. A Japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic.
Polio, measles, varicella-zoster, rubella, herpes simplex, maternal genital infections, Borna disease virus, and Toxoplasma gondii have been correlated with the later development of schizophrenia. Psychiatrists E. Fuller Torrey and R.H. Yolken have hypothesized that the latter, a common parasite in humans, contributes to some cases of schizophrenia.
In a meta-analysis of several studies, they found moderately higher levels of Toxoplasma antibodies in those with schizophrenia and possibly higher rates of prenatal or early postnatal exposure to Toxoplasma gondii, but not acute infection. However, in another study of postmortem brain tissue, the authors have reported equivocal or negative results, including no evidence of herpes virus or T. gondii involvement in schizophrenia.
Other factors
Schizophrenia May Start In The Womb
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Schizophrenia likely begins very early in development, toward the end of the first trimester of pregnancy, new research suggests.
This disease has been mischaracterized for 4,000 years
The finding opens up a new understanding of this devastating disease and the potential for new treatment possibilities in utero.
This disease has been mischaracterized for 4,000 years, says Michal K. Stachowiak, lead author and professor in the pathology and anatomical sciences department at the University at Buffalo, referring to the first time a disease believed to be schizophrenia appeared in the 1550 BCE Egyptian medical text, the Ebers Papyrus.
After centuries of horrendous treatment, including even the jailing of patients, and after it has been characterized as everything from a disease of the spirit or moral values or caused by bad parental influence we finally now have evidence that schizophrenia is a disorder that results from a fundamental alteration in the formation and structure of the brain, Stachowiak says.
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Animal Models Of Maternal Immune Activation: Impact On The Developing Brain
A wide variety of infections agents and chemicals have been used to induce maternal immune activation in animal models. The two most prominently investigated are those using either the bacterial endotoxin lipopolysaccharide and the more popular synthetic double-stranded RNA analogue polyriboinosinicpolyribocytidylic acid which mimic exposures to bacterial or viral infections respectively. These models have been thoroughly reviewed elsewhere. These agents allow discrete control of dose and timing of exposure allowing the study of critical developmental windows and exposure thresholds. This is far more difficult to achieve with live infectious agents.
The molecules most implicated in the adverse effects of MIA on brain ontogeny involve the acute production of inflammatory cytokines, most notably , IL-6 and IL-17. These cytokines affect the differentiation and maturation of neuronal circuits with molecules such as IL-1 directly mediating mesencephalic progenitor differentiation into DA neurons and TNF and IL-6 concentration-dependently regulating DA neuron survival. However, there are also interactions with stress pathways. An immediate and well-known consequence of MIA is the activation of the maternal HPA axis. Recently it was shown such effects are long-lasting with low dose poly exposure at GD9 rendering the adolescent brain more vulnerable to stress. Enhanced microglial activation in hippocampus and PFC correlated with these behavioural effects.
Does Schizophrenia Begin In The Womb Stem Cell Study Says Yes
It affects over 1.1% of the worlds population and 3 million people in the US alone, yet the underlying causes of schizophrenia still largely elude scientists. Now, researchers from the Salk Institute in California have demonstrated that neurons from skin cells of patients with schizophrenia behave oddly in early stages of development, supporting the theory that schizophrenia begins in the womb.
The researchers, who published their results in the journal Molecular Psychiatry, say their findings could provide clues for how to detect and treat the disease early.
Schizophrenia is a chronic, severe mental disorder marked by disorders in thought processes, perceptions and emotions. Some symptoms include delusions, hallucinations, lack of desire to form social relationships and blunted emotions.
According to the study authors, the financial and emotional costs of the disease are quite high. In 2002 alone, Americans spent around $63 billion on treating and managing the condition, and 10% of those with schizophrenia commit suicide after being unable to cope with it.
In previous studies, investigators had only been able to study schizophrenia in the brains of deceased patients, but it was difficult to identify the origin of the disease, as age, stress, medication or drug abuse can alter or damage the patients brains.
Prof. Fred H. Gage, professor of genetics from Salk, says:
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Schizophrenia Originates Early In Pregnancy Mini
In cerebral organoids generated from stem cells of patients with schizophrenia, , disruption in the layers of stem cell surrounding the brain-like ventricles was evident as early as two weeks into the development of the organoids roughly comparable to the first trimester of pregnancy. Formation of neurons is clearly impaired compared to the control figure. Photo: M. Stachowiak, Creative Commons image legend was removed from original.
BUFFALO, N.Y. Symptoms of schizophrenia usually appear in adolescence or young adulthood, but new research reveals that the brain disease likely begins very early in development, toward the end of the first trimester of pregnancy. The finding opens up a new understanding of this devastating disease and the potential for new treatment possibilities in utero.
A paper describing the research was published today in Translational Psychiatry by scientists at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and other institutions.
