Studying Neuron Signals to Find Relief from Essential Tremor

Dr. Huanghe Yang is the head researcher on the IETF’s 2017 funded study, “Elucidating the Roles of the Ca2+-activated Ion Channels in Essential Tremor.” This blog from him shows how detail-oriented this research study is and his depth of knowledge in this subject area.  

  

Photo of Dr. Huanghe Yang, from Duke University School of MedicineBy Huanghe Yang, PhD
Duke University School of Medicine

The exact pathogenesis mechanism (or manner of development) of essential tremor (ET) is still unclear. We do know, however, abnormal neuronal firing directly causes the ET phenotypes (characteristics or traits). Thus, various means to correct the abnormal neuronal firing in the key brain regions for tremor genesis have been developed to improve the life quality of ET patients.

In order to develop more effective ET therapy, we need to have better understanding on how neuronal firing goes awry in ET. Neurons are ‘excitable’, meaning that they can fire electrical signals called ‘action potentials’. These electrical signals can be rapidly propagated from one end of a neuron to the another end, thereby enabling fast information relay from one neuron to its targeting neurons. When the electrical signals fire at abnormal frequency, serious neurological disease will occur, including but not limited to ET, ataxia and epilepsy.

Neuronal firing is controlled by a group of electrogenic proteins residing on cell surface, called ion channels. Ion channels, like dams of water reservoirs, control charged ions to flux across cell membranes. When open, they quickly allow ions to go down their gradients, resulting in change of membrane voltage, thus generating electric signal. Ion channels, thus, are a class of essential proteins that control a cell’s electrical activities. Thus far, many ion channels have been identified to be associated with various neurological disorders.

Voltage-gated calcium channels (VGCCs) are absolutely required for all neurons. Increase of membrane voltage will open the VGCCs and allow calcium ions to flush into a neuron. This calcium influx will not only further alter membrane voltage, but also quickly increase intracellular calcium concentration. During evolution, calcium has been selected as a universal and master regulator of numerous cellular processes. Therefore, the activities of the VGCCs need to be tightly regulated. Too much or too little activities of the VGCCs will lead to severe diseases such as cardiac arrhythmias, epilepsy, ataxia and migraine.

The exact roles of the VGCCs in human ET pathogenesis have not been clearly dissected. Yet interestingly, the involvement of VGCCs in tremorgenesis in rodent models has long been established. In fact, in a routine rodent ET model, a VGCC in the inferior olivary (IO) nucleus is believed to be the major target of harmaline, a psychoactive alkaloid drug from hallucinogenic plants. Injection of harmaline into rodents quickly and reliably activates the VGCCs in IO neurons, resulting in severe tremor.

We recently discovered that in addition to the VGCCs, IO neurons also express various types of calcium-activated ion channels, including calcium-activated chloride channels (CaCC) and calcium-activated large conductance potassium (BK) channels and calcium-activated small conductance potassium (SK) channels. These calcium-activated ion channels stay in close proximity to the VGCCs and form a highly dynamic and balanced feedback network with the VGCCs. Once calcium influxes through the VGCCs, the calcium-activated channels will quickly respond; and the subsequent chloride and potassium flux through these channels will quickly change membrane voltage and in turn, shut down VGCCs. Indeed, when we genetically deleted the CaCC in IO neurons, the mice had severe defect on learning new motor tasks.

With the generous support from International Essential Tremor Foundation, we have been further exploring the dedicated interactions between the VGCCs and the calcium activated ion channels in the IO, one of the key brain region for ET tremorgenesis. We have discovered that there are multiple types of VGCCs in IO neurons, which have long been believed only express the P/Q type and T type VGCCs. We are currently dissecting the contributions of each type of VGCCs and their downstream calcium-activated ion channels in mouse tremorgenesis. Our findings will help understand the basic mechanism of tremorgenesis.

We aim to translate our findings into novel therapeutic interventions to alleviate tremor symptoms and lessen functional disability associated with ET.

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July is a time with the IETF draws awareness to its many research initiatives: funding research grants, advocating for more research on essential tremor,  recruiting for research studies, and more. Your generosity is the reason the IETF is able to carry out these initiatives and work toward improving the quality of life for every generation living with essential tremor. Help us keep hope alive. Donate today. 

Research for Essential Tremor Gives Hope to Young People

By Deirdre Maciak
IETF Scholarship Recipient

I was only 16 years old when I was diagnosed with essential tremor. Up until that point, I don’t think I ever really registered how young I was. I had started driving, going out with my friends without supervision, and doing all the things that are expected of teenagers finding their way in the world. It’s an incredibly careless time in one’s life—there is so much ahead of you that the lines between the past, present and future are blurred.

