Neurona Therapeutics Joins
The Facial Pain Research Foundation
Consortium
Cory R. Nicholas, PhD
Co-Founder and Chief Scientific Officer; Neurona Therapeutics
Assistant Professor, Adjunct; University of California, San Francisco
Dr. Cory Nicholas is Chief Scientific Officer at Neurona Therapeutics. Prior to co-founding Neurona, Dr. Nicholas was a faculty member in the Department of Neurology at the University of California, San Francisco where his research program was focused on investigating the ontogeny of human cortical interneurons. Dr. Nicholas pioneered methods to derive interneuron precursors from human pluripotent stem cells for transplantation into multiple animal models of neurological disease. He maintains an adjunct faculty appointment at the University. Dr. Nicholas’s post-doctoral studies were conducted at UCSF. His pre-doctoral work at both UCSF and Stanford University investigated germ cell development from primordial germline and pluripotent stem cells. He received his Bachelor’s degree from the University of California, Berkeley. Prior to his interest in stem cell and developmental biology, Dr. Nicholas was a member of the research team at Sugen.
Neurona Therapeutics
Neurona was conceived in 2008 to realize the therapeutic potential of neuronal cell-based therapy. The rationale for pursuing this translational effort was based on many years of rigorous scientific discovery. In the late 1990’s, co-founders John Rubenstein, MD, PhD, and Arturo Alvarez-Buylla, PhD, were among the first to demonstrate that interneurons, a type of nerve cell, in the cerebral cortex mostly originate from precursor cells in the medial ganglionic eminence (MGE), a transient structure during fetal brain development. In these early studies, MGE cells were isolated from fetal mouse brain and injected into the brains of post-natal mice. In contrast to other neural stem and progenitor cells from neighboring fetal brain regions that remained as large cellular masses post-injection, the MGE cells rapidly dispersed away from the injection site and appeared to seamlessly integrate into juvenile and adult mouse recipient brain tissue. The injected MGE cells appropriately matured into various sub-lineages of cortical interneurons that secreted GABA, the major inhibitory neurotransmitter in the central nervous system. Electrophysiology confirmed these cells to be functional neurons that both received and formed synapses, validating their integration post-transplant. The interneurons persisted long-term following transplantation. Moreover, the transplanted interneurons augmented functional inhibition in the brain regions where they were placed. Therefore, MGE interneuron precursor cells had unique properties that could be advantageous if developed into a transplantation cell-based therapeutic. These cells could potentially provide targeted inhibition to hyper-excitable neural networks in relevant neurological disorders. Rather than acting as a transient point source of GABA or a drug pump, the injected interneuron precursor cells integrated into neural circuitry, possibly allowing for stable repair of the injured nervous system.
To investigate the therapeutic potential of interneuron cell transplantation therapy, we first injected mouse MGE precursor cells into multiple rodent models of epilepsy, Parkinson’s, and Alzheimer’s disease. Although their etiologies are largely unknown and progression is divergent, these disorders can be associated with neural hyper-excitability and have overlapping co-morbidities. We collaborated with preclinical animal model experts in these disease areas, and, indeed, we found that the injected cells were effective. The injected MGE cells matured into inhibitory interneurons and virtually eliminated seizures, improved motor function, and reduced cognitive impairments, respectively.
In each of these animal models, the MGE cells were injected into forebrain regions where MGE-type interneurons would normally reside during endogenous brain development. To our surprise, the MGE cells also integrated into ectopic regions of the central nervous system, regions they do not normally populate during development. In collaboration with Allan Basbaum, PhD, mouse MGE cells were injected into the mouse spinal cord where they matured into inhibitory cortical-type interneurons and synapsed with resident spinal cord neurons. The mouse MGE cells were next injected into the mouse spinal cord after a sciatic nerve injury. Sciatic nerve injury produces chronic neuropathic pain that is associated with a loss of GABAergic inhibitory tone in key sensory pathways. This loss of inhibition leads to hyper-excitability of sensory neurons that send pain signals to the brain. The delivery of GABAergic inhibitory interneurons into the spinal cord was able to provide missing inhibition, rebalance sensory circuits, and suppress pain hypersensitivity. The transplanted interneurons achieved a complete rescue, reducing pain sensitivity to pre-injury levels without any observable side effects. Rather than a transient treatment of symptoms, the interneuron cell therapy was truly disease modifying by addressing the underlying pathophysiology of neuropathic pain following the administration of a single dose of cells. In addition, the disease modifying activity persisted long-term for six months post-transplantation, as long as was studied in a mouse. Dr. Basbaum’s laboratory has subsequently shown that interneuron cell therapy can be similarly effective at rescuing experimental pain hypersensitivity in mice following trigeminal nerve-injury or chemotherapy.
All of the studies above were performed with mouse MGE interneuron precursor cells. However, a human cell source is required to facilitate the translation of an interneuron therapeutic for patients. Since the MGE structure disappears before birth and human interneurons in the adult brain are not accessible, we turned to human pluripotent stem cell (hPSC) lines. These hPSC lines can be expanded to meet clinical demand and can be coaxed into becoming virtually any cell type in the body. We developed methods to direct hPSCs into the MGE-type interneuron lineage in petri dish cell cultures. These human interneurons produced in petri dishes were then isolated and provided to collaborators at UCSF for testing in many of the preclinical animal models described above. Encouragingly, Dr. Basbaum found that version 1.0 of the human interneurons also could reduce pain hypersensitivity in the sciatic nerve injury mouse model. Arnold Kriegstein, MD, PhD, in collaboration with another laboratory, next demonstrated that the human interneurons mitigated neuropathic pain and bladder dysfunction following spinal cord injury in mice.
