New Breakthrough: The new Treatment strategies for Bipolar Disorder and Epilepsy

Summary: A new study looks at how a gene associated with bipolar disorder affects the balance between inhibition and excitation; revealing a link with epilepsy.

People with bipolar disorder suffer from excessive emotional highs and lows that can cycle uncontrollably, severely distorting their awareness of self and others, impairing social and work ability and causing high risk of suicide. Current treatments are only partly effective. Researchers at Baylor College of Medicine have used mouse models and advanced molecular mapping studies in both mouse and human to learn how a gene associated with bipolar disorder controls the balance between brain excitation and inhibition and shown for the first time that it also is linked to epilepsy.

The findings, appearing recently in the early online edition of Molecular Psychiatry, open new treatment strategies for both bipolar disorder and epilepsy.

“We became very interested in a gene called ‘ankyrin 3’, or ANK3, a decade ago when we discovered it coded for a partner of two other genes that are mutated in some people with epilepsy. Soon afterward, ANK3 was connected with bipolar disorder by genetic testing of thousands of psychiatric patient volunteers around the world,” said Dr. Edward C. Cooper, associate professor of neurology, molecular and human genetics, and neuroscience at Baylor. “Although there are important differences, we noted similarities between bipolar disorder and epilepsy: both cycle, both are risk factors for the other, and both are currently treated using many of the same drugs. Reasons behind these overlaps were mysterious, and the specific parts of the ANK3 gene linked with bipolar had no known function. We decided to take a much closer look at the human brain and mice with bipolar-like behavior. In our study we found that reduced expression of one type of ANK3 removes a brake on the output of brain neurons, leading to excesses in firing in circuits for emotions, memory and epilepsy.”



Proteins coded by ANK3. Blue: output cells. Yellow: nerve impulse trigger zones of output cells. White: Inhibitory neurons that hold back output. Red: trigger zones with a different type of ANK3 protein, lost in bipolar disorder and epilepsy. NeuroscienceNews.com image is credited to the researchers.

Within each ANK3 gene are bits of DNA containing information coding for several different proteins. The research team found that, in both mice and human, different ANK3-coded proteins were expressed on brain cells responsible for increasing output (excitation) and holding back output (inhibition). Working with Cooper, Baylor genetics graduate student Angel Lopez discovered that an ANK3 type found in lower amounts in bipolar disorder patients was selectively lost by inhibitory neurons, lowering their output. Activity of neighboring excitatory cells proved unaffected. So, what scientists call “excitation/inhibition” balance, was shifted in the direction of excessive excitation.

When Lopez and colleagues engineered mice to lose this inhibitory form of ANK3, they found that the imbalance caused both frequent epileptic seizures and an increased risk of sudden death across the lifespan.

“This showed us that imbalance in ANK3 function can result not only in excessive circuit sensitivity and output leading to bipolar
disorder, but also severe epilepsy,” Cooper said.

Although diagnosis and care for bipolar disorder and epilepsy often are viewed as distinctly psychiatric and neurological issues, respectively, the study highlights an example of common genetic and biological underpinnings at a frontier between medical disciplines. The results open the door to additional lab and clinical research and could lead to new treatment options for both conditions by targeting ANK3 and its molecular partners in the brain.



“Our work also provides an example of how conducting and participating in unbiased human genetic studies, such as those that implicated ANK3 in bipolar disorder, can illuminate unforeseen connections between disease categories and the benefits of research that crosses disciplinary borders” said Cooper.
Source: Neuroscience News, Baylor College of Medicine

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Cannabis: A Cure For Epilepsy?

By: Alexandria Addesso

Although cannabis has been known for its therapeutic and medicinal functions for thousands of years, the United States seems to be slow to the learning curve. In a previous New Mind Journal article, the benefits of marijuana treatment for cancer were discussed, this article will focus on the use of the plant for another devastating disorder. Epilepsy.

Epilepsy is defined as a disorder in which nerve cell activity in the brain is disturbed, thus causing seizures. A person suffering from epilepsy is usually treated with a variety of drugs, but not all forms of epilepsy can be treated with such pharmaceutical drugs thus leaving their seizures uncontrollable.

Individuals that endure such untreatable seizures are often children suffering from pediatric epilepsy disorders, such as Doose, Lennox-Gastaut, and Dravet syndromes. Since marijuana began being legalized for medicinal use, floods of stories have been told of parents who have risked it all and even relocated so that their children can legally use cannabis oil to treat their epilepsy and have a normal life.



