Clinical Trials Are Vital to Improving Medical Care

Manish Gupta has over 15 years of experience in developing and executing global clinical trials in cardiac and neurological devices (including those developed to manage essential tremor). He shares how clinical trials work and how the IETF partners with Cala Health to recruit participants. 

 

By Manish Gupta
Vice President of Clinical Affairs
Cala Health, Inc.

Photo of Manish Gupta with Cala HealthClinical trials are research studies that explore whether a medical device, drug or treatment is safe and effective for humans. These studies also may show which medical approaches work best for certain illnesses, diseases, disorders or groups of patients. Clinical trials produce the most reliable data available for health care decision making. They follow strict scientific standards to protect patients and help produce dependable study results.

Clinical trials are one of the final stages of a long and careful research process. The process often begins in a laboratory, where scientists/technologists first develop and test new ideas. If an approach seems promising, the next step for higher risk devices may involve animal testing. This shows how the approach affects a living body and assesses its safety. However, an approach that works well in the lab or animals may not always work well in people. Thus, research in humans is needed.

For safety purposes, clinical trials start with small groups of patients to find out whether a new approach causes any harm. In later phases of clinical trials, researchers learn more about the new approach’s risks and benefits in larger groups of patients.

Quote from Manish Gupta for Research Month blogA clinical trial may find that a new device, drug or treatment

1) improves patient outcomes; or
2) offers no benefit; or
3) causes unexpected harm

All of these results are important because they advance medical knowledge and help improve patient care.

Patients participating in research are generally referred to as “subjects.” During a clinical trial, doctors, nurses, social workers, and other health care providers might be part of the subject’s treatment team. They will monitor the subject’s health very closely, conducting more tests and medical exams than standard care.

Taking part in a clinical trial can have many benefits. If a new treatment is proven to work, subjects are among the first to benefit.  Even if subjects don’t directly benefit from the clinical trial, the information gathered can help others and add to scientific knowledge. People who take part in clinical trials are vital to the process of improving medical care. Many subjects volunteer because they also want to help others.

Many government agencies, companies, patient advocacy groups and other organizations sponsor clinical trials. Collaboration between two or more of such groups/organizations is common in clinical research to create patient awareness about the clinical research and the disease. Cala Health’s collaboration with International Essential Tremor Foundation (IETF) is one great example of a partnership that creates patient awareness throughout the United States about essential tremor (ET) clinical trials. Cala Health, Inc. is actively conducting ET clinical trials of its wrist-worn therapy at leading centers in the US.

IETF is an essential partner to Cala Health informing the ET community of the clinical research opportunities to advance medical knowledge and patient care.

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About Cala Health, Inc.
Cala Health is a medical technology company pioneering a new class of electrical medicine. The company is merging innovations in neuroscience and electronics to deliver individualized, prescription neuromodulation therapies. These therapies treat chronic disease non-invasively by stimulating peripheral nerves with body-worn electronics. The company is headquartered in the San Francisco Bay Area and backed by leading investors in both healthcare and technology, including Johnson & Johnson Innovation – JJDC, Inc., Corp, Lux Capital, Lightstone Ventures, GV, dRx Capital and Action Potential Venture Capital.

The IETF funds research grants, advocates for more research on essential tremor, and works with companies like Cala Health to recruit participants for research studies. Your donations to research are 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.

 

 

 

 

 

 

 

 

 

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. 

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.”

High School Student Develops App to Detect Parkinson’s and ET

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High school student Erin Smith has developed an app that helps to diagnose Parkinson’s disease and possibly other neurological conditions through facial recognition. She serves as an example of how young people are stepping up to invest themselves in making a difference in the lives of others through their ingenuity and motivation. Here is her story.

By Erin Smith.
Senior at Shawnee Mission West High School
Overland Park, Kansas

About two years ago, I was watching a video by the Michael J. Fox Foundation when I noticed that whenever Michael J. Fox or another Parkinson’s disease patient would smile or laugh, it came off as emotionally distant. Further, as I talked to Parkinson’s caretakers and clinicians, they reported similar observations in their loved ones years before diagnosis. As I read medical studies, I found that the often overlooked sections of the brain that undergo the earliest changes in Parkinson’s patients are the same parts involved in the formation of facial expressions.

My mind instantly went back to a TV show I had watched as a child called Lie to Me,  where a deception expert would solve crimes by studying facial expressions to determine if people were lying. I wondered if facial expressions could have similar health care implications and provide external manifestations of neurological pathology. 

FacePrint App is Born
I then launched a study in partnership with the Michael J. Fox Foundation Trial Finder to expand my research on a national level. Using the data I collected, I developed FacePrint, a tool to diagnose and monitor Parkinson’s disease using the early stage facial muscle indicators that I identified. FacePrint provides an inexpensive, remote tool for early stage Parkinson’s disease, requiring only a computer and webcam. Further, FacePrint is compatible with facial recognition used by Snapchat and Facebook, creating a selfie that could save your life.