Based on this body of work, Drs. Rubenstein, Alvarez-Buylla, Kriegstein, and I officially launched Neurona Therapeutics in early 2015 to develop neuronal cell-based therapeutics, starting with interneurons. We have assembled an all-star team of 35 researchers from around the world to advance this technology toward the clinic. We believe that multiple neurological disorders are associated with interneuron dysfunction and/or imbalances in neuronal activity. Because they do not innately regenerate, stem cell technology is required to generate inhibitory interneurons to re-balance the nervous system. Technology to produce human interneurons was developed at UCSF using research-grade stem cell lines, materials, and methods. The company is now tasked with extending this work and developing clinical-grade product candidates. We have made tremendous progress and continue to passionately pursue regenerative neuronal cell-based therapies with the potential to successfully treat patients who have neurological disorders.
The Facial Pain Research Foundation
Dr. Michael Pasternak and Elizabeth Cilker Smith introduced me to the Foundation. They were familiar with Neurona’s efforts from our collaboration with Dr. Basbaum. I was immediately impressed with the progress being made by the Foundation, its ability to raise important research dollars, and the selective investment of those funds into breakthrough facial pain research efforts that are making critical advances. I was equally struck by Michael and Beth’s passion, dedication, and determination to find a cure - attributes undoubtedly shared by all who contribute and volunteer at the Foundation and responsible for its success thus far.
Neurona and the FPRF share a bold vision to achieve pain-free disease modification. Neurona’s mission is, in part, an extension of Dr. Basbaum’s work funded by the FPRF. We continue to develop a human inhibitory interneuron therapeutic for the treatment of neuropathic pain syndromes. We are pleased to be formally acquainted with the Facial Pain Research Foundation and look forward to an ongoing relationship.
Genetics Study
Finds Genes That Cause Trigeminal Neuralgia
Introduction by Michael Pasternak
In 2012 The Facial Pain Research Foundation approved a research study to find the genes responsible for trigeminal neuralgia.
While each of our Foundation’s scientific projects are valuable, the one that has been the most awesome and challenging for me has been the Genetics/DNA project. Dr. Doug Anderson (FPRF Director of Research) and I have had to communicate with scientists from four different countries (including Joanna Zakrzewska in London) and Collection Centers in 9 different cities in three countries! Doug has spent months on this project “everyday”! He has also had to communicate with additional scientists interested in our efforts and has done this while still overseeing the creation and development and evaluation of all of our Foundation’s other projects! How did we and he get so lucky?
While Doug has overseen and worked through the science some of our other Volunteers have been involved in working with the DNA Collection Centers, working through intellectual property problems, legal questions, raising the funds to pay for all of this, communicating to patients to give their DNA, creating PR pieces for the public to participate, keeping track of collection numbers, certifying completion of collections and data sent to OHSU and Rutgers, and making payments to the Collection Centers for their efforts. This project has been an enormous accomplishment. No Volunteer Foundation or organization has ever done this before! All completed while we grew our outstanding scientific project numbers to six and linked with two venture capital funded research projects.
The FPRF has spent over $650,000 of funds raised by our Volunteers and donors on this project. The FPRF Trustees have committed another $325,000 to complete the project in the next year.
So, now we have a team of scientists who have worked hard using their unique skills and understandings and have presented a report to our Trustees and asked to go forward to replicate the study during the next year to prove that what they have found are really the genes that will lead us to finding the cures. The Cilker Genetics/DNA Research Report has arrived. It is remarkable. We are extremely thankful to Drs. Devor, Burchiel, Seltzer, Diehl and Anderson for all of their voluntary efforts to create these findings. We are also truly thankful for Our Trustees and all of our Volunteers who helped raise the necessary funds to complete the tasks. This is an exciting time for all of us committed to ending the pain for all TN and related neuropathic sufferers.
The Following is a Non-Technical Summary Report…The detailed full Scientific Report has been presented to the Foundation Trustees and contains confidential information. It will be confidential until the replication of findings has been completed. Following the report is an article by Dr. Scott Diehl for general distribution.
Genome-Wide Association Study
Of Trigeminal Neuralgia Type 1 (TN1)
The William A. and Leila A. Cilker
Research Project
A Report Prepared for the Board of Trustees of the Facial Pain Research Foundation by Kim J Burchiel, MD (Oregon Health and Science University), Marshall Devor, PhD (Hebrew University of Jerusalem), Scott R Diehl, PhD (Rutgers Biomedical Health Sciences), and Ze’ev Seltzer, DMD (University of Toronto)
Findings and Future Plans – Non-Technical Summary
The main goal of our study is to find genes that cause “Classical” Trigeminal Neuralgia Type 1 (TN1). This information will help clinician-scientists find cures that relieve patients’ severe chronic pain or prevent it from developing. Thus far, we’ve searched the genetic material (DNA) of TN1 patients at over a million places where people are known to differ from one another in their DNA letters (A, T, G or C). On average, any two people have about five million DNA differences between them. Most differences have no effect on health, but some cause or predispose to disease. Our challenge is to find the “needles in a haystack” that cause TN1, hidden among the millions of differences with no relation to TN1. We do this by comparing DNA of TN1 patients (cases) with that of people who do not have TN1 (controls).
Our initial search focused on 348 Caucasian TN1 patients, a modest sample size for human genetic studies today. Nevertheless, we are delighted to report discovery of several regions in the human genome with promising evidence they may harbor genes causing TN1. Some regions include only one gene, but there are 17 genes in the genome location with the strongest statistical support, including 3 with biological functions involving nerve degeneration, excitability of neurons or responses to nerve injury. These genes are strong suspects, but to determine which genes actually cause TN1we need a combination of: a) more genetic data of the kind we have already been gathering, and b) information from a complementary approach that uses high speed DNA sequencing. This further research is absolutely necessary before our initial discoveries are ready for testing in animals or translation to the clinic.
