Thank you for being with us. This is a session on nutraceutical therapies, vitamins, and other alternative therapies in the use and treatment of brain disorders. We wish we could be with you today, but we know you'll have value out of this session and deeply enjoy it. I'm Ross Sifant, I'm at Mass General Brigham, Harvard Medical School, and Spalding Rehabilitation Hospital and Research Institute, and my colleagues will introduce themselves because of the format that we're using today. Among the things that we'll touch on today is some general issues about fundamentals of these kinds of agents. What does it mean? How much is used? And we'll try to take a common thema, which is a look at mechanism of action, some elements of uses and safety in animal models or humans, and what is the real evidence, if there is any, regarding recommendations. So let's get started. So fundamentally, we have to understand literally how huge this issue is. The growth of nutraceutical or other therapeutics in the United States is stunning. It's estimated to grow 19% year over year over year, and it's already nearly a $300 billion industry. And that is discounting the explosion of cannabis use, which I'll touch on just briefly today. Now one of the caveats with all of this is that our patients truly believe, hey, it doesn't matter, it doesn't matter. It's got to either help or it's harmless. And I would poise it to you that if it's strong enough to help, it's strong enough to harm. And we need to be really thoughtful about that and dosage. And is it deliverable? So what I mean by that is we don't know, in many cases, the right dosage in humans. We don't know if the agents you're getting or someone is getting from over-the-counters are good manufacturing practice. And in reality, although it might be biologically plausible in the laboratory, can you get enough into the brain? Does it cross the broad brain barrier? Can you deliver enough of a dosage in humans without a toxicity? And does it produce the effect that you're trying to produce? And lastly, is there a legitimate biological plausibility that it can produce that effect? Remember, there are large placebic effects as well. So the first agent we're going to start on is one that I'm well known for. And that is Cdp-choline or Cdp-choline. This is a naturally occurring endogenous compound. It's a key intermediary in the biosynthesis of phosphatidylcholine, absolutely critical to neuronal membrane function. And it is a precursor to acetylcholine. So one could see this as an important agent in both long-term therapeutics and potential in neuroprotection. And where does acetylcholine act? Well, it acts in a lot of different places. From a neuroprotective perspective, it acts on free radicals, it acts on calcium, it acts on phospholipase A2 over here, it acts on DAG, and it also acts on EMPA and NMDA. So a lot of secondary effects of acetylcholine. Almost an ideal agent for therapeutics. What is the animal evidence? Well, the animal evidence has been long going and for years. One of the critical labs in Wisconsin has done a series of work, mostly in stroke models, but also in other labs in brain injury. If you look at the figure on the opposite side of the slide from a batless lab, what you can see is a dose-dependent decrease in infarct volume in an animal based on the amount of acetylcholine. Prior work had also shown impacts on learning and memory, recovery from status epilepticus, improved chronic functional deficits after administration in human brain injury, and in animal brain injury. So what do we know about this agent and its work? Well, in stroke it's been tried several times, in fact a number of treatment trials. And what was found is that there might be a dose-dependent effect on lesion volume. But in the series of three different stroke studies that were done, only the first in its secondary metrics showed a positive result. The secondary two did not show a primary outcome change for the outcome-based or functional metrics they were looking to change. This study by Saver et al. looked at MRI-based burden and you can see a decrease in the lesion volume at the highest dose, nearly 2,000 mg per day for six weeks. So when you put all this together in Saver's study, what you see is the following. There is a tendency for acetylcholine in stroke to show a better total recovery output, and that's exciting because the side effect profile in theorem should be relatively de minimis. And in trauma there were a series of studies, among these the French study looking at number of people who recovered early and days to recovery in trauma. So this is Dave's so-called consciousness. Now look at the age of this study, 1982, but the CDP-choline group appears to do better. And when we look here at a critical study by Suzuki, we see improvements in arousal when given early on, improvement in global functionality. So there is some reason to believe that cetylcholine was an agent to take on. And indeed, when we first took this agent on, it was approved in 51 countries in the world, including Spain, Portugal, Japan, and a number of others, many with IV formulation. So we began the cetylcholine treatment study, or COBRIT, which is a study of mild, moderate, and severe brain injury to assess if a prolonged administration of cetylcholine resulted in improvement in a core battery of nine tests 90 days after the randomization. So people were randomized, placed on cetylcholine in the intensive care unit, or even in the ED. They continued for a prolonged period of time, and