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December 5, 2011

What will they think of next?

Who knew? In the 1960's up until the 1970's ablative stereotactic surgery was used to treat neurologic disorders and neuropsychiatric illness. This treatment was largely abandoned after the 70's due to the development of highly effective drugs to treat these problems, for example, "Levodopa" to combat Parkinson's disorder. Today there seems to be a virtual renaissance of similar techniques used to help those suffering.

The technique being employed uses high-frequency electrical deep brain stimulation (DBS) on specific targets to negate some disorders. Compared to the traditional ablative stereotactic surgery, which consists of lesions and very invasive brain surgery (irreversible), DBS is much less invasive in some respects. By applying high-frequency electrical stimulation to specific brain structures a similar (but different) effect of a lesion is essentially observed. Ever since this technique's rise in popularity (starting in the 1990's) people have the option of a "less permanent". These electrical pulses are delivered by electrodes chronically implanted into a persons brain at specific regions. The exact mechanism of action for DBS still isn't fully understood and clear, but the affects and benefits to patients are both lasting and clear.

Some of the diseases mentioned in the article include Parkinson's, Tourettes syndrome, obsessive compulsive disorder and depression. Patients receiving DBS to treat Tourettes syndrome had a >70% decrease of vocal or motor tics with disappearance of sensory urges. 35-70% of patients receiving DBS to treat OCD were benefitted by a significant reduction in obsessive and compulsive thoughts.

In my opinion, and it seems to be the case with most neurosurgical operations, DBS is the latest and greatest treatment available. Anytime patients can avoid a permanent/irreversible effect such as a lesion the better. My reasoning behind is vast. For example if a patient is suffering from body dissociation disorder and doesn't identify with their right arm and right leg and wants to have these two limbs removed. This persons could amputate these limbs without fully understanding the long term consequences involved or even without any benefit mentally. Or perhaps, the doctor could try a different technique, such as lesioning a brain region located using fMRI thought to be triggering body dissociation disorder. There is a chance the lesion might not properly treat the disorder or not treat it at all. Also the lesion may impair the individual in a more negative way in the long run, and since lesions are practically irreversible, the person is worse off. If DBS was used (tmi could be used as a pre-emptive mapping tool) the patient could be treated for their disorder in a non permanent way and avoid negative, unforeseen, long term issues.

I'm not entirely sure how invasive DBS is but the article made it out to be much less invasive as previous surgeries. Which to me makes sense since over time medical practices should become more and more efficient. Something haunts me about the fact little is truly known and fully understood about DBS and TMI. Little red flags go up in my head every time that fact is mentioned. Whether or not it is effective and beneficial I would prefer to know exactly why it is effective and beneficial before doctors implanted electrodes in my brain to deliver pulses of high-frequency electricity. This honestly sounds like something out of a science fiction story but the real freaky part is it seems to actually work. The big question is: Would you ever have DBS performed on yourself? My answer is yes.
Posted by      Dylan R. at 5:42 PM MST
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Morphine: Friend or Foe for People Dealing with Long-Term Pain?

Lights reflect off of the gleaming road in the rain. The highway embankment funnels traffic into a valley where pools of black water flood the lanes. Your car suddenly hydroplanes and you veer into the other lane. The sound of metal wrinkling like tin foil ricochets in your ear. You wake up in the hospital with a horrendous pain emanating from your broken legs. Morphine is dispensed to ease the pain. Rehabilitation is slow and the pain is incessant. Tolerance develops. Withdrawal symptoms like abdominal cramps and depression begin. You want to stop taking morphine, but the pain in your legs persists and makes it difficult to walk. What do you do?

Morphine has the possibility to help those in pain, but it also has the potential to create a dangerous addiction. Morphine has been in use since Byzantine times because it's a powerful and effective painkiller. Research is now looking into morphine's mode of action in the body, to better mitigate the unfortunate side effects of tolerance and addiction for long-term pain control. In the November 30th issue of the Journal of Neuroscience, a group led by Dr. Ping Zheng in China found that chronic morphine treatment actually switches the effect of dopamine from inhibition to excitation on pyramidal cells of the basolateral amygdala. Pyramidal cells in the BLA are involved in emotion. Excitation of these cells could change the emotional response, which is especially important in withdrawal, when negative feelings can contribute to a relapse.