First, we must be absolutely certain our TN1 patients and controls do not happen to be very different by chance alone, but that the DNA differences occur because mutations hidden in the regions actually cause TN1. To do this, we will repeat our experiment a second time and see if we get the same results. We will analyze variation across the human genome for a new set of TN1 patients and controls using the most advanced genomic assays now available, more than doubling our sample size. If the same genome regions are again different in TN1 patients compared to controls (like lightning striking in the same place twice), this replication will confirm that TN1 disease-causing genes are indeed located there. Some regions have initial statistical support stronger than others, so these are more likely to be confirmed, but only by doing the assays and carefully evaluating what the data tell us will we know for sure which regions are confirmed. We do not expect all of our initially positive regions to be confirmed, but even if only one region is strongly confirmed this will be an extremely important advance, not only for TN1 but for the entire biomedical field of neuropathic pain in general. 2 Submitted January 3, 2018
Moreover, it is not enough to just find regions of the genome that harbor genes that cause TN1 – we also have to identify the specific genes and mutations in these genes that cause them to biologically malfunction, as this information is essential for translation to new therapies. It is possible that some of the mutations that cause TN1 are extremely rare, found only in TN1 patients and their close relatives. To discover additional TN1 genes and TN1-causing mutations, including those that are very rare, we will use the latest technologies for “reading” the DNA sequence of the entire human genome in a select subset of our TN1 patients. This method is called Next Generation Sequencing (NGS), and we propose to perform this assay for 100 TN1 patients.
Combining our previously-studied as well as our new TN1 cases gives us a sample of approximately 900 TN1 cases, of mostly Caucasian racial origin but with some non-Caucasians included too. Combining these with a similar number of controls will provide us with substantially increased statistical power to ask several very important questions such as the following: Do different genes cause TN1in young patients versus those who experience their first symptoms when older? (We already started to ask this first question in a limited way in the first phase of our research and with a larger sample can address this more rigorously.) Are there different genetic effects in males versus females, as found in many other genetic diseases? Are there different genes causing TN1 in the (typically younger) patients without vascular compression of their trigeminal nerve compared to patients whose trigeminal nerve has been damaged by years of vascular compression?
Our research may lead to a more complex picture of TN1 as being caused by not just mutations of just one gene, but in fact mutations found in several different genes may be associated with various subtypes of TN1. Genetics may reveal TN1 clinical subtypes that we currently do not even recognize exist, as has been found in numerous other neurological conditions including the epilepsies and the many forms of ataxia caused by different genes. While our primary goal remains identifying gene mutations that cause TN1, the research described here for the next phase of our study may also identify genetically distinct subgroups of TN1 patients as a very important secondary benefit of our genetic approach. Progress towards a cure (or, more likely, “cures”) will be more rapid and have greater chance of success if it is built on a foundation of knowledge about what is really going on biologically in different TN1 patients rather than if forced into a “one size fits all” therapeutic approach.
Project Timeframe: With adequate funding all research can be completed within one year. 3 Submitted January 3, 2018
Genetics Study
Brings Precision Medicine
To Trigeminal Neuralgia
By Scott Diehl
The Genetics Study team supported by the Foundation has completed a search of over one million locations in the DNA of 348 Trigeminal Neuralgia (TN) patients. This “Big Data” effort has pointed to genes affecting excitability of neurons, nerve degeneration and responses to nerve injury. These genes are very strong suspects, and the team will now gather additional information from more patients and from a complementary approach that uses high speed DNA sequencing.
In the team's next effort, these genes will be tested in a new set of TN patients.
If the same results are found again, this replication will be like lightning striking in the same place twice and confirm that mutations in these genes cause TN in some patients. These next steps are essential to confirm the initial findings and they may also reveal additional genes not detected with a strong enough signal in the initial search. Once confirmed, these discoveries will then be ready for testing in animals and translation to patients in the clinic.
The genetics data gathered thus far are painting a complex picture of TN as being caused by not just mutations in any one gene. It appears more likely that several different genes are involved in different patients, a phenomenon known as “genetic heterogeneity.” For example, one of the most strongly supported genes is important only for TN patients whose symptoms first appeared after age 55. A different gene with different biological functions is implicated in patients who developed TN at a younger age. Genetic heterogeneity has been found in other neurological conditions including the epilepsies and the many forms of ataxia caused by different genes. This strategy, known as Precision Medicine, is a major US and International effort getting underway focusing on nearly all human health problems today (https://allofus.nih.gov/).
While the primary goal of the genetics study is to identify gene mutations that cause TN, this research may also identify genetically distinct subgroups of TN patients as a very important secondary benefit. Progress towards a cure (or, more likely, “cures”) will be more rapid and have greater chance of success if built on a foundation of knowledge about what is really going on biologically in different TN patients rather than if forced into a “one size fits all” therapeutic approach.
The Genetics Study Team supported by the Foundation is an international collaboration of leaders in the fields of neurosurgery, pain biology and human genetics at Oregon Health and Science University (Dr Kim Burchiel), The Hebrew University of Jerusalem (Dr Marshall Devor), the University of Toronto (Dr Ze’ev Seltzer) and Rutgers School of Dental Medicine (Dr Scott Diehl). Numerous additional locations have provided valuable assistance with recruiting patients.
The Long Pain Road
For Chris Nolze
By
Kathleen Sweeney
Chris Nolze was diagnosed with brain cancer in 2007 at the young age of twelve. It was his initial diagnosis and the first of his major medical health issues.
He received radiation treatment after they did a biopsy on the tumor and placed a shunt in his head. It seems that where the tumor was located there was a lot of spinal fluid built up in his skull that was not draining. It was only the beginning of a number of challenges to follow.
During and after the radiation treatment he wasn’t “presenting” as well as other patients. They were not sure what was going on. There were signs of other medical issues that kept coming up and they are finally now discovering that the medical issues he has been dealing with since that time “are related either directly or correlated, to the radiation treatment”.
