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"Cytokines, such as tumor necrosis factor (TNF) alpha, have been described extensively in the literature to have a tremendous impact on the etiology of neuropsychiatric disorders induced by damage to microvascular endothelial vasculature including the BBB." This paper highlights the importance of maintaining the delicate balance of neuromodulatory chemicals in the brain, and the vast interconnectedness of the various transmitter systems. What do you make of this focus on the BBB? Can you think of other neuropsychiatric disorders that result from a compromised BBB? Explain. TNF-alpha is suspected of causing the initial deterioration; do some investigation into this cytokine and offer hypotheses as to what factors may increase the likelihood of schizophrenia.

Useful links:

[Tumor necrosis factor-alpha] http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha

[Blood-Brain Barrier] http://en.wikipedia.org/wiki/Blood-brain_barrier

I thought the review did an interesting job on giving a brief overview of the current literature on a compromised BBB?s effects on various cytokines and its relationship with schizophrenia. A non-functioning BBB is well known to either directly or indirectly cause a number of diseases and disorders, such as, Multiple sclerosis in which the body?s immune response is able to penetrate the BBB due to inflammation and once the neutrophils have entered crossed the BBB, they begin to attack Myelin sheaths, causing a weakening or degradation of signaling that causes the various symptoms associated with MS.
One reason I can offer as to why TNF alpha may be associated with a compromised BBB is that it is described as a powerful chemoattractant of neutrophils (white blood cells) which could in part account for some of the cell death observed when antibodies target various neuronal proteins such as the NMDA receptor. Additionally, TNF is strongly associated with the inflammatory response, occasionally leading to cell death (though it has a number of pathways that are oftentimes in conflict) which could possibly account for inflammation or death of endothelial cells in the BBB. TNF alpha also promotes the formation of additional adhesion molecules in those same endothelial cells. I?m not really sure what exactly that implies, does it mean that TNF actually helps the endothelial cells of the BBB stick together more effectively, thus strengthening it? Or does it perhaps cause other proteins such as white blood cells to adhere to the BBB and subsequently weaken it? In any case, I think it is likely that more study into the varying levels of cytokines like TNF in patients in various stages of schizophrenia could help shed some light on exactly how the disease progresses and perhaps offer potential avenues for pharmacological treatment to slow down or stop its progression.

In addition to schizophrenia and multiple sclerosis (as Drew mentioned), a compromised blood brain barrier can also cause a myriad of other neurological disorders such as epilepsy and Alzheimer?s disease. We all undoubtedly know that epilepsy is an illness characterized by seizures. Less widely known is its exact etiology. One proposed cause of this disease is actually defective sodium channels within the central and peripheral nervous system, which remain open for too long, resulting in overly active neurons releasing too much glutamate. This obviously brings about the same physiological response that the article outlines, i.e excess glutamate initiates exitotoxicity, which activates calcium ions leading to cell death and a reduction in NMDA receptors and GABA levels. Hence, the RMA procedure proposed by this review to study and treat schizophrenia could also easily be applied to benefit this genre of epileptics. Alzheimer?s patients suffer from heightened levels of TNFa, explaining their BBB deterioration following a remarkably similar pathway.

I highly agree with Drew that TNFa?s apoptotic effects are likely an explanation for this BBB breakdown. It?s only logical that a cytokine that signals cell death would deteriorate additional cells when circulating levels are high/unregulated. However, TNF-a is also involved in the activation of NF-kB and MAPK pathways. Do schizophrenics also see in increase in those TNF-a pathways? Why/why not?

TNF-a is also active in appetite suppression and promoting insulin resistance. Additionally it signals CRH release from the hypothalamus (involved in the stress response). Thus I would hypothesize that malnutrition and anxiety levels may factor in to the likelihood of getting schizophrenia.

