Electromagnetic Stimulation on Patients with Epilepsy

Dr. Joel Voss discussed his research on the neurological effects associating with long-lasting memory. His research demonstrated the linkage of improving memory through multiple-day electromagnetic stimulation. Voss’s research assessed electromagnetic stimulation of rTMS (transcranial magnetic stimulation) which targeted the HPM network. These findings suggest the effective implications that magnetic stimulation have on the functions of memory. His reports indicate that improvements in memory lasted up to ~2 weeks after stimulation.  While his methods aim at improving memory precision, each assessment performed on his participants was collected with electroencephalogram (EEG) as well. While electromagnetic stimulation demonstrated improvement on brain network associated with long-lasting memory, this method is used as treatment for patients with epilepsy as well.

In a recent study, JAMA Neurology demonstrated the effective treatment of continuous electrical stimulation on patients with epilepsy. Epilepsy is a central nervous system disorder that occurs when the nerve cell activity is disrupted, causing seizures. According the World Health Organization, approximately 50 million people worldwide have this neurological disorder. Patients experiencing seizures show signs and symptoms of: temporary confusion, staring spell, uncontrollable jerking movements of the arms and legs, and loss of consciousness. While many seek surgery and medication, patient with drug-resistant epilepsy limits their treatment. Drug-resistant focal epilepsy may even occur in areas of the brain that controls the neurological functions of speech, language, vision, sensation, or movement. For this reason, resective surgery is not an option for patients with drug-resistant epilepsy.

However, non-invasive electromagnetic stimulation has proven to be effective as a treatment option of those patients with epilepsy, especially drug-resistant focal epilepsy. To accurately grid the seizures occurring in these patients, electrical contacts is placed on the brain of these patients to record the interictal epileptiform discharges (IEDs) affected by epilepsy. IEDs are electrical discharges that are used as biomarkers to locate areas of the brain that correlates to seizures. Prior to the stimulation, the IED rate reduced significantly; thus, the immediate reduction in IED rate suggest that electromagnetic stimulation effectively treats patients with epilepsy. Out of the 13 patients that participated in the study, a large percentage of the patients reported improvement of epilepsy severity, life satisfaction, reduction of seizures, and free of disabling seizures. Overall, continuous electromagnetic stimulation in the brain produces changes on neurological activity and has implications on the treatments for patients with neurological disorders.

Works Cited

“Continuous Electrical Brain Stimulation Helps Patients with Epilepsy.” ScienceDaily, ScienceDaily, 19 Sept. 2016, www.sciencedaily.com/releases/2016/09/160919220132.htm.

Lundstrom, Brian Nils. “Chronic Subthreshold Cortical Stimulation to Treat Focal Epilepsy.” JAMA Neurology, American Medical Association, 1 Nov. 2016, jamanetwork.com/journals/jamaneurology/fullarticle/2553322.

Nilakantan, Aneesha S., et al. “Stimulation of the Posterior Cortical-Hippocampal Network Enhances Precision of Memory Recollection.” Current Biology : CB, U.S. National Library of Medicine, 6 Feb. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5302852/.

Gene Therapy: Does it Really Work?

Gene Therapy is a direct transfer of therapeutic genes into a patient's cells that will help correct the genetic disease. The idea of being able to modify a person's DNA to treat a disease was just a dream before, but it is finally taking flight with major success stories.

 Gene therapy is different from normal drugs. It does not treat symptoms but instead targets the disease to correct the underlying genetic causes. Gene therapy can do this in many ways. Someways are by replacing a mutated gene with a healthy copy that produces a functional copy, by silencing a mutated gene that is not functioning properly, or by introducing a new gene that will help fight the disease. Gene therapy can be treated in vivo or ex vivo. In vivo gene therapy simply means that the therapeutic DNA is introduced directly into the affect cells of the body. Contrarily, ex vivo gene therapy is when cells from the patient with the genetic disease are removed, normal functioning copies of the mutated gene are then inserted into the cells, then finally the cells are transplanted back into the patient. The therapeutic gene will then express normal copies of the required protein. 