“Ever since my cancer I’ve had over 20 surgeries; … the majority of them were considered to be brain surgeries. Between the trauma from the tumor and then the trauma from all of the surgeries and then the trauma of radiation treatment my nerves were put at high risk … My cranial nerve and my trigeminal nerve just happened to be in that mix. “
When Chris had his wisdom teeth removed in 2012 he had complications that resulted in dry sockets. He was in pain but both he and his doctor thought it was due to the surgery. But it didn’t go away. Finally his dental surgeon suggested that they look into trigeminal neuralgia. It was a stretch since he did not fit the “norm” being a young boy with pain on both sides that was constant.
Neither Chris nor his parents had ever heard of trigeminal neuralgia. But since they had tried every possible medication at least twice and then in combinations and none of them gave him any relief they sought out his neurologist.
His neurologist and oncologist both thought it was highly “unlikely” that he had TN since he wasn’t showing the “proper” symptoms. Besides, it “just wasn’t possible”! For the next six months his parents took him all over this country looking for a doctor who would have another diagnosis.
Eventually they found Dr. Ben Carson in Maryland who tested the nerve on the right side of his face with a Rhizotomy treatment, which is the numbing or affecting of the nerve directly to see if it is the cause. “It helped the pain completely! … It was definitely a breath of fresh air.” It was the first relief he had had in six long months. “But I still did have constant pain on my left side.“
Shortly thereafter Dr. Carson scheduled Chris for an MVD (micro vascular decompression) on the other side, the left side. As he was recovering from that surgery the Rhizotomy “gave out” on the right side so they scheduled him for another MVD on the right side this time.
The pain was relieved but the incision would not close. They discovered that the skull bone itself was infected. They brought in a plastic surgeon to remove a piece of the skull about the size of a quarter. He placed a mesh plate over the opening created and then pulled the muscle up and over it (some of which had also been removed.) Eventually the incision closed properly.
Chris was pain free for about a year.
Then both sides came back and at about the same time. And around this same time he also contracted a rare case of intractable singultus (out of control hiccups). His is only the third case in medical history with this particular form. “They were speeding up on a daily basis and it got to the point where I would be doing over 200 hiccups in a minute! And it just kept getting faster and faster.”
It was a chiropractor, thinking outside the box, who put pads near his mesh plate and connected a tens unit to it. When it was turned on the hiccups stopped “instantaneously!”
So began another search for another doctor, this time with a tens unit connected to his head! Chris and his parents traveled the entire country again, finally finding Dr. Mark Linskey in California. He was actually Chris’ last and final hope of not having to live the rest of his life with a tens unit taped to his head.
“In every sense of the word, Dr. Linskey saved my life” says Chris. An MRI showed compressions on both his brain stem and on his facial nerves. Dr. Linskey thought the compressions on Chris’ brain stem might be the cause of the hiccups. While performing a repeat MVD on the right side of his face he tried lifting two major arteries off the brain stem. The hiccups stopped.
Out of curiosity and for research sake, Dr. Linskey released them and allowed them to go back where they were and the hiccups started back up again. When he lifted the arteries, they stopped. This confirmed that the cause of the hiccups was finally found! Since that surgery his right side has been not only TN pain free but he hasn’t had an abnormal case of hiccups since.
Once Chris recovered from that surgery they did a repeat MVD for trigeminal neuralgia on the left side. That was in 2014 and he is still pain free to this day!!
Although he cannot do any activities that might cause trauma to his head and has to avoid all sports, Chris is able to work part time. He is also studying online for his college degree, which he plans to receive this year.
In that same year of 2014, he joined the Young Patients Committee of the Facial Pain Association. It is a small group of less than 10 people who are supportive of anyone with facial pain under the age of 40. They promote awareness and help research for the really young suffering from all types of facial pain (not just trigeminal neuralgia.)
Chris also started his own foundation after his bout with cancer. He wants to give back to the community who “gave to my family and myself as we were going through everything. … I also wanted to raise funds for medical research for a lot of these radical conditions out there, especially trigeminal neuralgia.
“I focus on raising funds for research … and I have actually raised and donated $692 from my foundation to the Facial Pain Research Foundation” by selling teal colored t-shirts with his foundation logo on the front. A school friend of his hand knits teal scarves and he sells them also. All proceeds are donated to FPRF.
Chris does all he can to get the word out and to bring awareness. He has been recognized by the mayor of his town in Tom’s River, New Jersey, a couple of times already, with township proclamations that show that his foundation’s efforts are being recognized. He received one in 2016 from Governor Christy proclaiming October 7th Trigeminal Neuralgia Awareness Day! Since then, Chris has also received multiple proclamations from the town council recognizing every time the foundation helps out or works to spread awareness.
Chris volunteered that he wouldn’t change a thing if he could. “It helped sculpt me into the man I always wanted to be, that I was meant to be, and even if I had the opportunity to somehow stop everything from happening and go back in time and just live it out as ‘normal’ I wouldn’t change anything.” He is very insightful for his age. And very brave I might add.
When asked for what advice he would give to anyone new to the pain of trigeminal neuralgia he replied “The number one piece of advice I would give is to not give up and to not lose hope because even though you may be faced with a hundred people saying ‘No. It’s not possible.’ that doesn’t mean that there is absolutely no help out there for you.” And “Let your heart kick in and just say ‘no I’m not going to give in until I get the answers - until I get the proper treatment. I know something wrong is going on right now.’”
He added “It made me grow up much faster than I anticipated but in a way it also helped me.” I can vouch for that. Chris certainly seems a whole lot older and wiser than any 22 year-old I’ve ever known!
CODA Joins Facial Pain Research Foundation
International Scientific Consortium
By Michael Pasternak
I am excited to say on New Years Day 2018, The Facial Pain Research Foundation (FPRF) has six Foundation and two corporate funded scientific research projects actively working to find the cure for trigeminal neuralgia and related neuropathic pain. The scientists working on these projects are members of our International Scientific Research Consortium. In the past this World Famous WebNewspaper has printed numerous stories about the Foundation funded projects (see Dr. Douglas Andersons 2017 Report). In October, 2017 the FPRF announced that Neurona Inc. (a corporate funded research project joined the FPRF Scientific Consortium. Neurona is focused on the discovery and development of cell-based therapies to treat intractable neurological diseases including TN and related neuropathic pain. Today the Foundation is pleased to announce that CODA, another corporate funded scientific project, is joining the FPRF International Research Consortium.