Differentiating Between Parkinson’s and ET
However, after developing FacePrint, I quickly began to notice distinct facial movement differences in patients with other neurological diseases. I started formulating the idea that facial behavioral biomarkers could non-invasively differentiate between Parkinson’s disease and Essential Tremor patients. My new mission has become to create a robust, differential diagnostic and monitoring tool for Parkinson’s disease and Essential Tremor patients. It is my hope that developing accurate diagnostic and monitoring systems for these two diseases will lead to improved, earlier treatment options and ultimately a cure.

Ridding the World of Neurological Disorders
Beyond my goals for my research from a medical perspective, I also hope to create a source of hope.

I firmly believe that change occurs on an individual level. It is one person doing one thing different one time. It is one person caring about one topic and doing everything that he or she can to make a difference in that area. It is one person taking one step forward one time.

I believe that the journey towards a cure for Essential Tremor and Parkinson’s disease will follow the same pattern. However, while change occurs on an individual basis, impact occurs when we all come together to leverage that change. My work is just one piece of the larger puzzle. We must all come together and put the pieces together. It will take everyone devoting their time, efforts, and stories to lead to a day when Parkinson’s disease and Essential Tremor are cured conditions. Although it is easy to become discouraged, my research has filled me with a deep sense of optimism for our future. There are researchers, patients, caretakers, clinicians, and everyday citizens around the world who are making remarkable progress and strides in this field. We are not marching alone. Rather, we are marching hand-in-hand, striving towards the day when our collective impact will create a world without neurological disorders.

YOU CAN PARTICIPATE IN ERIN’S STUDY

Erin is expanding her original research to include essential tremor and persons with no neurological disorders to determine if this test (her app) can easily differentiate between the two, possibly saving patients years of misdiagnosis. The study takes about 10-15 minutes and requires a computer with a webcam. It typically works best on Chrome, which can be easily downloaded online if not already installed (see link below). If you have ET or Parkinson’s Disease please take this test and please encourage your friends and family members without either disease to participate as well.

Three new IETF-funded research projects announced

Research-Appeal-2015-Facebook-CoverEach year researchers with an interest in studying the various aspects of essential tremor are encouraged to submit scientific proposals for grant funding from the IETF. To date, your research donations have provided nearly $1 million to fund numerous promising studies. This year, the IETF will fund three essential tremor research grants totaling $80,000. Grant funding was provided to the IETF from donors, people directly affected by this life-altering condition, like you.

The IETF will award $35,000 to the study entitled “Testing the GABA Nucleo-Olivary Hypothesis of Essential Tremor.” The goal of this research is to systematically test whether impaired function or degeneration of GABAergic N-O neurons induces action tremor, supporting the hypothesis that such mechanisms underlie at least some cases of ET. Read more…

The second study to be awarded $20,000 from the IETF is “Essential Tremor Research Program: Cannabidiol Anti-Tremor Action and Mechanisms.” This research will explore the effects of a particular cannabinoid known as “CBD” (cannabidiol) on ET. Unlike the well-known cannabinoid “THC” (tetrahydrocannabinol), which has mood-altering effects, CBD does not impact mood. CBD has already shown some promising initial results in the treatment of epilepsy, pain, anxiety, and other disorders. Read more…

The final study, “Abnormal Climbing Fiber-Purkinje Cell Synapses in Essential Tremor” will be awarded $25,000. This study will be conducted by Dr. Sheng-Han Kuo, Assistant Professor of Neurology at Columbia University in New York. Dr. Kuo’s team will build upon previous research after discovering an unknown abnormality in essential tremor patients at the location in the brain where the neuron’s electrical and chemical signals are transmitted and received. Read more…

Your research donation could make the difference between critical research being funded, or being turned away. Every donation, no matter the size, counts. Help us keep research moving forward! Make a research donation today and learn more about IETF-funded research.

IETF Funds Ground-Breaking Research for 2014

Brain-blk-and-bluThe IETF is excited to fund three new research studies totaling $85,000 this year. These studies are stepping stones to moving our knowledge forward and can provide progress to change the world for everyone with ET.

The Role of Excitotoxicity in ET Cerebellum – IETF Funded $25,000
The goal of this research is to investigate the role of excitotoxicity in the postmortem ET cerebellum. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters. It has been a suggested approach for ET, however there has yet to be any direct evidence that excitotoxicity plays a role in ET patients. Read more.

Cerebello-Thalamo-Cortical Coupling in ET: Effects of High-Frequency Cerebellar Stimulation on Brain Activity & Tremor – IETF Funded $25,000
Tremor is associated with abnormal activity within different brain regions, particularly the thalamus and cerebellum. Transcranial stimulation (tACS) of the cerebellum may represent a non-invasive therapeutic option for ET patients. TACS is a new technique allowing manipulation of rhythmic patterns in the brain’s cortex with externally applied electrical frequencies. Read more.

