Change the Brain; Relieve the Pain; Transform the Person
Research
Research is directed toward clinical studies designed to clarify and exploit underlying mechanisms of neuroplasticity in the development and resolution of persistent pain disorders. The overall goal is to explore the relationship between neuroplastic treatment approaches with positive clinical outcomes of pain reduction, improved function and improved quality of life. Studies will bridge the gap of clinical practice and basic science, with a goal of designing techniques and products to help people with persistent pain to develop effective strategies to stay involved in the satisfying activities of life. While transformative neuroplastic approaches to treat pain persistence require motivation, relentlessness and practice, positive outcomes should reward the participant with pain relief, healthier brain function and a decreasing need for conscious intervention, as the brain’s positive adaptivity prevails. Research will focus on practical solutions, naturally occurring somatic processes and recognition of brain-body unity to reverse the maladaptation of persistent pain. While recognizing the importance of the randomized, double-blind, placebo-controlled clinical trial, this approach is not seen as an inherently higher form of evidence than other work in applied science, basic neuroscience, anatomy, physiology, cellular biology, molecular biology and genetics. Hypotheses will be tested using clinical case series, retrospective studies and double blind trials, selecting the best and most accessible method for the information being studied. A great deal of data and ideas have already been published regarding persistent pain in a multitude of disciplines and another direction of this research will be unification of what is often hidden in plain sight.
Scent
Scent provides an often random access to the brain and to the molecules, cells and circuits involved in pain processing. The first Cranial Nerve, the olfactory nerve, provides a way to smell the environment, allowing our brains to react with disgust, pleasure, revulsion, attraction, hunger and memory activation. The olfactory nerve is the only cranial nerve that starts outside of the brain. It’s origins are in the upper 1/3 of the mucous membranes in the nose, quickly entering the cranium through a series of holes at the top of the nasal bones, called the cribiform plate. The first synapse of the scent circuit in the brain occurs in the olfactory bulb and the second is in the amygdala, traveling to the insula, ventral medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex and posterior parietal cortex. Hence, scent is perceived in part of the same circuit we experience pain and pleasure, establishing the importance of scent for basic survival, with avoidance of scents that provoke disgust and pursuit of those that give pleasure. Human beings are capable of distinguishing 300 to 400 distinct scents, and combinations of them allows us to determine thousands of specific odors.
When scents are purposefully used the brain can be accessed for specific effects. This is the basis of aroma therapy. Ironically, this is often dismissed by mainstream medicine, despite some excellent research in this area regarding effects of many naturally occurring scents. These can be soothing and stimulating, invoking a sense of well-being and happiness. The brain releases substances that produce pleasure, including GABA, endorphins, oxytocin, anandamide and adenosine. These brain neurotransmitters oppose those in the equivalent pain circuits, Glutamate, Substance-P, Calcitonin Gene Related Peptide, Adenosine Triphosphate.
One scent in particular, peppermint, blocks the main pain neurotransmitter, Substance-P at presynaptic release sites, while also blocking calcium in post-synaptic calcium channels. Since the amygdala is the second synapse in the scent circuit and the first synapse in perceived pain, the activity of peppermint blocking Substance P and calcium channels theoretically makes it a potential pain reliever. Substance-P is a very specific neurotransmitter dedicated to five known effects, pain, nausea, anxiety, depression and inflammation. There is some evidence of peppermint’s effectiveness with irritable bowel and local burning skin pain. Peppermint tea is used for it’s soothing and calming effects, and most people have positive memories associated with its scent and taste. Additionally, peppermint has long been used in hospital wards to cover harsh scents to help with urinary hesitancy.
Over the last several years we have conducted a large case series in conjunction with aromatherapist, Sharon Thom, MA, MS, using a proprietary blend of peppermint and several other compatible scents. Results have been positive for pain relief, decreased nausea and stress reduction. Future studies will include a prospective trial of pain relief using peppermint oil blend, pain scales and functional imaging.