As we are all aware, the blood-brain barrier (BBB) is extremely important to the protection of the brain. It serves as almost a surrogate immune system for the brain since immune cells are not able to access the tissues of the brain itself due to the highly selective nature of the blood vessels comprising the BBB. This limited permeability of the BBB creates a natural point of focus for research since the only way anything could get into the brain is by breaching this barrier, and it seems rather unlikely that every neuropsychiatric condition stems from purely internal causes. Indeed, many such conditions are hypothesized to be instigated by exogenous materials. Take multiple sclerosis, for example: partial breakdown of the BBB allows white blood cells to cross into the tissues of the brain and destroy the myelin of the oligodendrocytes that surrounds each neuron. Normally, the BBB is intact and white blood cells are unable to cross the membrane it creates, but in this auto-immune disease, the body attacks its own tissue and partially breaks down the BBB, creating a means of access for the white blood cells. Meningitis is also thought to have effects on the BBB as well as the meninges it directly infects. The thought is that once the meninges become inflamed, this can interrupt the BBB, making it possible for toxins and other substances to cross into the neural tissue and inflict change and damage. Other research shows that certain strains of bacterial meningitis are able to pass through the BBB through use of a certain protein displayed on their surface and that a lack of this protein renders the bacteria unable to traverse the barrier. This, while in itself is not a defect of the BBB, is still an example of a disease closely linked with the BBB. Finally, it is thought that Alzheimer?s disease may be in part due to a disrupted BBB that allows through substances that attach to astrocytes and neurons which eventually cause cell death and plaque deposition, a hallmark of the disease. All of these neuropsychiatric disorders and more do or potentially stem from a compromised BBB.

As for TNF-alpha, the cytokine is implicated both in inflammatory processes and triggering apoptosis. It is also capable of inhibiting tumor growth and regulates immune cells. Specifically, it is a chemoattractant for neutrophils, a particular type of white blood cell. This leads me to believe that TNF-alpha present near the BBB could cause the tissues to inflame and bring white blood cells into the area, possibly causing damage to the BBB if the leukocytes recognize it as foreign. The fact that it also induces apoptosis seems ominous in that TNF-alpha may possess the capability to wreak massive damage on the BBB should the membrane have the correct markers or be seen as a foreign invader. Even if it didn?t entirely break down the BBB, it could still cause enough damage that the membrane could become more permeable or that somewhat larger particles could squeeze through it.

In light of all of this, it seems that precipitating factors for schizophrenia could include being related to someone with schizophrenia (since you may share some genetic code that weakens the BBB), high blood insulin levels (TNF-alpha can cause insulin resistance in tissues), high blood prostaglandin levels (TNF-alpha stimulates the production of this chemical), and possible signs of undernourishment (effects on hypothalamus as well as in general can cause this condition).

It seemed that this paper was much more of a review that the previous paper which was clearly a lab study. I definitely found it helpful for them to give a background on the blood brain barrier since it is not something I am very familiar with. From this paper, it is clear that the etiology of schizophrenia is unknown and is a prevalent study in neuroscience. It appears that schizophrenia is considered a psychological disorder more than a neurological disorder. We know that many psychological disorders have heavy roots in neurological dysfunctions, which makes them, specifically schizophrenia in this case, a very interesting topic to study.

Another disease that can cause disruption in the BBB is meningitis. While meningitis is not directly caused by a compromised BBB, it can lead to one. When the meninges become inflamed it can cause stress in the BBB which can allow other toxins to cross the BBB and enter the brain. This can cause neurological problems down the line, showing correlation to the BBB in general.

Agreeing with both Caley and Drew, it is logical to say that since TNF-alpha is capable of apoptosis of certain cells, the dysregulation of it can also cause the death of surrounding cells. It therefore makes sense to say that malfunctions in TNF-alpha can cause a breakdown in the BBB and effect the development of schizophrenia. Since TNF-alpha is associated with fever and inflammation, effects produced by the hypothalamus, perhaps disorders with regulation of TNF-alpha in the hypothalamus could specifically affect the BBB. By this I mean that maybe someone who often has fevers and signs of inflammation may have the inverse effect, causing the regulation of TNF-alpha to be thrown off kilter and affect the development of schizophrenia or the breakdown of the BBB.

Earlier research studies have shown that in patients with Schizophrenia, there are structural abnormalities in the brain in comparison to controlled groups. Volumetric analyses indicate that there is an average of 4% decrease in the hippocampal volume in schizophrenic patients, as well as enlarged ventricles. fMRI, ERPs can test for a decrease in brain activities when given a complication of tasks. However, significant changes might not be detectable at an early enough stage to produce a reliable diagnosis.