CODA Biotherapeutics is a San Francisco based pre-clinical stage biotechnology company developing a novel therapeutic platform for the treatment of chronic pain and other severe neurological disorders. CODA’s innovative platform relies upon a gene therapy approach to modulating aberrant neural activity, which CODA’s co-founders -- a team of forward-thinking biotechnology entrepreneurs, scientists, and clinicians -- believe will provide relief to patients suffering from intractable neuropathic pain such as that associated with trigeminal neuralgia and establish a new treatment paradigm for severe neurological disorders. The entire CODA team enthusiastically welcomes the opportunity to join the Facial Pain Research Foundation’s Scientific Consortium in developing new treatment options for patients with trigeminal neuralgia.
Building upon the groundbreaking work of the company’s founders and Scientific Advisory Board members, several of whom have been associated with FPRF, CODA is using advanced synthetic biology approaches to engineer novel neurotransmitter receptors that respond selectively to non-addictive and non-opioid-based small molecules. These engineered neurotransmitter receptors are delivered to pain-signaling neurons using viral vectors by standard of care neurosurgical procedures. Hyperactive target neurons that express the receptor, including those in the trigeminal ganglia, can then be controllably silenced by oral administration of the safe small molecule. Because the treatment molecule exclusively activates the receptor, it is possible to achieve highly selective blockade of the critical pain signals from reaching the brain. This effectively opens the “therapeutic window”, reducing the potential for adverse side effects. Preclinical studies in multiple neuropathic pain models have demonstrated that this technology provides robust, durable, tunable, and reversible pain control, without the side effects experienced with existing small molecule therapies (e.g. opioids, anticonvulsants, tricyclic antidepressants) or neurosurgical procedures (e.g. ablation, neurostimulation implants). CODA anticipates that this technology will be used to manage intractable chronic pain across a multitude of conditions, including trigeminal neuralgia, and it will be applied broadly to other peripheral and central nervous system disorders in the future.
$500,000 Matching Gift
For
“The William H. and Leila A. Cilker Genetics Research Program
To Find a Cure for Trigeminal Neuralgia”
EVERY DOLLAR YOU GIVE
WILL Be Matched
HERE’S YOUR CHANCE TO DOUBLE YOUR GIFT....DONATE NOW
First Published Sept 23, 2014
We’ve come a long way! Join us and make our journey shorter!
By Roger Levy
Back in 1990, when the Trigeminal Neuralgia Association was first organized, its growth and development depended on the volunteer founders and some leading neurosurgeons who were concerned that little was being done to help patients understand their condition and gain access to specialists who could treat their condition. The Internet had yet to develop and getting the word out was managed through support groups started by volunteer patients who had become acquainted with the Association.
As time went on and the number of patients who looked to the Association for information and support began to grow so did the association’s awareness of the limitations which affected the medical and surgical options available as treatment. The drugs, after all, do nothing but dull the pain and most of the surgical procedures involve permanent damage to the nerve and that damage can often result in increased and, sadly, inoperable pain if the procedure fails. Gamma Knife treatment which involves radiation is promoted by many centers as non-invasive and yet there are too many patients who have increased pain where the radiation treatment failed. Even microvascular decompression which has a high success rate and involves no permanent damage to the nerve has its limitations because it involves a hospital stay and general anesthetic, for which some patients are not candidates either through choice or some other medical condition.
Still, over the years, the Association has helped many tens of thousands of patients to gain relief and regain a good quality of life. This is an important and continuing part of the Association’s mission on which it continues to deliver. But what of tomorrow’s patients or those today with unresolved pain? What’s to be done about them?
That is a question which the Association began to address when your Founding Trustees, Michael Pasternak, Mike Hirsch and I were members of the Association’s Board. Faced with that challenge, we embarked on an ambitious plan to establish a facial pain research program at the McKnight Brain Institute at the University of Florida, where Doug Anderson, Foundation trustee, was then the Executive Director. However, raising sufficient funds for research and meeting other parts of the Association’s mission was too great a challenge. Thus we chose to establish The Facial Pain Research Foundation.
That was over two years ago and look how far we have come! In a short period of time, The Facial Pain Research Foundation has raised over $1,300,000 and has provided funding for 4 separate research projects intended to find a permanent end to the pain of trigeminal neuralgia. Now, as word gets out across the internet via our Web Newspaper, people are contacting us from all over the world to ask “How can we help?” - Something unimaginable in 1990. When I was diagnosed with TN in that year, there were few places to turn. My neurologist could only recommend Tegretol or, when I proved allergic, acupuncture. Surgery, he warned me, was to be avoided at all costs. It was not until 1997 that the internet lead me to the Association and to a quick path to relief through microvascular decompression. Even with all those years of pain, though, I count myself lucky now that I am pain and medication free. Not every patient enjoys that success and for them and the patients who have yet to come, the work of the Foundation is imperative.
If you are reading this, chances are you are doing so because of the reach of the internet and, so rather like the support groups of the ‘90s, you have the opportunity to support our cause and bring our journey to a successful conclusion more swiftly. You can help in many ways as you can read elsewhere in our Newspaper, including making a financial contribution. Contributions are now coming to us almost daily with words of support and encouragement. No amount is too small to win our gratitude or to help.
We have world class scientific investigators enthusiastically working on behalf of facial pain patients, without national or other boundaries. They are our researchers “sans frontieres” and the benefits of their research will similarly lack borders. We are a community brought together by common cause. Be part of that community and help us to achieve our goals.
https://today.duke.edu/2017/11/why-head-and-face-pain-causes-more-suffering
Why Head and Face Pain
Causes More Suffering
Sensory neurons in the head and face tap directly into the brain’s
emotional pathways
November 13, 2017
Hate headaches? The distress you feel is not all in your -- well, head. People consistently rate pain of the head, face, eyeballs, ears and teeth as more disruptive, and more emotionally draining, than pain elsewhere in the body.