we looked to see, did it make a difference? What we found was a lesson here. So we're not meant to discuss the details of the study, but rather, hey, what is going on? This is a paper we published some years ago in JAMA, but it's a lesson for all of us. This is a study, a drug, remember, approved in 59 countries. No difference in outcome, no difference in people with complicated mild injury, but I'll talk more about that at 90 days, and no difference in moderate severe patients. What happened is we had to group these together because there were very few people with moderate injury. So maybe I'll help a few people. What's the problem? So the problem was that when we looked at the 180-day outcome, those people with complicated mild injury may have actually done worse in a non-primary analysis. So it teaches us that if it's strong enough to help, it might be strong enough to harm. In addition, one of the things to remember is that the Europeans traditionally have delivered this drug acutely intravenously. We could only deliver it enterally, but even in the enteral recent study from Europe that was IV in early administration, there was no difference in outcome. So let's look at another agent, and this is an agent that is really quite fun to look at because it's counterintuitive but very cool, and that is the mucolytic N-acetylcysteine. Most people know N-acetylcysteine for people with mucus plugging. They also note it for protection for people who are on acetaminophen overdose, and there are theoretical improvements in those in Parkinson's disease. One of the ideas is can you get it there and can you get there fast enough? So let's look at what it might impact. So N-acetylcysteine has a number of different impacts, but most of its impact here is on glutathione. It also acts via a number of different agents, and so reducing that early oxidative stress might in fact be beneficial after brain injury or, frankly, in continuous neurotrauma or even neurodegenerative diseases, and that protection against inflammation and oxidative stress is something that's being explored. Now the question would be, in practicum, can you deliver it on a contiguous basis the same way we do as a mucolytic, and can you get enough there, and that is yet to be determined. But there are a couple of studies in humans that are quite interesting. They're both run out of the military. One looking at symptom resolution, the other over global effectiveness of N-acetylcysteine. One run by Hoffer et al., the other by Aiken, same group out of San Diego. And what they were able to show is that early NAC treatment resulted in fewer symptoms, total number of symptoms, and a number of other sequelae in military personnel who had been treated with early N-acetylcysteine, suggesting that early treatment with N-acetylcysteine warrants further exploration. Here, since the side effect profile, at least at the doses they delivered, is more modest, if we could really do this, it might warrant further exploration. It does not yet appear to be warranted to think about this in the more chronic setting. And now let's think carefully about cannabinoids. So this is an issue that has exploded into the United States and all over the world, but is remarkably under-understood. And when we have our patients in clinic, I always clinically ask, hey, at least in a state where it's legal, like the Commonwealth of Massachusetts, are you using either medical or recreational cannabis? So part of the reason we know little about it was the Controlled Substance Act of 1970. And it was a study or a theory about drug abuse and marijuana, and there really wasn't this overwhelming linkage. And so for both political and potentially other reasons, it was, however, classified as Schedule I. What that meant in reality was a limitation on clinical trials, on accessing NIH funding, and the fact that the only research-grade controlled product you could get was isolated to a certain area within a development program within the University of Mississippi. And so the actual data has been remarkably limited. But cannabis is super complex. It's more than just tetrahydrocannabinol, which gets you high, and cannabinodiol, which is referred to as a anti-inflammatory multi-use. There are CB1 and CB2 receptors. Really cannabis is a constituent plant of over 400 different constituents with over 100 different cannabinoids and turbinoids, and it has active and integrated action within the endocannabinoid system. So it's really, really complex, and you can't just simply talk about one constituent and try to come up with a strong evidentiary basis. But patients use it, and they use it contiguously with an increasing frequency because what went from horrors in the nighttime is now believed to be completely benign. So there are potential uses in brain injury. There's neuroprotection. There's pain and possibly headache. There are behavioral health issues, people with PTSD, people with depression or more likely even anxiety, sleep dysfunction, and people with seizures, as we know that epitalex is an anticonvulsant agent used for specific syndromes. We're not going to talk about that one today. So let's talk about neuroprotection in cannabinoids. So the synthetic cannabinoid dexanabinol was evaluated in a phase three study in Europe. There were 861 patients, 86 centers in 15 countries run by very prestigious people. Patients received 150 milligrams of intravenous dexanabinol or placebo. And the prior studies had been suggestive of a possible benefit. But in this large phase three study, as