In March of 2017, in France, there was a teenage boy cured of his disease through gene therapy. The boy had sickle-cell anemia, which is an inherited disease of the blood of a single mutation. Sickle cell anima is a condition in which there are not enough healthy red blood cells to carry enough oxygen throughout the entire body. The boy received an experimental gene therapy that was developed by Bluebird Bio. Bluebird Bio decided on an ex vivo gene therapy approach. They began by taking cells from the boy's bone marrow and then modifying the cells by introducing a new gene to help fight the disease by preventing the blood cells from becoming sickled. When those new cells were implanted back into the boy they began to make normal blood cells. Two years after the treatment the boy's body was able to produce enough normal red blood cells, with the help of the gene therapy, to bypass any side effects of the disorder. 

Another success story with gene therapy comes from a boy in Germany who has epidermolysis bullosa. Epidermolysis is a skin disease where the skin becomes very fragile and can blister easily. These blisters can arise through minor injury or friction from something as little as rubbing or scratching. This disease threatened the life of the boy so doctors in Germany were determined to save this little boy through gene therapy. The doctors decided to make new skin with ex vivo skin therapy. These doctors extracted healthy skin cells, skin that was not blistered, isolated them and, similar to that of the teenage boy from France, added copies of a healthy version of the gene. They let the cells grow into small sheet and transplanted them onto the boy’s body with only 3 surgeries. 

Both of these cases correlate with the talk that Subhojit Roy gave about potentially using gene therapy to treat Alzheimer’s disease (AD). There is still a lot that is not known about Alzheimer’s disease but Roy discovered, through his experiments, that by using CRISPR/Cas9 to target certain genes like APP C-terminus in the brain of those with AD. He also discovered that it only took CRISPR 5 days to work and correctly target the APP C-terminus in the brain. By using what he has learned through his studies and other successful attempts with gene therapy maybe one day Roy could discover a way of treating AD with gene therapy. 

https://www.technologyreview.com/s/609643/2017-was-the-year-of-gene-therapy-breakthroughs/

Memory

It is a well-known common fact that the brain is involved in memory. But which part of the brain? That would be the hippocampus. The hippocampus is a small organ located with the brain’s medial temporal lobe, and is considered to be the center of emotion and memory.

Dr. Joel Voss, a researcher at Northwestern University, attended Loyola University Chicago to give a talk about his latest researches, which included one research he and his colleagues did about Targeted enhancement of cortical hippocampal brain networks and associative memory. In this research it is stated how the “influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans.” (p.1054) This is why in this research study they used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation in memory. Their goal was to strengthen the hippocampal brain networks and see if this would strengthen associative memory. Results of this experiment were positive when it was discovered that “the increase in performance for baseline to Post-Tx was greater for stimulation than for sham.” (p.1055)

            In a study by researchers at Brigham Young University in Provo, Utah, they talk about how exercise may help the memory grow stronger. As mentioned earlier, memories are coded into brain cells in the hippocampus, and if they weren’t written into those cells, then they wouldn’t be available for long term memory. For the research, they used healthy, male mice. After a month of normal life, they exposed some of the mice to stressful experiences, like for example, a mild restraint. To see how this affected their memory, “the researched had some mice from each group learn a maze with a treat in one hidden corner.” (Reynolds) After three days of the exposure to a stressful situation, they saw that they had reduced the effectiveness of the memory in the stressed-out mice, compared to those mice from control group. So, we see how stress weakens the brain’s availability to retain information, whereas regular exercise can counteract those effects by bolstering communication between brain cells.

            We can see the correlation between these two experiments when we compare how in the experiment conducted by Dr. Voss and his colleagues it was stated, as mentioned before, that “multiple-session stimulation increased functional connectivity among cortical-hippocampal networks and tested effects of this manipulation in memory.” (p.1044) Basically, what we want for a better memory is a really strong synapse, which are the connection in between neurons. Just like TMS treatment, which was used in Voss’s experiment, we are able to strengthen our memory if we exercise regularly. 

Sources: 

·     Memory Enhancement: Targeted enhancement of cortical-hippocampal brain networks and associative memory. Wang J.X., Rogers L.M., Gross E.Z., Ryals A.J., Dokucu M.E., Brandstatt K.L., Hermiller M.S., Voss J.L. (2014) Science, 345 (6200) , pp. 1054-1057.