Duke University scientists have discovered how the brain's wiring makes us suffer more from head and face pain. The answer may lie not just in what is reported to us by the five senses, but in how that sensation makes us feel emotionally.
The team found that sensory neurons that serve the head and face are wired directly into one of the brain’s principal emotional signaling hubs. Sensory neurons elsewhere in the body are also connected to this hub, but only indirectly.
The results may pave the way toward more effective treatments for pain mediated by the craniofacial nerve, such as chronic headaches and neuropathic face pain.
“Usually doctors focus on treating the sensation of pain, but this shows the we really need to treat the emotional aspects of pain as well,” said Fan Wang, a professor of neurobiology and cell biology at Duke, and senior author of the study. The results appear online Nov. 13 in Nature Neuroscience.
Pain signals from the head versus those from the body are carried to the brain through two different groups of sensory neurons, and it is possible that neurons from the head are simply more sensitive to pain than neurons from the body.
But differences in sensitivity would not explain the greater fear and emotional suffering that patients experience in response to head-face pain than body pain, Wang said.
Personal accounts of greater fear and suffering are backed up by functional Magnetic Resonance Imaging (fMRI), which shows greater activity in the amygdala -- a region of the brain involved in emotional experiences -- in response to head pain than in response to body pain.
“There has been this observation in human studies that pain in the head and face seems to activate the emotional system more extensively,” Wang said. “But the underlying mechanisms remained unclear.”
To examine the neural circuitry underlying the two types of pain, Wang and her team tracked brain activity in mice after irritating either a paw or the face. They found that irritating the face led to higher activity in the brain’s parabrachial nucleus (PBL), a region that is directly wired into the brain’s instinctive and emotional centers.
Then they used methods based on a novel technology recently pioneered by Wang’s group, called CANE, to pinpoint the sources of neurons that caused this elevated PBL activity.
“It was a eureka moment because the body neurons only have this indirect pathway to the PBL, whereas the head and face neurons, in addition to this indirect pathway, also have a direct input,” Wang said. “This could explain why you have stronger activation in the amygdala and the brain’s emotional centers from head and face pain.”
Further experiments showed that activating this pathway prompted face pain, while silencing the pathway reduced it.
“We have the first biological explanation for why this type of pain can be so much more emotionally taxing than others,” said Wolfgang Liedtke, a professor of neurology at Duke University Medical Center and a co-author on Wang’s paper, who is also treating patients with head- and face-pain. “This will open the door toward not only a more profound understanding of chronic head and face pain, but also toward translating this insight into treatments that will benefit people.”
Chronic head-face pain such cluster headaches and trigeminal neuralgia can become so severe that patients seek surgical solutions, including severing the known neural pathways that carry pain signals from the head and face to the hindbrain. But a substantial number of patients continue to suffer, even after these invasive measures.
“Some of the most debilitating forms of pain occur in the head regions, such as migraine,” said Qiufu Ma, a professor of neurobiology at Harvard Medical School, who was not involved in the study. “The discovery of this direct pain pathway might provide an explanation why facial pain is more severe and more unpleasant.”
Liedtke said targeting the neural pathway identified here can be a new approach toward developing innovative treatments for this devastating head and face pain.
This research was supported by grants from the National Institutes of Health (DP1MH103908, F31 DE025197-03, K12DE022793). Dr Liedtke is also supported by the Facial Pain Research Foundation (Gainesville FL).
CITATION: "A Craniofacial-Specific Monosynaptic Circuit Enables Heightened Affective Pain," Erica Rodriguez, Katsuyasu Sakurai, Jennie Xu, Yong Chen, Koji Toda, Shengli Zhao, Bao-Xia Han, David Ryu, Henry Yin, Wolfgang Liedtke and Fan Wang. Nature Neuroscience, Nov. 13, 2017. DOI: 10.1038/s41593-017-0012-1
First Published June 13, 2014
Dr. Mark Linskey is a Professor of Neurological Surgery currently practicing at the University of CA, Irvine, in Orange County, CA (http://www.faculty.uci.edu//profile.cfm?faculty_id=5322). He trained in microvascular decompression (MVD) for 7 years with Peter Jannetta and in Gamma Knife stereotactic radiosurgery (GKSR), glycerol rhizotomy and radiofrequency lesioning for 7 years with L Dade Lunsford at the first US gamma Knife unit at the University of Pittsburgh. He has continuously served on the Medical Advisory Board of TNA - The Facial pain association since 2003; currently serving as their Western Regional Director. In practice and out of training for more than 20 years, he published the first prospective cohort comparative clinical trial of MVD versus GKSR for typical trigeminal neuralgia and is an internationally-recognized expert, and experienced surgical subspecialist, in trigeminal neuralgia. He is currently the American College of Physicians (ACP) Trigeminal Neuralgia module editor for their physician point of care decision support tool "Smart Medicine" (formerly PIER - Physician Information & Education Resource). He is also the Co-Editor of the Trigeminal Neuralgia module for the rigorous evidence-based medicine periodic systematic review tool and physician decision-support resource, "Clinical Evidence", published by the BMJ (British Medical Journal) for the British Medical Association.
Facial Pain The Research Imperative
By Mark E. Linskey, M.D.
From a twisted and perverse perspective, among facial pain patients, patients with classical trigeminal neuralgia (TN), are comparatively fortunate. We at least have surgical treatment options with reasonable chances for successful pain relief when current medical therapy fails. Yet even for TN patients, not all patients fare well. While in expert and experienced surgical hands, microvascular decompression (MVD) can lead to durable complete pain relief in about 80% of patients, this still leaves one in five TN patients still suffering. Patients seeking care in the general medical community are not so fortunate. MVD results can vary significantly surgeon-to-surgeon. Empiric experience over the last 20 years in my practice, would suggest that the success rate among less experienced and expert surgeons might run as low as 50%.