we've become so unfortunately accepting of, there was no difference in Glasgow outcome scale at six months and no improvement via sub-grip analysis. However, in a follow-up paper, it was noted that there was a lot of observer variation and there may have been issues in the way that some of the observational-based metrics and secondary metrics were evaluated. So one of the greatest problems in brain injury and in other entities is the issue of pain. And cannabinoids have been used in several different types of pain-based syndromes. MS-based central pain, spasticity, neuropathic pain, chronic headache. And there are real issues in understanding its role in pain. First of all, combustibles are probably not the optimal agent inhaled via smoking or inhaled via vaping because they cause bronchospasm, potentially in certain groups of people, cardiac spasm. What we really need to look at is number needed to treat versus number needed to harm. What is the optimal dosage? What is the formula control? And do we have objective metrics in what we're trying to show? So this is a Cochrane-Dace review, and I want to have you look at this. This is non-cancer chronic neuropathic pain, but you see similar sorts of numbers in non-cancer axial non-neuropathic pain, although less compelling. And when you look at the quality of the evidence, one of the things that you do see from a small signal perspective is participant-reported pain relief of 30% or greater in the group of people that got it with moderate quality evidence. One of the problems here is the sham basing. The other problem is that placebo often shows a 30% to 40% benefit in some subgroups of people. That said, because of its antinociceptive qualities and potential anaxolysis, it might be a future utilization and something for us all to study. There is mixed evidence in anxiety. There is some evidence in sleep. And there are other behavioral health issues, PTSD, other issues. Who do we want to think about avoiding this in? Well, probably those with pre-existing psychiatric symptoms. Probably those who are younger with pre-existing psychiatric symptoms. People with known dizziness. People who are on certain medications that are processed through the P450 system that may well be affected by cannabinoids, an underappreciated concern. So let's look at that briefly. When we think about things, I always think about number needed to harm versus number needed to treat, or NNT versus NNH. And Stockings from Australia did this very interesting review in which they looked at number needed to treat versus number needed to harm. And if you see some of these side effect profiles, odds ratio fives, odd ratios, these are some of these things that people get dizzy. People get nauseated. People get other symptoms from this. So patient selection in the future as we refine this agent is critically important. Drug interaction is critically important. What I'm saying is that it's not good for everybody, but it might be helpful for some. We need to think about that perhaps more carefully. Who gets what? For what reason? In what setting? And what are the susceptibilities from a number needed to harm or a side effects perspective? And might they benefit from a small dose from an anaxolysis or a sleep enhancement perspective to avoid other complications of brain injury, either nocebic or otherwise? Thank you for spending your time with me, and my next colleague will be joining us. Hello, everybody. I am Shelby Halsey. I am an assistant professor in the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center in Dallas, Texas. And I will be touching on four different supplements and their use in traumatic brain injury. And those supplements include omega-3 fatty acids, creatine, resveratrol, and vitamins C and E. I have no disclosures. And we'll be touching on several learning objectives today. And so discussing the mechanism of action for these selected supplements, current literature for the supplements and their role for potentially treating and or preventing traumatic brain injury, as well as reviewing any current human trials for those selected supplement use in concussion. So the first supplement that we'll be touching on are omega-3 fatty acids. They are polyunsaturated fats found usually in plants and fish. And there are several different forms that exist. But the most commonly studied ones are ALA or alpha-linolenic acid. There's EPA or eicosapentoic acid. And then DHA or docosahexaenoic acid. And DHA and EPA are long-chain omega-3 fatty acids. And ALA is usually present in flax seeds, soybean, canola oils, whereas EPA and DHA are usually found in fish, fish oils, krill oils. They're usually concentrated in the synaptic membranes in the brain. And DHA is primarily stored in the neuronal cell phospholipids. And there are studies that show that after brain trauma, there's actually a reduced quantity of neuronal DHA. And that deficiency then heightens the pathophysiologic response and impairs neurologic recovery after a traumatic brain injury. Studies also show that most individuals in the United States actually don't meet the dietary intake that's recommended for omega-3 fatty acids. In touching on the mechanism of action of omega-3 fatty acids after a traumatic brain injury, the role that it usually plays in the central nervous system is focusing on membrane stability, neurotransmitter modulation, antioxidant properties, and anti-inflammatory properties. And so the pathophysiologic focus of it is looking at the acute axonal loss, inflammation, neuroprotectin