The measurement of BBB-related proteins might provide a better indication of the progression of the disease at an earlier stage, due to it?s ability to measure the exact elevations in damage to the BBB. Measurements for TNF alpha, S100B, antibodies to NMDAR and GADR in combination is a very good confirmation test for schizophrenia, if the patient is already confirmed to have that disease beforehand. As mentioned in the above answers. I wonder how specific it is to measure schizophrenia. Inflammation to the Blood Brain Barrier can indicate many autoimmune diseases such as MS. The excitotoxicity occurs in many diseases such as Alzheimers. Both of these symptoms may also be caused by TBI, chronic drug abuse or a tumor. So testing the healthiness of the BBB may be an additional way to confirm the existence and progress of schizophrenia, but without additional tests, it alone cannot prove schizophrenia in a clinical setting.

The RMA method suggested tests for indications of schizophrenia in favor of the glutamate hypothesis. What if it also tested for the dopamine hypothesis? If they could find a way to visualize the mesolimbic and mesocortical dopamine activity, it could provide more evidence for schizophrenia etiology and for assessing the progression of the disease.

I think that creating a link between a compromised BBB and the disruption of the synchronization desynchronization mechanism explained by calcium homeostasis dysregulation in response to changes in complex connected neurotransmitter systems serves not only to provide an explanation of schizophrenia, but also possible avenues of research into newer treatment options and BBB based research of neuropsychiatric disorder development. Like other people in this group, I knew that the BBB existed, but did not really understand it or see the importance until doing outside research after reading this article. Most classes that I have been in have not discussed the BBB extensively, really only mentioning it as a problem for drug development. Therefore, the importance of the BBB is not emphasized. The focus on the BBB seen in this paper, could spur advances in our understanding of the now apparent critical role of the BBB.
Autism is not a neuropsychiatric disorder, however the lab that I work in is doing research into the connection between an overactive immune response and autism. Doing outside research on TNF-a, I learned that it is released by mast cells, responding to the influx of a pathogen. Perhaps newer research into the effects of a compromised BBB due to overactive microglial activation in the dorsolateral prefrontal cortex could explain why there is such a strong link between early childhood infections and autism, also why children with autism have shown higher levels of TNF-a in their CSF (I can site sources if you want in the future, let me know). This early developmental immune stress is also indicative of an increased risk of schizophrenia. I would like to also say that caley's comment on the link between anxiety and schizophrenia is very interesting and a very good point.
Like many people have said, the initial deterioration of the BBB may be due to TNF-a's effect to initiate an immune response as a chemmoattractant, also through cell signalling apoptotic MAP-kinase pathways. Then that would start the pathway of glutamate excitotoxicity and disruption of the calcium homeostasis discussed in the article. Therefore anytime there is an overactive immune response in the brain, there is the risk of inflammatory cytokine degradation of the BBB. Perhaps another risk factor would be the natural sensitivity of the individual's NMDA receptors. People with Huntingtons disease have a natural over-sensitivity to glutamate due to poor energy metabolism and decreased energy within the cell. Because of this, there is an excitotoxicity theory that is used to explain the apoptotic effects seen in huntingtons. If an individual has a compromised BBB, along with a higher, but non-huntington's level of natural glutamate sensitivity, then they could be at higher risk for the theorized development of schizophrenia seen in this article.

Perhaps stress in vitro could have a hand in this...

"Children whose mothers had consumed more than 100 grams of pure licorice during pregnancy performed worse than their peers on a variety of cognitive functions, including vocabulary, memory and spatial awareness. They were also more likely to be diagnosed with ADHD.

The culprit appears to be a component in the candy called glycyrrhizin, which, in addition to harboring a severe vowel deficiency, may impair the placenta and allow more stress hormones to pass from the mother to the fetus. This makes the baby stressed by proxy, so the fetus starts producing a hormone called cortisol to deal with it.

This leads to the children having levels of cortisol up to one-third higher than their peers have."