For those patients with multiple sclerosis-related TN, or who fail MVD, their plight can be improved with palliative destructive procedures directed towards the trigeminal nerve [stereotactic radiosurgery (SR, radiofrequency lesioning (RFL), glycerol rhizotomy (GR), and balloon compression (BC)]. However, these procedures serve best as temporizing measures, with up to 50% of patients with classical TN recurring within five years of the procedure. Each palliative destructive procedure runs the risk of facial numbness with its associated risk of new de-afferentation pain from nerve damage, and these risks accumulate and compound as destructive procedures are repeated. Thus overall, across the U.S., even for patients with classical TN, surgical intervention may realistically not provide adequate or long-lasting relief in an estimated 30-50% of cases.
But what about those patients with other forms of facial pain? In 2008, after 18 years of existence, The Trigeminal Neuralgia Association (TNA) changed its name to TNA – The Facial Pain Association (TNA-FPA) in recognition of the fact that patients with facial pain other than classical TN also needed education, support and help too. These conditions include TN2, neuropathic facial pain, facial pain of obscure etiology, and anesthesia dolorosa, among many others. For these patients, MVD rarely leaves a patient pain-free. Furthermore, while palliative destructive procedures can, and do help, they not only are less successful than for classical TN patients, they may actually worsen the situation through increased de-afferentation, despite the best of surgical intentions. While surgical stimulator surgery can help these patients in very select cases, the overall percentage of patients enjoying significant and durable relief is disappointingly small. If we now broaden our inquiry to include all facial pain patients that seek help from TNA-FPA, it seems likely that only about half will achieve adequate or long-lasting relief from their suffering through surgery. Clearly surgery alone is not the answer for too many of our patients, friends, and family who suffer from facial pain.
The word imperative refers to something that is both necessary and of vital or crucial importance. It may also refer to the expression of a command. For facial pain syndromes new discovery and therapeutic breakthroughs through basic science research is an absolute imperative in the first sense and an imperative from our patients and their loved ones in the second sense.
We know that vascular compression is a necessary cause for the majority of classical TN patients. Yet up to 40% of normal living patients and up to 50% of patients studied at autopsy have these vascular contacts without having TN. Clearly vascular compression, while necessary, is not sufficient. The logical additional factor, that many have speculated about, likely involves additional predispositions related to genetics and/or the biology of myelin nerve insulation, axonal damage, or both. In my opinion, studies of deferential gene expression comparing classical TN patients to normal population controls carry the highest chance of uncovering potentially new fruitful areas for investigation and future therapeutic exploitation for patients with classical TN.
While the hoped for discoveries from studying differential gene expression in cases of classical TN might be more generalizable to help patients with other facial pain syndromes, this is by no means certain. Thus, simultaneous additional lines of research inquiry are also desperately needed. These include the urgent need for a better understanding of the neurochemistry and the psycho-biology of chronic neuropathic pain and the fast-track development of new agents for clinical testing. It includes studies into the biology of nerve repair and regeneration, through both pharmacological means as well as potential cellular therapies including stem cells. It also includes the need to study safe means of modulating pain perception at the brain level through brain stimulation technology.
While it is simple and conceptually satisfying to talk about the search for one “cure”, this may be an elusive goal given the heterogeneity and wide variety of facial pain syndromes suffered by patients seeking help through the TNA-FPA. More than one “cure” may be needed depending on the individual circumstances of each patient. Yet the quest for a “cure”, whether one or many, all still depend on basic science research advances which are expensive and which take years to develop, test and realize.
As a surgeon, I long for the day when we have therapies that can increase our MVD results to near 100% success, as well as offer hope and more predictable treatment success chances to our non-classical TN facial pain patients. While I am biased by my surgical background, I doubt that these advances will involve a new pill distributing an agent non-specifically throughout our body. I strongly suspect that they will involve therapies that will be most effective locally and selectively at the site of pathology or damage, either through direct open surgical application, or needle or electrode delivery into the trigeminal nerve root, ganglia, or brain. Thus surgery will likely be an important component of any success realized through our research efforts.
If we wish the state of care for patients with facial pain to improve from the levels currently available, we are indeed faced with a research imperative. The need is great and the costs are considerable. The best way that most can help is through generous donation and ongoing, sustained, support for efforts such as those fostered by our own Facial Pain Research Foundation http://www.facingfacialpain.org/ . We need everyone’s help and support to drive this mission forward and ultimately succeed.
Editorial Note
Mervyn Rothstein
|
Mervyn Rothstein who was an editor and writer at The New York Times for 29 years. Mr. Rothstein now writes the monthly "Regional  Theatre" column for Playbill Magazine and is a former member of the Tony Awards Nominating Committee. His first symptoms of trigeminal neuralgia occurred in 2005. |
John K. Neubert, D.D.S., Ph.D., is the principal investigator for the scientific research project entitled Mapping Towards a Cure: Identification of Neurophysiologic Signatures of Trigeminal Neuralgia Pain, at the Evelyn F. and William L. McKnight Brain Institute of the University of Florida. Dr. Neubert is a tenured associate professor in the Department of Orthodontics at the University of Florida College of Dentistry. He also has an adjunct appointment in the Department of Neuroscience at the University of Florida College of Medicine and is on the faculty of the McKnight Brain Institute. Dr. Neubert spoke by telephone from Florida with Mervyn Rothstein, who was an editor and writer at The New York Times for 29 years. Mr. Rothstein now writes the monthly “Regional Theatre” column for Playbill Magazine and is a voting member of the Drama Desk, an association of theater journalists. His first symptoms of trigeminal neuralgia occurred in 2005.
The Interview
MR: Why did you decide to focus on pain in your career?