factors, and then excess glutamate and trying to decrease the cytotoxicity from the glutamate, as well as oxidative stress. And that's where you get your antioxidant activity and your anti-apoptotic pathways. And then going next into dietary supplementation. So there's been a number of studies with omega-3 fatty acids after traumatic brain injury. And it's shown that they help reduce the synthesis of inflammatory cytokines, normalizing BDNF levels, decreasing oxidative damage, helping with that membrane stability, the homeostasis. DHA specifically has been shown to help ameliorate cognitive deficits, minimize axonal injury, and then inhibit neuronal apoptosis and enhance autophagy. And dietary supplementation of the omega-3 fatty acids has been shown to not significantly prevent tissue loss after traumatic brain injury with the impact region. However, pre-injury treatments with omega-3 fatty acids can help specifically with hippocampal and neuronal loss, and then reducing pro-inflammatory cytokine and microglial activation. There's been studies in NCAA Division I football athletes with different DHA doses. And it's shown that supplementation might attenuate elevations in serum neurofilament light, or NFL. There's a neuroprotective effect, like we talked about, with minimizing axonal injury. And athletes, based on this study, possibly require a higher dose of DHA than the average population. There's also a study that looked at the combination of DHA, prebiotic fiber, and resveratrol in preventing injury-related deficits. And the combinations show that there is longer-term behavior measures that they look at, and different levels of aquaporin-4, GFAP, IGF-1, NFL, and SIR2N1 expression in the prefrontal cortex. And then looking at ALAs specifically, or alpha-linolenic acid, this, like we talked about, is usually plant-based. It's obtained through the diet. And so this includes your flaxseed oil, chia seeds, canola, soy, walnut oils. It has been shown to inhibit production of nitric oxide and pro-inflammatory cytokines. And studies have shown that if you supplement with ALA, it actually increases your neuronal DHA levels, again, reducing inflammation in the brain, improving functional recovery. And that subchronic treatment with ALA can prevent loss of your inner neurons that are GABAergic, as well as prevent that hyperexcitability in the amygdala. It can reduce the impact injury. And then any anxiety-like behaviors after the TBI that might develop could possibly be prevented with the subchronic treatment with ALA. And then looking at overall, there are three current clinical trials that are investigating the use of omega-3 fatty acids in brain injury that you can find on clinicaltrials.gov. There's one at ECU that's looking at high-dose omega-3 fatty acids in the treatment of sports-related concussions. The study is completed, but currently pending publication. And it's specifically in an area called And it's specifically in NCAA Division I athletes looking at DHA supplementation for 30 days after a concussion. There's another study at UT Southwestern looking at DHA supplementation in adolescents daily for three months and the impact of treatment for pediatric concussion related to sports injury. It's active, just pending completion and publication. And then there's one more study at the University of Michigan that is a pilot trial phase 2. It's double-blind randomized controlled, and it's comparing the effect of a placebo versus omega-3 fatty acids on blood biomarkers of brain injury, inflammation, neurogenesis. And that study is actively recruiting currently. So omega-3 fatty acids, adequate intake of aphelanolic nic acid in women is about 1.1 grams per day for ages 19 through 50. For men, it's 1.6 grams per day. Omega-3 fatty acids are found to be safe. They can be ingested daily for prevention, but they usually take several days to weeks for an effect. That's where some studies are suggesting possibly IV formulation. However, this is not FDA approved currently. So further investigation is needed looking at prophylactic and pre- and post-injury treatments with omega-3 fatty acids in traumatic brain injuries, specifically mild traumatic brain injury. And these studies should better define specific dosage, the delivery, oral versus IV, and then different safety concerns such as for those patients who might have blood clotting disorders. And then the next supplement that we'll touch on is creatine. And so this supplement is a naturally occurring nitrogenous organic acid usually obtained through endogenous production, dietary consumption, of protein-rich foods like meat, fish, and poultry. This supplement is usually seen traditionally for muscle mass growth in bodybuilders. And there have been studies, including these two, that have shown that so creatine is usually found in high levels in the brain where it maintains energy homeostasis by replenishing energy stores. But after there is a diffuse mild traumatic head injury in these studies, specifically in rodents, it's been shown that there's a time course and there's a significant reduction in cerebral creatine and phosphocreatine levels after mild traumatic brain injury. And then it's suggested that concussion may cause concomitant decrease in cerebral and acetyl aspartate and creatine levels. And so this might provoke longer time for normalization of metabolism, as well as resolution of any concussion associated clinical symptoms. And then looking at creatine supplementation specifically, it can improve short-term memory and