A Feasibility Study for an ET Brain Bank at the Arizona Study of Aging & Neurodegenerative Disorders – IETF Funded $35,000
Now in its third IETF-funded year, researchers will continue to examine the brain tissue of those with ET and other neurological disorders after death, searching for a greater understanding of how ET changes the features of the brain, and hopefully leading to more effective diagnostic tools. Read more.

Grant funding was provided to the IETF from its own annual donors, people directly affected by this life-altering condition. If you’d like to become an annual donor, please click here. As our way of saying thank you, you will also receive the new e-book “Essential Tremor: What the Experts Say.”

Researchers prove resistance training benefits dexterity in ET patients

hand_weights_on_workout_matA recent IETF-funded study shows resistance training to be a possible therapy for individuals with ET. A team of researchers from Griffith University and Bond University in Australia identified that a generalized resistance training program for the upper limb is capable of improving manual dexterity in individuals with ET, and to a lesser degree, reduce abduction force tremor.

“Given that resistance training (RT) can reduce tremor amplitude and improve upper limb fine motor control in older adults, it is surprising that few studies have explored RT as a therapy for older adults with ET,” said Dr. Justin Keogh, Faculty of Health Sciences and Medicine of Bond University.

The lack of existing research inspired Keogh and his research team to compare healthy, older adults living with ET to those without ET through function tests. The function tests were used to assess activities common to everyday life. After a six-week resistance training program involving dumbbell bicep curls, wrist flexion and wrist extension exercises, functions test results significantly improved.

Results show that a simple dumbbell-based resistance training program had many significant benefits for older adults, with and without essential tremor. This indicated that both groups of older adults can significantly improve many real-world measures of manual dexterity. The greatest benefits following resistance training were gained for the limb most affected due to the disorder. This study is great news for individuals with ET to further explore the use resistance training as a viable therapy for improving upper
limb-function and ultimately, improving their quality of life.

To learn more about other IETF-funded research, please visit: http://essentialtremor.org/research/ietf-funded-research/.

NIH joins together five brain banks

The NIH announced the formation of a new brain and tissue repository network, NeuroBioBank, in order to create better access to post-mortem samples for those researchers studying brain disorders. Brain banks accept brain and tissue donations from people affect by brain diseases and from non-affected individuals, searching for changes that may offer insight into the cause of disorders such as essential tremor, depression, multiple sclerosis and autism.

Until now, brain banks were funded in a piece-meal sort of fashion; individual researchers requested funds for a specific disease or their specific bank. With this project, the NIH is looking to consolidate its funding efforts into a larger, more effective, standardized repository.

In September of 2013, contracts totaling $4.7 million were awarded to five brain bank repositories:  Mt. Sinai School of Medicine, New York City; Harvard University in Cambridge, MA; University of Miami; Sepulveda Research Corp., Los Angeles; and the University of Pittsburgh.  These banks have already begun developing a web-based sharing system that will allow the whole of the neuroscience community access to brain tissue samples and data, with a simple click of a mouse.

“Instead of having to seek out brain tissue needed for study from scattered repositories,   researchers will have one-stop access to the specimens they need,” explained Thomas Insel, MD, director of NIH’s National Institute of Mental Health.

Other brain banks, such as those funded by the IETF for the study of essential tremor, may become eligible to become contract sites of the NeuroBioBank in the future. In the meantime, the five current NeuroBioBank sites will soon be uploading their specimen inventories and clinical data (early 2014) so that researchers from around the globe can identify available specimens and further our understanding of the inner workings of brain and brain disorders.

For more information about the participating brain banks visit www.neurobiobank.nih.gov. You can also learn more about IETF funded brain banks in the IETF Funded Research section of our website.

Study seeks DBS advancement

DBSDeep Brain Stimulation (DBS) has been around for many years and is one of the most common surgical options for the treatment of essential tremor.  Recently, a new system has been developed that takes DBS to the next level. The new device actually senses and records the brain signals that cause the symptoms of essential tremor and other movement disorders, allowing researchers the opportunity to see exactly what signals are related to abnormal movements.

Although approved for use in the European Union in January, Medtronic’s Activa PC+S system has not been approved by the Food and Drug Administration (FDA) for use in the United States. However, the new device is currently cleared for study in the U.S. and two patients with advanced Parkinson’s disease have already undergone the surgical implantation of the new device.

The hope is that in the near future, this technology will develop to a level where the device itself will monitor the patient’s brain activity and automatically adjust therapy based on the individual’s needs– just as a pacemaker does for heart patients today. This would be a big advancement in DBS if this technology can be developed. Instead of DBS sending a constant, unchanging signal to cancel out tremor symptoms, the device itself would automatically make adjustments and changes to offer patients optimum benefit.

Read more about this study here or learn more about surgical options for essential tremor in this webinar.