That’s a good question. When you go through your dental-student career, you learn that pain is very much a part of the public perception of dentistry. That’s what people associate dentists with. As a dental student, I was fortunate enough to be able to do research with someone with studied facial pain and who saw facial pain patients. And I became interested in trying to find better ways of eliminating pain.
MR: Your research involves locating and imaging the signature centers in the brain for trigeminal pain, and the pathways to those centers. Once you do that, what happens next? What are the research steps that need to be taken to find the cure – to stop the pain – and how difficult is this process of moving from finding the cause to eliminating it?
The first step is the imaging part. We’re hoping that we can find a common signature center, where the pain starts, in the different patients that we’re scanning. We’re also doing a similar study in our animal models. We’re hoping also that there’s an overlap in what we see in trigeminal injury models in rats, and in what we see in humans. Once we can identify the signature center, that will be the target for possible future therapeutic treatments.
It’s a difficult process. The first problem is the relatively small number of patients who have trigeminal neuralgia. It’s a relatively rare disorder. So to get a sufficient number of subjects is the first challenge. And the next challenge is to see if there’s that overlap in brain activity in a signature center. The last difficulty comes in translating these results into therapies, and in getting those therapies approved. What’s helping us is that we are working in parallel on the basic side – our animal work – trying therapeutics, so once we are ready to move to the human side we will hopefully have things ready to go as far as therapeutics are concerned.
MR: What is the importance of this trigeminal neuralgia study and what potential is there for having an impact on the study of other diseases and possible cures?
We’re hopeful we can come up with new therapies, because it’s a disease that’s largely resistant to many treatments, and people even after surgery can still have horrible pain. As far as impacting other disorders, the mechanisms that occur in the face are very similar to mechanisms that occur elsewhere in the body, so we have a very clean model for studying pain.
MR: How have you and your research colleagues attacked this problem from a new perspective?
The neural imaging aspect is one of the more novel parts. People have done imaging for a number of years, and they’ve gotten very good at it. We’re using it in the sense of a biological marker, and we’re hoping that this neural image may also serve as a diagnostic tool. It could help people diagnose trigeminal neuralgia versus some other disorder that’s causing the pain. Our project Co-Investigator, Mingzhou Ding, is reknowned for his imaging expertise. I also work with a lot of very innovative investigators here at the University of Florida in terms of the therapeutic side of things. My collaborators on the project, Robert Caudle and Marcello Febo, have some novel therapeutics as far as targeting specific pain fibers. And we’re working with another investigator here, Todd Golde, who is an expert on viral delivery of pain therapeutics.
That’s the direction we’re going to take in terms of innovation, in what we think will be the best approach for treating trigeminal neuralgia. It’s basically a very safe virus that you can program to modify certain genes. You can have genes and proteins increase or decrease, depending on what you program into this vector.
The nice thing about these vectors is that it’s just an injection. People who have trigeminal neuralgia start out with some medication like Tegretol and if that doesn’t work they go to some kind of surgery and they may go to another surgery. So the idea of using one of these viral vectors would be to do the injection prior to having surgery, to see how it works, Because you could always do the surgery afterward. It makes sense to have this kind of therapy. I think people would prefer it if we could just inject something to end the pain.
MR: Why haven’t researchers completed this research years ago?
Two main reasons come up. It’s like a lot of things – technology and money. Advances in technology relating to computer power have really accelerated in the last five or ten years. Our imaging studies, as far as analyzing the data and narrowing the resolution of what we’re trying to locate, use very powerful magnets and computers.
It also really comes down to funding. Trigeminal neuralgia is a relatively rare disease, and there’s not a lot of emphasis on trying to get money to study this disorder. Pain is one of those disorders that’s not a disease. There’s a tremendous need to find new products, new pain therapies, but the situation doesn’t fit nicely in any of the National Institutes of Health categories as far as funding needs go.
MR: What are the biggest obstacles you face in translating your preclinical findings to the clinic?
Probably it’s just going to be dealing with the Food and Drug Administration’s regulatory process as far as getting a new therapeutic treatment approved. That process can take many years. So if we’re thinking about injecting a viral vector or using some kind of other therapeutic, a lot of other studies have to be completed first. Toxicology has to be worked out – we have to make sure it’s a safe approach. And then evaluate the therapeutic efficacy later. One of the problems we run into as researchers and trying to translate things is that many substances or therapeutics work very well in mice or rats, but we’ve seen previously that when you take the same substances and try them on humans, a lot of times they fail. That’s always an issue. Something that works on a rat doesn’t always work on a person.
MR: Every day many people in pain are contacting the Facial Pain Research Foundation asking if it is truly possible to find a cure for trigeminal neuralgia. How would you respond to their question?
I would say it is possible. We’re putting a lot of resources and a lot of brainpower into the problem and we’re hopeful that we can find something. This is a collective “we” I’m talking about – including the other investigators who are involved with the Facial Pain Research Foundation, the groups in Israel, Toronto, Portland, San Francisco, London, New Jersey, North Carolina and Florida. There are a lot of smart people working on this project to find a cure.
Volunteers Suffering from Trigeminal Neuralgia Needed for this Brain Imaging Study
Enrolling eligible volunteers to participate in a research study about brain imaging:
To be eligible you must be:
-18-75 years old
-Suffer from Trigeminal Neuralgia…diagnosed with Trigeminal Neuralgia
-Prefer Classical TN (Type 1) and Atypical TN (Type 2)
-Average Pain in the moderate to severe range
-No additional major health problems
-Be able to go to Gainesville Florida and spend approximately 4 hours
-Fluent in English (written and spoken)
Exclusion:
-Unable to complete a magnetic resonance imaging (MRI) scan due to implanted
or un-movable metal material in your body or severe claustrophobia.
For further information about volunteering for this study call or email:
Dr. John Neubert (352) 273-5687 or This email address is being protected from spambots. You need JavaScript enabled to view it.
This Study is directed by Dr. John Neubert, UF College of Dentistry, McKnight Brain Institute