Facial Pain Research Foundation
Funds Brain Research
McKnight Brain Institute
By Michael Pasternak
“Mapping Towards A Cure—Identification of Neurophysiologic Signatures of Trigeminal Pain” is one of four scientific projects to find a cure for trigeminal neuralgia and related neuropathic funded by our Foundation. It is entering a new phase and it is important that we share its progress. We are announcing the need for trigeminal neuralgia patients, both Classical TN (type 1) and Atypical TN (type 2) that are experiencing pain to participate in this research to find a cure.
We need volunteers for this active ongoing research project that the Foundation has funded for several years and is actively raising additional funds to continue its incredible progress. (see end of this article for volunteer information)
“As you know, the goal of the Foundation is to find cures by the end of 2020. This project update is very favorable and reflects the “lightning speed” our research is moving.”
Introduction by Douglas Anderson, Ph.D., Trustee and Foundation Director of Research:
The mission of the Facial Pain Research Foundation (FPRF) is to develop a translational (i.e., fundamental discovery to clinical application) research continuum dedicated to identifying the underlying mechanisms responsible for causing neuropathic facial pain. With the critical mechanism(s) known, groundbreaking therapeutic strategies that will cure or permanently stop the pain of trigeminal neuralgia (TN) and other related neuropathic pain syndromes can be developed. This research project to find a cure is an excellent example of this translational approach.
In 2012 a proposal entitled “A Neural Signature of TN Pain” was submitted to the FPRF by Andrew Ahn, M.D., Ph.D. who at the time of submission was an assistant professor in the Department of Neurology at the University of Florida College of Medicine (UFCOM). The FPRF committed funds to this projects first phase whose primary goal was to acquire a neural signature or “map” of the brain in individuals with TN pain.
Stated differently, Dr Ahn and his team were focused on discovering the areas of the brain that are activated in individuals experiencing TN pain. Shortly after starting this study, Dr. Ahn was recruited to the Eli Lilly Company and left UF.
Fortunately, there was another recognized expert in orofacial pain with a specific emphasis on the causes of and treatments for TN on faculty at UF. John K. Neubert, D.D.S., Ph.D. is a tenured associate professor in the Department of Orthodontics at the University of Florida College of Dentistry (UFCOD). He also has an adjunct appointment in the Department of Neuroscience at the UFCOM and is on the faculty of the Evelyn F. and William L. McKnight Brain Institute of the University of Florida (MBI). Dr. Neubert is eminently qualified to be the Principal Investigator of and has assumed responsibility for this project.
In response to queries from both Michael Pasternak and myself, Dr. Neubert has assembled an impressive team of co-investigators and has submitted to the FPRF a proposal entitled: “Mapping Towards a Cure-Identification of Neurophysiological Signature of Trigeminal Neuralgia Pain” that not only addresses the specific aims from Dr. Ahn’s original project but also extends it in a novel new direction.
The Trustees of the Foundation have committed additional funds to Dr. Neubert’s project.
The experiments outlined in this project are designed to study the cause of TN using a translational approach, which means determining if the neurobiology of TN in animals (rats) replicates or is very similar to the neurobiology of TN in humans. Usually this progression is done sequentially, i.e., the condition or disease is studied first in animals and then in humans.
However, because of the outstanding intellectual and technical capabilities available at the McKnight Brain Institute, Dr. Neubert and his team (Dr. Mingzhou Ding, Dr. Robert Caudle, Dr. Mercelo Febo, and consultant Dr. Andrew Ahn) will be carrying out their research project simultaneously in humans and animals.
Using state of the art magnetic resonance (MR) scanners for humans, they will be looking for specific areas of the brain and spinal cord that will be activated by TN pain...so called “signature” centers of activity.
They will attempt to locate these centers in individuals with TN before and after their pain has started….The importance of identifying the brainstem nerve tracts responsible for activating cortical areas in TN patients cannot be overstated.
Discovery of the relevant nerve tracts provides targets for treatments that can specifically block the pain of TN and eliminate or limited unwanted side effects because the treatment can be delivered locally and not systemically.
This group of investigators already has access to existing therapies that they speculate will be successful in blocking TN pain that can be tested on the rat once this animal model has been shown to be clinically relevant. This is generally last required step in bringing treatments from the dish to the doctor.
Executive Summary and Specific Aims by Dr. John Neubert:
Trigeminal neuralgia (TN) is an idiopathic pain disorder that is characterized by episodic attacks of intense facial pain, described as paroxysms of stabbing, electric, or explosive pain, and lasting for a few seconds or longer, often producing a tic-like facial movement, and can occur up to hundreds of times per day.
This pain is known to be one of the worst pain conditions that a patient can suffer and has been called the “suicide disease”.
Given the severity of this disorder, figuring out the cause becomes essential for finding a cure. This project will study the cause of TN using a translational approach, which means we will be completing our research project in both humans and animals.