Photo of Deirdre Maciak, IETF Scholarship WinnerMy main goals were always so clear to me. I wanted to get through high school consistently getting better at playing saxophone, study harder and get better grades, get into nursing school, and come out at the end with my dream job. But, being told that you have a chronic condition, one that won’t go away and will probably only progress over time, will bring even a busy-minded teenager to a halt.

Suddenly I had to reevaluate everything that I wanted in life. My diaphragm was spasming too much to have a good control on my air supply while playing saxophone. My physics class only had stools, and because there was no support, I spent more time trying to control my shaking core than paying attention to the teacher. I had a lot of questions. How am I going to be steady enough to draw blood when I’m a nurse? And, why did this have to happen to me, a 16-year-old girl, before I could achieve any of my dreams?

I’m not the first or last teenager out there whose plans have been derailed in some Quote from Deirdre Maciak about the importance of ET researchcapacity due to essential tremor. But, I am part of a generation of people with the condition who have better access to experimental treatments due to research and new discoveries.

Working with my neurologist, I’ve tried one medicine so far, but the side effects were difficult, so I’m exploring other options and I expect to need some of the new innovations in my lifetime for sure. Knowing that there are options out there to help control the frustrating symptoms has helped me put everything in better perspective.

Today, I follow what’s happening with ET by reading the International Essential Tremor Foundation (IETF) website, and watch what hospitals in my area, such as Brigham and Women’s, are doing with focused ultrasound. I was also excited to learn that a family friend, who is a research scientist, recently starting working for a company that is hoping to release a new drug that would be a big step in helping people with neurological disorders including ET. They hope to know this fall if they receive their next approval – and I am optimistic that it can help me and people of all ages who are dealing with this condition.

I was accepted into nursing school and start this fall! So despite this condition, and maybe also partly because of it, I’ll give it my all with the hope of helping people in general, and possibly those who suffer specifically from lifelong conditions as I do.

I still have a lot of questions. But, the new and ongoing research for ET gives hope to us young people, that even though our conditions may worsen over time, there are also so many ways that modern medicine can help us live our lives normally and we all need to work toward that goal together.

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July is a time with the IETF draws awareness to its many research initiatives: funding research grants, advocating for more research on essential tremor,  recruiting for research studies, and more. Your generosity is the reason the IETF is able to carry out these initiatives and work toward improving the quality of life for every generation living with essential tremor. Help us keep hope alive. Donate today. 

 

 

Partnering for Successful Essential Tremor Clinical Trials

By Spyros Papapetropoulos, MD, PhD
Chief Medical Officer
Cavion, Inc.

Collaboration with the International Essential Tremor Foundation (IETF) is critical for advancing new treatment approaches for essential tremor (ET). Our company, Cavion Inc., has been engaged in the discovery and development of a new class of T-type calcium channel (Cav3) inhibitors for the treatment of neurologic diseases like essential tremor. Last fall we initiated a Phase 2 clinical trial of our lead investigational oral drug, CX-8998.

Photo of Dr. Spryos PapapetropoulosAs a small precision medicine biotechnology company, we needed to recruit for our clinical trial as rapidly as possible. Our trial, called T-CALM (Tremor-CAv3 Modulation Trial), was designed to assess whether CX-8998 decreases the severity of tremors and improves quality of life by reducing abnormal activity in certain regions of the brain. In addition to evaluating a completely new class of therapy, our trial design also incorporated state-of-the-art digital tools to objectively quantify tremor. We needed to recruit more than 90 patients to participate at 25 research centers around the U.S.

While ET is relatively common, many patients are not under the regular care of a physician for the condition and do not seek out clinical trial opportunities. In addition, ET patients often do not understand the role of clinical trials in advancing new treatments. The IETF has built a community of engaged patients across the country and is a well-established source of news and information regarding tremor. Our intention was to reach patients through a trusted channel and we turned to the IETF to partner with us in informing patients and their loved ones about our clinical trial. They featured a story about T-CALM on their website, sent emails and mailed printed flyers to patients that live in our trial site communities. The information we provided explained the value of clinical trials, the design of our trial and set expectations for what patients would experience as participants in the clinical trial.