Sound
Extensive animal studies performed in the hippocampus have helped elucidate the way nerves behave when repetively stimulated in a process such as persistent pain. A pattern of self perpetuating firing called Long Term Potentiation (LTP) can be established, as can a state of inhibition of nerve cells from being fired over time, known as Long Term Depression (LTD). These processes explain the property of lifelong plasticity in the Central Nervous System. Studies of brain slices, anesthetized animals and freely roaming animals were refined over time, leading to the discovery of pioneering techniques that have become the standard in animal studies. These experiments have demonstrated how to create LTP and LTD. In early studies non-physiologic frequencies were used to create LTP by firing receiving nerve cells for one second at high frequencies. Subsequent approaches used trains of low frequency stimuli every few milliseconds resulting in the post synaptic nerves firing anywhere from an hour to the lifetime of the animal after presynaptic nerves had stopped firing. Subsequently, researchers used one cycle per second presynaptic firing frequencies for fifteen minutes to not only stop the LTP firing postsynaptic nerve cells, but to make them resistant to subsequent presynaptic electrical barrages.
While these studies were done in the hippocampus, subsequent studies have shown LTP and LTD to be present throughout the brain. The basic principles of neuroplasticity require the presence of LTP and LTD. Pain persistence occurs when LTP in pain circuits in the brain establishes a pattern of firing, with or without peripheral input.
These studies were done in living animals by stimulating presynaptic cells with electrical signals using implanted microarrays of electrodes. Researchers were already working to implant electrical stimulators in various parts of the human brain for treatment of highly resistant Parkinson’s Disease and Depression. There had even been studies done with brain implants using stimulators to control severe pain. Since this approach is neither feasible nor desirable in any except the rarest intractable cases of pain persistence, the question to be answered was how to get a low frequency electrical signal in the pain circuitry of the brain, without using an implanted device.
Auditory circuits turn out to be some of the broadest ranged and connected circuits in the brain, incorporating sound, emotion, movement, balance, pleasure and pain circuitry. Clearly music can soothe and stimulate. We hypothesized that LTD could be induced using low pitched sound. The problem was that sound this low in frequency was below human hearing ability and in some studies was actually shown to induce unpleasant phenomena, such as fear, panic and nausea. We decided to use low frequency sound at the bottom end of the range of hearing and vary it in volume and rhythm to attain the desired low frequency stimulation of the brain used in the invasive studies, while moving sound fields from one brain hemisphere to the other. We oscillated the sound at 0.33, 0.5 and 1.0 cycle a second initially. Ultimately we created sounds that oscillated between 1.3 and 2.7 cycles a second, using two extremely soothing and pleasing sources.
We have gathered case studies on this subject. We are planning studies using functional imaging techniques to determine if pain patterns change in the pain processing circuits of patients with a variety of pain disorders, using these sounds.
Vibration
Vibratory sense is an extremely important input from the body to the brain. We need an intact sense of vibration and proprioception (position sense) to be able to walk upright, establish motor memory for repetitive tasks and provide balance. Every step we take sends vibration signals to the spinal cord and brain, used to establish and maintain normal reflex arcs, allowing the body, spinal cord and brain to make dynamic adjustments to movement, without conscious intervention.
Sound perception is dependent on very fine vibration of the tympanic membrane and subsequent vibration of the ligaments, bones and nerve endings in the ear. Thus vibration links exteroception (perception of the external world), interoception (perception of internal experience of the body) and proprioception (perception of body parts in space). This sensation has a profound effect upon neuroplasticity.
As noted in the Research section on sound, we developed an approach using low frequency sounds rhythmically oscillating at 0.33, 0.5, 1.0 and between 1.3 to 2.7 hz to see if we could induce Long Term Depression (LTD) in pain circuits perpetually firing with or without a peripheral stimulus due to Long Term Potentiation (LTP). To this end we decided to apply the vibration associated with the same sounds on or near painful areas of the body. Early data shows a synergy between sound and vibration for reduction of pain.
We studied over 100 cases and saw significant reduction of pain, induction of pleasure and reduction of stress using vibration and sound together. We have developed 9 prototype devices to demonstrate this principle with a high level of success. Future studies are planned to include randomized, controlled trials of these sounds alone, these sounds and their vibrations and random sounds and vibration, to study their effect upon pre and post stimuli pain scales. We will also study functional imaging before and after sound and vibration to see if we can detect any significant change in pain circuits, hedonic circuits, release of GABA and other pleasure chemistry.
Inflammation
The connection of brain and body is maintained by the nervous system. The peripheral nervous system keeps the brain informed about what is happening to the body and allows the brain to make adjustments. This loop cycles at 30 times a second over the entire course of a person’s life. We tend to pay far less attention to the molecular communication between brain and body. Unlike the 30 hz communication via the nervous system, molecular information is always on. The truth is that the two systems rely upon each other for total information and adaptation.