·     Reynolds, Gretchen. “How Exercise May Help the Memory Grow Stronger.” The New York Times, The New York Times, 20 Feb. 2018, www.nytimes.com/2018/02/21/well/move/how-exercise-may-help-the-memory-grow-stronger.html.

Alzheimer's Disease: New Research in Screening and Treatments

Dr. Roy, a medical scientist studying Alzheimer’s disease at the University of Wisconsin Madison, recently drove down to Chicago to talk about his incredible new research into the exact mechanism of the disease and how researchers might go about actually utilizing this information.  Alzheimer’s disease is a degenerative disease which most often occurs during middle or old age, and up to this point, there has been no easy and cost-effective way to successfully identify this disease and the extent to which it might occur, nor have there been any major breakthroughs in an effective treatment that doesn’t involve the ever-popular “diet and exercise” method.  Alzheimer’s disease is physiologically identifiable post-mortem through an examination of the brain tissue, but is also signaled in living people by the unusually high levels of beta-amyloids in the brain and cerebrospinal fluid.

Dr. Roy’s approach utilizes the popular CRISPR/Cas9 technology, which he is trying to use to modulate this beta-amyloid production.  CRISPR/Cas9 is particularly popular among researchers because of its ability to actually edit DNA and subsequently alter what proteins the genome can produce.  While less than 10% of Alzheimer’s cases are believed to be inherited, this method is still valuable to edit mutations that might have arisen due to natural errors in genome copying and maintenance.  This potential treatment would target an amyloid precursor protein -- a protein that is responsible for generating such large amounts of beta-amyloid fragments -- and aim, in a one-time procedure, to effectively “turn off” the pathway for beta-amyloid creation.  This treatment is a long way off, but seems to be a promising possibility for Alzheimer’s disease in the future.

However, one problem remains: how do we know who actually has Alzheimer’s disease?  In America, 10% of people aged 65 and older are affected by and 32% of people aged 85 and older have the disease.  Currently, there are two ways to test for the disease by measuring the amount of amyloids in a living body: positron emission tomography (PET scans) and lumbar punctures.  PET scans are cost-prohibitive and lumbar punctures come with a host of risks, including infection and paralysis. Neither are realistic for mass screenings, which, with the sheer quantity of the population being affected, would be optimal.  Mass screenings would be an ideal way to determine who needs a treatment if technologies like Dr. Roy’s actually work. An article published by Scientific American details a promising and inexpensive new way to test for these amyloids that are caused by Alzheimer’s.  The researchers studying this thought outside of the box and tried to detect amyloids in a place we don’t currently look for them: the blood.

These researchers, based in Japan, believe enough amyloids making it through the blood-brain barrier to be able to effectively test for them with a simple blood test.  This test, if successful, would not only provide a much cheaper and safer alternative to traditional Alzheimer’s testing, but would even be able to help in distinguishing between Alzheimer’s and other forms of dementia in patients experiencing symptoms.  Their blood test is based on a technique called immunoprecipitation with mass spectrometry, which uses specific antibodies to bind and identify specific proteins. In this case, the protein being bound is the amyloid protein.

Amazingly, this blood test is something that’s already in clinical testing stages.  In a controlled trial setting which included 121 people from Japan and 252 people from Australia and individuals with normal brain function ranging all the way to severely impaired by the disease, it was found that the amount of amyloid present in the blood did, in fact, correlated with the degree of cognitive impairment.  The group conducting the research is currently trying to expand to other parts of the world and reach a larger audience in order to generate a better dataset for the amyloid concentration to Alzheimer’s impairment ratio.

Ultimately, treatments like Dr. Roy’s would be most effective if combined with wide-spread, cost-effective and non-invasive screening measures such as the one being researched by the Japanese group.  While the implementation of either is a long way off, the research being done on them now could help generate new ideas and produce more novel medical technologies.

1 https://www.dshs.texas.gov/alzheimers/qanda.shtm

Stetka, Bret. “A Big Step toward a Blood Test for Alzheimer's.” Scientific American, 31 Jan. 2018, www.scientificamerican.com/article/a-big-step-toward-a-blood-test-for-alzheimers/.

The physical approximation of APP and BACE-1: A key event in Alzheimer's disease pathogenesis. Jichao Sun and Subhojit Roy*

Developmental Neurobiology 2017 Nov 6. doi: 10.1002/dneu.22556.