The response to the IETF’s targeted outreach was very positive, with many patients visiting our trial website to learn about the trial and contacting the sites to inquire about participating. Thanks in part to the IETF, we were able to complete our study recruitment in time. As ET research continues, I am hopeful that the IETF will continue playing an invaluable role in educating patients and their families about clinical trial opportunities for emerging therapies targeting the treatment of essential tremor.

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July is a time with the IETF draws awareness to its many research initiatives: funding research grants, advocating for more research on essential tremor,  recruiting for research studies, and more. Your generosity is the reason the IETF is able to carry out these initiatives and work toward improving the quality of life for every generation living with essential tremor. Help us keep hope alive. Donate today. 

Hope is Alive, Thanks to You!

Providing hope is the undercurrent of everything we do at the International Essential Tremor Foundation. We want to let people with essential tremor know there is hope for better treatment options, hope for increased understanding, and hope for a cure.

The key component in all of this is research. We have to continue to investigate what causes ET, how it is passed down from one family member to another, what tames it, what stimulates it and how we can stop it.

Since 2001, the IETF has dedicated a portion of its funds annually toward research initiatives. To date, and with your support, we have provided more than $750,000 in research grants. These grants have helped fund a study on gene variants associated with ET and one that identified changes in specific cerebellar proteins that could play a role in ET. They have focused on assistive devices and medications that suppress tremor. And, they have helped to establish the ET Centralized Brain Repository (located at Yale School of Medicine) to study, post mortem, the brains of people with ET.

July is a time when we hold our annual Research Appeal. All money donated during the appeal goes toward our research grants. These grants keep hope alive. They are a promise for a better tomorrow, for a tremor free life for the millions of people who are afflicted with ET.

As you consider donating to our research grant program, take a look at this year’s IETF Research Grant recipients that you helped fund through your 2017 donations. Donations can be made online.

2018 IETF GRANT RECIPIENTS

Research Study Subject: Optogenetic Interrogation of Cerebellar Circuitry of a Novel Mouse Model of Essential Tremor.

Sponsoring Institution: Columbia University

Principal Investigator: Sheng-Han Kuo, MD

Overview: The major obstacle for the effective therapy development for essential tremor is the unclear brain structural alterations that leads to tremor. To overcome this obstacle, we have previously identified structural alterations in the cerebellum, the brain region important for motor coordination, in essential tremor patients. Now, we will determine how this brain pathology can lead to tremor by establishing a mouse model with similar pathological alterations in the cerebellum. We will use the novel neuroscience tools to specifically silence the neuronal activities within the cerebellum in this mouse model and we will assess how these manipulations can influence tremor. The results of our proposal will establish a new platform to screen therapies for essential tremor and will advance our knowledge of essential tremor.

“The continued support for the International Essential Tremor Foundation is instrumental for my research in the tremor field,” Kuo said. Only through the continued research, we can advance our understanding where the tremor comes from in the brain and find ways to treat tremor.”

 

Research Study Subject: A Pilot Study for Quantitative Assessment of Gait in Essential Tremor Using Wireless Sensors; Potential Diagnostic Tool and Measure of Progression

Sponsoring Institution: University of Kansas Medical Center

Principal Investigator: Vibhash Sharma, MD

Although essential tremor (ET) is the most common tremor disorder, its diagnosis can be challenging, and misdiagnosis of ET is not uncommon. The most common movement disorder confused with essential tremor is tremor predominant Parkinson’s disease (PD). Dopamine transporter (DaT) scan is the only available diagnostic tool utilized in the differentiation of ET from PD. However, due to its expense and limited availability it is important to develop a relatively inexpensive tool that can easily and efficiently be utilized in clinical settings to aid in the accurate diagnosis of ET. With growing evidence of gait abnormalities in ET, studying quantitative gait measures may potentially aid in differentiating ET and PD. In this pilot study, we aim to quantitatively analyze gait and balance in the clinical setting using wireless sensors to determine if the gait abnormalities are present in early ET, and whether comparing various aspects of gait and balance can help to differentiate between ET and PD. In this study, we will include patients who have received a DaTscan as part of their clinical care, to help confirm a diagnosis of either ET or PD.  The DaTscan results will be considered the “gold standard” diagnosis, which will be compared to the results of the gait and balance assessments to determine if these assessments can similarly differentiate the patients as either ET or PD.

“The IETF has played a vital role in expanding research in ET,” Sharma said. “This research grant from the IETF will provide a good platform to conduct a pilot study to explore the clinical spectrum of ET related to subtle changes in gait and balance and potentially develop a new tool to aid in the accurate diagnosis of ET.”