The researchers used rats to test the effects of chronic morphine treatment. They induced morphine tolerance in rats and then used brain slices to study excitatory postsynaptic currents (EPSC) using the whole-cell patch clamp method. Compared to the control group injected with saline, the morphine treated rats had higher amplitude EPSCs by 50%. After this observation, the team wanted to investigate the reason behind this change. They used a dopamine D1 receptor antagonist in the morphine treated rats, and the EPSC was now the same as the saline control group. Thus they concluded a change in D1 receptors is responsible for the excitatory response.

But what changed about the dopamine D1 receptors at the molecular level? The researchers determined that morphine treated rats had a higher release of glutamate from the presynaptic neuron. Looking at the expression of D1 receptors using Western blotting, they saw there was increased expression of D1 receptor, versus saline. The researchers hypothesized this increased expression might be dependent on protein kinase A (PKA) so they tested this with a PKA inhibitor. They indeed found that the increased release was due to PKA activation.

To supplement these studies, a behavioral test called conditioned place aversion (CPA) were performed on the rats. In this test, rats were placed in one section on days when they received the drug, and in another section on days when they did not receive the drug and were experiencing unpleasant withdrawal symptoms. The rats were then allowed to freely go into either section, plus a third section. Time was clocked for how long the rats spent in each section and the CPA score was determined by the difference between the time spent in the withdrawal-paired compartment divided by the time spent in the drug-paired compartment. The researchers used this to test to determine whether the increase of D1 receptors is responsible for the withdrawal induced conditioned place aversion. The morphine rats strongly avoided the withdrawal compartment, but when a D1 receptor antagonist was injected into their BLA, they no longer avoided that compartment. Therefore, D1 receptors are responsible for part of the withdrawal process.

This study could lead us to understand more about the molecular nature of morphine tolerance and addiction. Using these findings, new ways to combat the negative side effects of morphine use could be implemented.

Li, Z., Luan, W., Chen, Y., Chen, M., Dong, Y., Lai, B., Ma, L., Zheng, P. (2011). Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala. Journal of Neuroscience, 31(48): 17527-17536.
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A Terrible Mistake Has Been Made

Human Immunodeficiency virus (HIV) today has been wrecking the lives of the people today. Categorized as one of the top world killers in the world, scientists have worked hard to find the cure. For those who are patiently waiting for a cure, many participate in CARTs or combination antiretroviral therapy which uses the combination of different antiretroviral drugs to stop HANDS or HIV associative neurocognitive disorders. Patients participating in this therapy were found to experience increase damage to brain. It was concluded the therapy is not an effective way to combat HANDS. Mihyun and her team exposed hippocampi of rats to gp120 for different lengths of time, than inhibited suspected proteins of the pathway such as CXC4R and then viewed the results with Open Lab software and calcium imaging.

Gp120, a surface protein that functions to bind to T-cells, is a toxin that enhances NMDA activation, but how, no one knows how. Studies found by disrupting the trafficking of NMDA resulted in disorders such as Alzheimer's. Evidence suggested that gp120 assembles NMDA receptors into clumps or modified microdomains. This occurred by increasing the size and stability of lipid rafts which are involved in receptor trafficking. Mihyun and her team used this theory as a baseline to discover the mechanism.

The team was successful in finding a mechanism. First gp120 enhanced the transport of NMDA receptors into the membrane by signaling phosphorylation of the C terminal which regulated transportation of NMDA. Exposure of gp120 to the hippocampi was found to increase the levels of phosphorylation, specifically phosphorylation of serine 897 and serine 896. Finally inhibition of PKA or PKC resulted in halting gp120 activity. PKA and PKC were thus concluded as the kinases activated by gp120 to phosphorylate the C terminal.

Then gp120 stabilized NMDA receptor microdomains by increasing the size of lipid rafts. Ceramide, a substance used by lipid rafts, was believed to be involved in increasing the size and stability of lipid rafts. Ceramide is synthesized by hydrolysis of sphingomyelin, a type of lipid. By blocking hydrolytic pathways in the hippocampi, the lipid rafts were observed not to be increase in size. In particular the enzyme nSMase2 which hydrolyzes sphingmyelin, was found to be the one responsible for increasing lipid raft sizes. Mihyuan took this further and inhibited key factor from a separate pathway that also increased lipid rafts. CXCR4, a protein that HIV uses, was found to increase lipid rafts with the use secondary messengers called IP3 and PKC.