We hypothesize that there are specific areas of the brain and spinal cord that will provide a “signature” center of activity.
We will use state of the art magnetic resonance imaging (MRI) machines to locate these centers in people with TN before and after their pain has started. In a similar and parallel study, we will image the brain and spinal cord in rats that have different trigeminal nerve injuries.
The Phase 1 of this proposal aims to identify and compare the different imaging patterns in both TN patients and rats. If we find similar patterns across humans and rats, then we will fast track our studies in Phase 2 to evaluate novel therapies.
If there are dissimilar patterns identified from Phase 1 studies, then Phase 2 will continue to evaluate more subjects (humans and rats) in order to get a larger sample size to strengthen the statistical power and results. We have existing therapies that we anticipate will be successful in this regard and we will test them using the animal models, providing a requisite step before considering use in patients.
This translational approach is important because identifying similar regions of neural activity will allow for us to study novel therapies in search of the cure for TN.
Trigeminal neuralgia (TN) is an extremely painful and highly disabling orofacial pain disorder, often referred to as the “suicide disease,” for which presently available therapies are largely ineffective or inadequate.
Both the unpredictable response to treatment and variability in long-term clinical outcomes in TN strongly suggest that a range of peripheral and central mechanisms remain to be understood. Our long-term goal is to identify the mechanisms involved in the initiation and progression of TN, and uncover rational targets for the safe and effective treatment of TN.
The objective of this application is to explore the use of multimodal neuroimaging and neurophysiologic techniques in defining neural signatures of the disease using a parallel animal and human study design. This is an important and necessary step utilizing a translational research approach for discovering diagnostic pathways that can reliably predict response to therapy and for evaluating novel therapies. The rationale for the proposed research is that identification of signature peripheral and central activation sites will allow for individualized treatment strategies for TN patients. As such, the specific aim of this project is:
Obtain neurophysiologic signatures of TN pain. We will utilize established expertise in combined EEG- functional MRI to profile the neurophysiological mechanisms leading to TN pain. We hypothesize that there is both a peripheral trigger and a central generator within the brain and these sites will be characterized in parallel human and animal studies. In addition to the distinct triggers and generators of TN pain there are likely dynamic relationships between somatosensory and association areas of the brain that determine response to treatment and progression of the disease. Therefore, we will evaluate therapies that extinguish those neurophysiologic signatures associated with TN pain.
We hypothesize that the relative predominance of these neurophysiologic signatures of TN pain will distinguish between those who do and do not benefit from therapy. Novel peptide-toxin conjugates will be evaluated in this sub-aim.
This study is designed to comprehensively characterize TN using state-of-the-art imaging and behavioral techniques in humans and rats. The benefit of this translational approach is that a validated animal model that is derived from the human condition lends itself to the direct conversion of novel therapies. Phase 1 of this study will provide validation of this translation (i.e., do we see the same results in humans and rats) and Phase 2 will provide the more comprehensive characterization of TN using these novel approaches. If Phase 1 provides sufficient data regarding the neural mapping of TN, we will focus on additional peptide-toxin conjugates in Phase 2. This will allow a more fast-track evaluation of novel therapies in the process of discovering a cure for TN.
Our project tests whether the presence of peripheral and central pain generators can predict clinical success from different therapies. The proposed research is innovative because it applies advanced multimodal and statistical methods to address the mechanisms underlying TN pain and uses a translational approach that builds on existing animal and human studies centered on understanding trigeminal neuralgia.
This project is significant because use of fMRI and EEG will deliver both high- temporal-resolution and high-spatial-resolution data to provide a neurophysiological signature of TN pain. This in turn can be used to improve patient selection for treatments as well as to investigate new therapies.
This would be of benefit by sparing the risk, expense, and morbidity of the existing and novel therapies. Successful and coincident mapping between the animals and humans is significant because it will provide validation of the animal injury procedures as a model of TN.
The translational approach used in this proposal is expected to yield the global benefit of being able to investigate novel therapies in an animal model that may lead to a breakthrough therapy in humans. By completing parallel studies, we will establish the framework for future therapeutic studies.
This project builds on the foundation of excellent projects previously funded by the Facial Pain Research Foundation, including the genetics project (PIs: Devor, Burchiel, Seltzer), myelin project (PI: Notterpek), and stem cell project (PI: Basbaum).
These funded projects focus on either basic science mechanisms/therapies or genetic findings in humans, providing valuable information into the translational research paradigm.
Our proposal “Mapping Towards a Cure – Identification of Neurophysiologic Signatures of Trigeminal Neuralgia Pain” incorporates both the basic science and clinical research components of translational research and asks the same question across both fields. Essentially, what is the neurophysiologic signature of TN pain?
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:
-18-65 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)
-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 Study is directed by Dr. John Neubert, UF College of Dentistry, McKnight