Although inflammation is a major contributor to most disease processes, it is also the process that protects and heals. Glial cells in the brain mediate inflammatory processes. In the peripheral body, connective tissue cells called fibroblasts and transformed tissue-based blood cells, known as macrophages, plasma cells and mast cells play major inflammatory roles. Trimming of synapses, necessary for forming new synapses, is an inflammatory-based process with astrocytes directing microglia to release local inflammatory cytokines at specific synapses to trim them away. Inflammation is also a response to invasion of foreign particles, such as viruses or bacteria across the blood brain barrier. Inflammatory processes in the periphery occur because of the arachadonic acid cascade and Leukotriene cascades. There is also an active anti-inflammatory cascade that occurs via corticosteroid receptors, Interleukin-10, interleukin-18 and anandamide. Furthermore, mechanisms built into each cell in the body are maintained and regulated by GABA to serve as a collapsable barrier to inflammation when tissue damage occurs.
When all works properly, an exquisitely tuned system between body and brain mounts an inflammatory response, informs the brain of the problem and resolves it with an anti-inflammatory response. Something else happens when inflammation does not resolve and it is in the chronic inflammatory state that most disease flourishes.
In the body, the connective tissue, composed of fascia, ligaments, tendons, mounts the inflammatory response. At a cellular level, every tissue in the peripheral body is full of fibroblasts. They are migrating cells and outnumber all other cell types. When injury, infection or local inflammatory processes occur, local fibroblasts stop their primary job of tissue repair and maintenance, change shape and migrate to local capillary and nerve complexes. They stop making collagen and start making inflammatory components. Circulating blood cells are called out of the capillaries by the chemokines released by fibroblasts and are transformed in the tissue to inflammatory cells that release more inflammatory substances into the tissue. These cells change shape in the tissue and begin to engulf and destroy foreign invaders and dead tissue. They can live in the tissue for a much longer time than they do in blood vessels and produce inflammatory molecules throughout their existence. In abnormal inflammatory states common to most disease processes, a resonant circuit is set up with the brain, mediated by the constant firing of pain nerves. In the brain astrocytes and microglia get into the act of perpetuating nerve firing in pain circuits and releasing and directing more inflammatory substances in the periphery. A loop is set up that involves nerve and electrical transmission, taking on a life of its own.
The fluid that exists between tissue layers is known as interstitial fluid. It is in this environment that fibroblasts and transformed blood cells migrate. Interstitial fluid, despite being ignored in clinical practice, has several important properties that make it an appealing target for enhancing the anti-inflammatory cascade. Interstitial fluid is, essentially, the ocean we all live in. While blood consists of 5.6 liters of volume in the blood vessels, interstitial fluid consists of an average of 15 liters of fluid between tissue layers and surrounding the cells of tissues throughout the body. It is within the interstitial fluid that fibroblasts construct the fine connective tissue latices that make up the scaffolding for collagen production to repair and maintain body tissues. It is also the substance in which these fibroblasts transform shape, migrate and release inflammatory compounds and mediators, calling forth cells from the bloodstream to enter into local tissues and transform into inflammatory scavengers. When the brain makes more Substance-P in its response to stimuli in the pain circuit from the peripheral injury sites, it sends it back out to local areas dumping it in the interstitial fluid, perpetuating chronic inflammation. Volume, acid-base balance, viscosity and pressure are all dynamic properties of the interstitial fluid. When the interstitial fluid pressure drops, capillaries in the local area will release 10 to 20 times more fluid into the area. In the gut wall one of the component of interstitial fluid is filtered to make lymph, which flows through the lymphatic system to lymph nodes causing a reaction to cytokines and cell types and fragments. Lymph ultimately ends up back in the blood vessels.
We are currently researching all aspects of interstitial fluid as an avenue to promote resolution of chronic inflammation. Additionally, a greater understanding of the processes that are mediated by non-nervous tissue in the body and brain and how they coordinate with each other is another area of intense interest to us. Furthermore, clarifying details of the peripheral body’s natural anti-inflammatory cascade, its use of energy and its interactivity with the brain are critically important if we are to come up with ways to break the grip of chronic inflammation. Currently, we are studying these processes and working on novel ideas to try to reverse them locally and systemically.
GABA
Gamma Amino Butyric Acid (GABA) is the body’s most common neurotransmitter. In the Central Nervous System (CNS), it is second only to Glutamate. The two neurotransmitters combined make up 90% of all CNS Neurotransmitters. In the peripheral nervous system there are GABA receptors on the axons of nerves. GABA is a mostly inhibitory neurotransmitter, although it can also be excitatory when it turns off other GABA receptors that are inhibiting excitatory synapses.