What is most commonly prescribed is a treatment called Charlotte’s Web, named after a young girl suffering from Dravet syndrome to the point that her multiple seizures that lasted for hours at a time were causing serious cognitive problems as well as delaying her developmental growth. Her name was Charlotte Figi.

Charlotte’s Web is cannabis oil extracted from a strain that is high in Cannabidiol (CBD) and low in Tetrahydrocannabinol (THC) which is the chemical that gets people “high”.

“The biggest misconception about treating a child-like little Charlotte is most people think that we're getting her high, most people think she's getting stoned," Josh Stanley, one of the owners of the dispensary that originally grew this strain.



Yet this treatment is still considered controversial. The Epilepsy Foundation does not endorse nor discourage this treatment, but instead states that each individual should follow their physician's recommendations in congruence with the law.

The University of Colorado Anschutz Medical Campus is currently engaging in a study on Dravet with epilepsy patients who have tried Charlotte's Web. The genetics of the subjects who have seen a drastic change after using Charlotte’s Web will be compared with those who have not. The findings could be highly significant for the use of the treatment. Only time will tell.

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Brain Waves, a new Source of Silent Electricity

Finding may help in understanding memory formation and treating epilepsy.

By: Jaime F. Adriazola

Brain waves that spread through the hippocampus are initiated by a method not seen before. According to researchers at Case Western Reserve University, this is a possible step towards assimilating and treating epilepsy.

The researchers discovered a traveling spike generator that appears to move across the hippocampus which is a part of the brain mainly associated with memory function and changing direction, while generating brain waves. However, the generator itself produces no electrical signal.

“In epilepsy, we’ve thought the focus of seizures is fixed and, in severe cases, that part of the brain is surgically removed,” said Dominique Durand, Elmer Lincoln Lindseth Professor in Biomedical Engineering at Case School of Engineering. “But if the focus, or source, of seizures moves–as we’ve described–that’s problematic.”

The findings in the Journal of Neuroscience builds on Durand’s work published late last year; identifying brain waves that appear to be spread through a mild electrical field. These are not the known transmissions through synapses, diffusion, or gap junctions.



The speed of the waves most closely matches those found in epilepsy, healthy sleep, and theta waves, which are thought to help form memories.

On this latest study, the leader Durand worked with PhD students Mingming Zhang, Rajat S. Shivacharan, postdoctoral researcher Chia-Chu Chiang, and research associate Luis E. Gonzales-Reyes.

Source Search

Working from the same data that revealed the brain waves, the team found that the source was also moving too slow for synaptic transmission, and a little too fast for diffusion.

“We don’t know what’s causing the propagation,” Durand said.
The engineers estimate the size of the source’s diameter is 300 to 500 micrometers. It appears to generate spikes all around its periphery, but the source moves nearly 100 times slower than the spikes.

“The source is like a moving car with pulsing lights,” Durand said.



To find the source of the waves, the team tracked spikes propagating through an unfolded rat hippocampus. They used a penetrating microelectrode array of 64 electrodes arranged in a grid on the tissue to record the activity.

The delay between the initial spike and the peaks recorded along consecutive electrodes in the grid was measured in milliseconds.
By inserting time values surrounding those recorded by each of the electrodes, the researchers refined the grid to include a total of 256 points or pixels.

Using this data, the researchers created an isochrone map; a map of lines connecting locations where a given spike arrived at the same time. The maps look something like topographical maps, but instead of showing elevations, the lines show the wave fronts as they spread over time.



The source of each wave propagation was estimated to be the geometric center of the electrodes that recorded the first neural firing at maximum amplitude.

Each brain wave appeared to have a slew of sources, firing it along either from the temporal region toward the septal or vice versa.

The team applied Doppler effect equations to the frequency of spikes in front and behind the source. Like the direct observations, the results strongly indicate the sources are moving smoothly across the hippocampus.

When a source reached the hippocampus edge, it started in the opposite direction. That may explain observations by others that waves moving in opposite directions have been found in the same brain tissue at the same time.



Digging deeper

Durand’s lab is trying to understand how a source that moves without diffusion can move without electricity and still generate electrical spikes.

The team is also trying to understand what these non-synaptic events do, and whether they are relevant to processing neural activity. Because the speed of these waves is close to the speed of sleep and theta waves, the researchers speculate that they may be involved in consolidating memory.

If the phenomenon is relevant to epilepsy, it may provide a target for therapies. “Can we block the spikes without blocking the source?” Durand asked.

The lab is now developing new neural imaging methods to better track sources and learn how they propagate spikes.



“The present discovery opens the door to future studies in transmission of thoughts, based on the diffusion of the Quantum Electrodynamics.”

Sources: Neurosciencenews.com NMJ Library

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