Fetal beginnings
The findings provide powerful evidence that schizophrenia begins early in fetal development, said Michal K. Stachowiak, PhD, lead author and professor in the Department of Pathology and Anatomical Sciences at UB. This disease has been mischaracterized for 4,000 years, he said, referring to the first time a disease believed to be schizophrenia was described in the 1550 BC Egyptian medical text, the Ebers Papyrus.
Growing mini-brains
Brain-machine interfaces
Influenza And Markers Of Infection
Previous work describing associations between prenatal exposure to a variety of viral agents has been considered for some time and extensively reviewed elsewhere . The PDS study is among the first studies capable of performing serologic measures for exposure to influenza. For this analysis in stored maternal serum from cases and matched controls, the hemagglutination inhibition test was performed on four antigens of influenza strains known to be prevalent between 1959 and 1966 in northern California, including A/H2N2/Japan/57, A/H2N2/Japan/62, A/H2N2/Taiwan/64, and B/Massachusetts/66. Exposure to influenza usually results in a rise in antibody titers, referred to as seroconversion. Typically, seroconversion is characterized as a 4-fold rise in antibody titers taken in serial samples. As most subjects in this study had single samples taken within each trimester, a single cutoff level was sought as a proxy of influenza exposure during pregnancy. Validity studies demonstrated that levels of 1:20 in a single serum sample were highly specific and sensitive.
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Overlap With Other Disorders
Several studies have suggested a genetic overlap and possible genetic correlation between schizophrenia and other psychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, and major depressive disorder. One genome-wide association study analyzed single-nucleotide polymorphism data for the five disorders four gene areas overlapped with the five disorders, two of which regulate calcium balance in the brain.
Potential For Diagnostic Tests At Early Stages
The researchers say other studies have suggested that mothers who experience extreme stress, infections or malnutrition during pregnancy have a higher risk of having children with the condition, however, the reason for this is unknown.
Prof. Gage says their study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage.
When they studied the effects of antipsychotic medications such as clozapine and loxapine they found they did not improve migration in NPCs, and loxapine actually worsened migration.
Brennand says this was the opposite of what they expected. Though in hindsight, using drugs that treat symptoms might not be helpful in trying to prevent the disease, she adds.
They conclude their study by noting that though their methods and findings could be used to pinpoint new cellular phenotypes of schizophrenia, they caution that, because of our small sample size, these phenotypes may not generalize across all patients.
As such, they plan to increase their sample size in future studies in order to assess a wider range of patients.
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Childhood Central Nervous System Infections And Epilepsy
Data from the same Finnish cohort as discussed above, showed that individuals who had suffered a viral central nervous system infection during childhood were almost five times more likely to develop schizophrenia than the comparison group. The incidence of schizophrenia was particularly high, at 12.5%, among a group of 16 individuals who had contracted neonatal coxsackie B meningitis during an epidemic in one maternity unit. The incidence among the rest of the study population was 0.7%. Patients with schizophrenia in this series were also two to three times more likely to have a history of childhood epilepsy than the rest of the study population.
Disturbances Of Early Development
Prospectively collected measures of premorbid function have consistently revealed neuromotor abnormalities and developmental delays. In the British 1946 Birth Cohort pre-schizophrenic children were found to have delayed motor and speech development by the age of 2 years. In the Northern Finland 1966 Birth Cohort the ages that children learned to stand, walk and become potty-trained were related to subsequent risk for schizophrenia and other psychoses earlier milestones reduced the risk, whereas later milestones increased it. Cannon et al.showed, in a birth cohort from New Zealand, that children who went on to develop schizophreniform disorder had persistently poor motor function over repeated measurements in childhood. In an innovative study using home movies filmed during childhood, pre-schizophrenic individuals could be differentiated from their healthy siblings by viewers who were blind to the psychiatric outcomes.
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Psychosocial Factors During Pregnancy And Delivery
Some studies suggest an association between antenatal stress and schizophrenia. The children of mothers whose husband died while they were pregnant have been found to have a significantly increased rate of schizophrenia compared with children who lost their father in infancy in the first year of life. In The Netherlands, rates of schizophrenia have been found to be very slightly higher in individuals exposed in utero to war and flood disaster than in reference subjects.
In the Northern Finland 1966 Birth Cohort the risk of later schizophrenia among unwanted children was elevated 2.4-fold compared with wanted or mistimed children, even after adjustment for confounding by sociodemographic, pregnancy and perinatal variables. Unwantedness might be a marker for features associated with risk in either the mother or the child. In the same cohort, the level of schizophrenia in the offspring of antenatally depressed mothers was elevated by a factor of 1.5-foldly, but the association was not statistically significant. Those mothers of schizophrenia patients with a psychotic first-degree relative had suffered from depressed mood during pregnancy twice as often as other mothers. The familial risk for psychosis, including genetic risk for psychosis, might explain the elevated prevalence of depressed mood during pregnancy among the mothers of the offspring who went on to develop schizophrenia.