In addition to its profound role as a neurotransmitter, GABA is also the body’s main built-in anti-inflammatory. It acts as a wall against inflammation and allows the neuroimmune system to continue functioning. It also allows inflammatory tissue-based dendritic cells and cytokines to respond to breaches in the body’s natural barrier to infection and trauma without establishing chronic inflammation. The barrier that GABA provides during inflammation can be overwhelmed and broken down, allowing the body to mount a proper inflammatory response, address the problem and re-establish homeostasis. In chronic inflammatory states, the GABA barrier is also overwhelmed, but local and brain-based events prevent return to a normal non-inflammatory condition.
NeuroplastixTM is pioneering research in novel uses of GABA in the treatment of pain. We have a patent pending on the use of GABA to treat pain and have focused on multiple routes of administration, including topical, intradermal, transdermal, intranasal, transbuccal, transvaginal, transrectal and parenteral delivery systems.
We have conducted extensive clinical case studies and have gathered data for a retrospective study of patients using GABA to control their pain over time. Future research plans are directed at randomized controlled trials to study the use of GABA to control pain using functional imaging, NMR and standardized pain scales.
Hedonics
Pleasure and pain are interoceptive (internally focused and experienced) senses that are critical to survival. The prime directive of all living things is to pursue pleasure and avoid pain. Persistent pain is so vexing, because it is, by definition, unavoidable. It negates pleasure perception in most people suffering from it. Pleasure and pain perception share many of the same circuits and the same cells. Neurotransmitters, however are opposites, with pleasure neurotransmitters including GABA, endorphins, oxytocin, anandamide, dopamine and adenosine and pain neurotransmitters including Glutamate, Substance-P, Calcitonin Gene Related Peptide and Adenosine Triphosphate. Theoretically, as a corollary to pain blocking pleasure, if pleasure neurotransmitters flood the same circuits and brain regions, pain neurotransmitters should be counteracted.
Recently, the field of hedonics has played an increasingly prominent role in neuroscience and neuroimaging literature. Work by Smith, Berridge and Kringelbach, among others has steadily clarified the importance of pleasure and the clear distinction between pleasure (liking) and addiction (wanting). This has lead to an understanding of the anatomic, physiologic, electrical and functional aspects of pleasure. Functional imaging studies have delineated the relationship of pain and pleasure, even providing evidence of the pleasure of pain relief, itself.
The idea of replacing pain with pleasure is an enticing one, made all the more intriguing by contemplating the three rules of neuroplasticity (1. What is fired is wired; 2. What we don’t use we lose; 3. New synapses require breaking old synapses), the commonalities of pleasure and pain brain activity and the biological imperative of pursuit of pleasure and avoidance of pain. We worked with our patients on these principles, instituting various approaches, including constructing a gratitude list, a comparison of pleasure to pursue and pain to avoid, gathering a personal pleasure pack, going on a one day pleasure hunt and using soothing and pleasing sensory stimulation. The results have pointed out that in people suffering with chronic pain, pleasurable experience is transformative. While researchers struggle with the definition of happiness, we have found that the experience of happiness is that of balancing soothing and stimulation.
We have conducted a case series on sound and vibration, showing excellent pain relief. As mentioned in the sound and vibration areas of Research, we plan to institute randomized trials and functional imaging to see what regions of the brain are stimulated and how that correlates with pain relief and pleasure induction. We also want to study the phenomenon known as “flow,” in which a person becomes so pleasurably involved in an activity, that they lose their sense of being separate from it. Furthermore, a major research target to control persistent pain is establishing practical clinical applications of the balance between hedonia (pleasure) and eudaimonia (a meaningful, well-lived life), as described by Berridge and Kringelbach. The endocannabinoid system is another area of intense interest for hedonic research, and new research showing that this system plays a far more extensive role in many brain and immune system based activities than previously offer up many interesting research possibilities we will be exploring.
Touch
Recent published results have supported the fact that massage after excessive exercise reverses resultant inflammatory activity, muscle damage and mitochondrial destruction. In a 2012 research article by Crane, et al, eleven young men exercised to exhaustion on a treadmill. Following this one thigh was massaged for ten minutes and they were then biopsied on the anterior aspect of both thighs. These biopsies showed breakdown of muscle tissue, release of inflammatory substances and breakdown of cellular energy centers. Two-and-one-half hours later the biopsies were repeated. On the thigh that was not massaged the process of muscle breakdown, inflammatory release and loss of cellular energy centers had progressed, while on the massaged thighs all of this had reversed itself.