Finally Mihyun and team found that by stabilizing the lipid rafts, NMDAR receptors were prevented from dispersing from the microdomains. Gp120 were first exposed to hippocampi then exposed to Beta cyclodextrin, a drug that is used to disrupt lipid rafts.
Mihyun and her team had made a great contribution which will has brought us one step closer to finding a cure. Though it may seem like only a baby step, at least we are one step closer.

Bae, Mihyun, et al. "The Human Immunodeficiency Virus Coat Protein gp120 Promotes Forward Trafficking and Surface Clustering of NMDA Receptors in Membrane Microdomains." The Journal of Neuroscience 31.47 (2011): 17074-17090
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December 2, 2011

One gene to ruin them all: schizophrenia, bipolar, and DISC1

Discovered over a decade ago by scientists studying a Scottish family riddled with mental disorders, variations in the gene DISC1, or "discovered in schizophrenia-1", have been heavily linked to development of schizophrenia and, to a lesser extent, bipolar disorder. Only recently, however, have scientists begun unraveling the importance of the gene and its mechanistic functions. DISC1 encodes a scaffolding protein, a protein whose function is to help organize signaling pathways via formation of complexes with multiple other proteins in a way that allows them to interact. Experiments have shown the critical importance of DISC1 in a multitude of developmental functions, including neuronal migration, axonal and dendritic growth, and synaptogenesis, and neurogenesis, to name a few. Of the half-dozen or so DISC1-dependent signaling pathways discovered, a recent paper shows that disruptions in the Wnt pathway is implicated in a significant amount of the abnormal neurological features seen in persons with schizophrenia (and bipolar).

The Wnt pathway is critical for cell proliferation during development and plays key roles in embryogeneis, neuronal growth, and certain types of cancer. Activation of this pathway results in an increase of B-catenin, which associates with other proteins to upregulate transcription of certain genes necessary for proper neuronal development. Recent experiments have showed that schizophrenics and bipolar patients with genetic variations of the DISC1 gene show inhibited Wnt signaling and reduced neuroblastoma (N2a) cell proliferation. These studies also showed that the most common DISC1 variants had a decreased affinity for the protein GSK3-B, an intermediate in the Wnt pathway, to which it normally binds and inhibits. GSK3-B is responsible for the phosphorylation and subsequent degradation of B-catenin in the absence of Wnt signaling, and it is thought that in the absence of Wnt DISC1 is responsible for its inhibition. Since schizophrenic variations of DISC1 show a decreased affinity for GSK3-B, this may suggest a mechanism for the reduced signaling seen in many areas of the schizophrenic brain.

So why does any of this matter? Drug treatments. Lithium, the classic mood-stabilizing drug used to treat mania, was shown to inhibit GSK3-B just a little over a decade ago, and its mechanism of action is only now coming to light. Some antipsychotics have also been shown to indirectly stimulate the Wnt pathway, which might be a significant aspect of their pharmacological actions. With this knowledge in hand, selective inhibitors of GSK3-B (mimicking the actions of DISC1) or agonists for Frizzled, the Wnt receptor, could effectively attenuate many of the symptoms associated with schizophrenia and bipolar disorder. Along with brain imaging and genetic testing, disruptions in this pathway could also serve as an early marker for children predisposed for these mental disorders. Drugs such as those mentioned above could also prove useful in children with a high risk for developing schizophrenia or bipolar, in which an early drug regiment could blunt the onset of the disease and possibly prevent a lifelong struggle with a mental disorder. Although there are many other genes and pathways implicated in these cognitive disorders, the massive developmental impact of DISC1 variants and their effects on the Wnt pathway opens up promising new therapeutic opportunities for the treatment of schizophrenia and bipolar disorder.

Paper: "Common DISC1 Polymorphisms Disrupt Wnt/GSK3ő≤ Signaling and Brain Development", Singh et. al
Posted by      Kevin K. at 4:43 PM MST
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