Recent research done by Reed and Rubin demonstrates the importance of interstitial fluid pressure in establishing and regulating inflammatory responses and anti-inflammatory mechanisms. There is evidence that general massage reverses chronic inflammation. Looking at these factors, several potentially useful tissue massage techniques offer interesting treatment possibilities for chronic pain and inflammation. Gently milking swollen tissue toward the heart with light pressure may help reduce local swelling, inflammation and pain, by increasing local interstitial fluid pressure. Another technique of gently anchoring a finger or thumb on a myofascial trigger point and while maintaining that anchor rubbing vertically, horizontally and in both diagonal directions every four strokes in the pattern of the British Union Jack has relieved the pain of these trigger points, without deeper and more painful approaches. Use of pressure clothing and bandages may help to raise interstitial fluid pressure at injury sites in the periphery.
Chocolate
Anandamide is a substance found in both the brain and peripheral body that has unique properties. It is one of the body’s natural cannabinoids and works on receptors in the brain to produce pleasure, euphoria and a state of well-being. In the body (and at times in the brain) it works on other receptors to promote the anti-inflammatory cascade. When inflammation occurs in the brain, cells known as microglia are activated. They produce inflammatory substances and devour their targets. The brain uses microglia to destroy synapses that will be replaced by new connections, to perpetuate long term potentiation, to repel invading microbes and devour debris. Unfortunately microglia may also attack other brain tissue in various degenerative conditions.
When these microglia are activated, they go through a shift in appearance, sprouting tentacles and surface receptors known as cannabinoid-2 receptors (CB-2R). Meanwhile a mix of various molecules in synaptic spaces forms together to become anandamide and this attaches to CB-2R on nearby activated microglia, stopping them from producing inflammatory substances and reverting them back to an inactive state. Anandamide is one of several substances that helps the brain turn off the inflammatory process. Local synapses are no longer destroyed, long term potentiated nerve cells quiet down and inflammatory activity is halted. Without this type of off-switch, any inflammatory process, including normal synaptic replacement, would run amok and destroy the brain.
In the peripheral body, anandamide is one of the substances involved in the anti-inflammatory activity that leads to resolution of inflammation, as well. As in the brain, CB-2 receptors, expressed on the surface of inflammatory cells in the tissues, receive anandamide and begin the process of deactivation and return to a normal state, resulting in tissue maintenance and repair. As in the brain, anadamide alone is not sufficient to reverse inflammation, but it is one of the molecules that promotes the resolution of it.
Anandamide itself is a short-lived substance that breaks down in a matter of seconds to other, inactive components. However, there are two enzymes that keep it active longer during inflammatory states, making it more effective by preventing it from quickly being neutralized.
The question is, what does this have to do with chocolate? It turns out that among other anti-inflammatory compounds, raw chocolate, known as cacao, is a food rich in anandamide and the enzymes that prevent its rapid destruction. Unfortunately, once the cacao bean is roasted at 470 degrees F for a day to make chocolate, most of the anandamide and its helper enzymes are destroyed. While cooked chocolate maintains other substances that have anti-inflammatory properties, the amount of anandamide is negligible.
We have been studying raw cacao with our patients to see if it is helpful with pain. While this is not a taste most people enjoy, we have found that by mixing it with honey, fruit or chocolate, the brain perceives a pleasant change to the taste of cacao and it becomes quite enjoyable for most people. In a demonstration of the brain’s neuroplastic processes, the bitter taste of the raw cacao is instantly replaced with the sweet and pleasurable taste of the other substances, allowing the chocolate flavor of the cacao to emerge and dominate the senses. Remembering that one of the molecules the brain releases during pleasure is anandamide, we assume that this also occurs while eating the anandamide containing cacao. Additionally, since the cacao contains the two enzymes that slow down breakdown of anandamide in the body, we also have hypothesized that this makes more of this molecule available to fight inflammation. Additionally, we are currently exploring transdermal approaches to delivering this molecule locally by itself and combined with other anti-inflammatory substances, that are naturally present in the body. We have explored the use of raw cacao with several patients and have found positive benefits. We are planning to collect data on a case series of patients with persistent pain to evaluate their response. We will then design a prospective study to test clinical benefits of regular consumption of raw chocolate vs cooked chocolate for reduction of persistent pain, using standardized pain scales and functional imaging.