intelligence or reasoning in healthy individuals. And so there's suggestion that there is potential benefit in patients who might be aging and those with mild cognitive impairments. There was a double-blind placebo-controlled crossover trial that showed oral creatine monohydrate supplementation of five grams per day for six weeks might have a beneficial effect on memory. And then exogenous supplementation can affect membrane stabilization, prevents depletion of ATP, stimulates protein synthesis and prevents degradation. And then brain levels of lactate and free fatty acids increase after TBI due to accumulation of excitotoxic levels of glutamate. So there was a study by Sheff and Dillon that demonstrated decreased cortical and hippocampal levels of lactate and free fatty acids with creatine supplementation that was exogenous. There was also evidence that shows supplementation has been found to increase neural creatine in the primary motor cortex, which results in protection against a hypoxia-induced reduction in attention. And there was another study that was looking at pretreatments of mice with creatine and seen in figure B that was for five days that showed a significant reduction in cortical lesions seven days after TBI. And then looking at figure D, that shows that there was animals that were fed a creatine-rich diet for four weeks prior to the traumatic brain injury that was induced. Cortical damage was reduced by 50% in these rats that were fed the diet compared to rats who were fed a regular diet without creatine supplementation. And so pre-injury treatment with creatine before traumatic brain injury, there is reduced cortical damage, oxidative stress, and improved mitochondrial function in these animal studies. There was a study that was looking at children and adolescents with moderate to severe traumatic brain injury and the effects of creatine supplementation. And the results show there's improved cognitive function, personality behavior, self-care, and communication, as well as decreased headaches, dizziness, and fatigue. So optimal supplementation or dosing required to increase the levels of cerebral creatine is currently unknown. There's the studies that show improvement in moderate to severe traumatic brain injury is mentioned. However, there's more studies that are needed regarding the neuroprotective effects of creatine supplementation on outcomes in mild traumatic brain injuries specifically. And the next supplement that we'll talk about is resveratrol. So this is a naturally occurring non-flavonoid polyphenolic compound that's usually found in fruits like red grapes, berries, can be found in red wine, soybeans, and nuts. And resveratrol crosses the blood-brain barrier. It has minimal side effects and usually has prolonged activity in the brain when it's given peripherally. And it has antioxidative, inflammatory, apoptotic effects and it's neuroprotective. When given in healthy adults, it usually improves memory performance with improved glucose metabolism and hippocampal connectivity. These properties are usually mediated through the activation of SIR2N1 or SIRT1. And in animal models, it's been shown to attenuate cognitive deficits like spatial memory and reference memory. This is usually by suppressing oxidative stress mediated apoptosis in the brain. There was a study that was done by Singleton's group in 2010 looking at the hippocampus specifically and rodents who are treated post-injury with 100 milligrams per kilogram of resveratrol. And compared to the group without the post-injury resveratrol supplementation, the animals that had the supplementation had preserved neuronal numbers in both CA1 and CA3 hippocampal subfields, as well as in the figures on the right regarding contusion volume that was reduced with hippocampal preservation in the animals that were treated with the resveratrol supplementation versus those that weren't. And so pretreatments with resveratrol, usually there is diminished activation of the microglia astrocytes. It's been shown to inhibit nuclear factor kappa B. Post-injury treatment inhibits inflammation, apoptosis, improves memory, decrease tissue loss, improves the visual spatial memory specifically. And that was done in the same study that was looking at the 100 milligrams per kilogram of the resveratrol. And they had looked at beam balance and beam walking as far as motor performance improvement. And then testing a visual spatial memory, they looked at Morris water maze. And so more studies in humans are needed regarding the use of resveratrol in mild traumatic brain injury as the dose and the timing is still unclear. There is a current phase one double-blind placebo-controlled randomized trial called the REPAIR study that is evaluating the use of resveratrol to decrease acute secondary brain injury in boxers who have sustained concussions. And this study is completed, but it's still awaiting publication of the data. And then the last two supplements we'll talk about for my section are vitamin C and E. These are antioxidants. They protect the brain from oxidative stress by scavenging free radicals and suppressing neuroinflammatory processes. For vitamin E specifically, a lot of the studies look at alpha tocopherol, which is the most biologically active form of vitamin E. And so there was a study that was done in 2011 that evaluated the effects of vitamin C and E on mortality, patient outcome, evolution of perilesional edema in severely head injured patients. And this was a randomized double-blind placebo-controlled trial. There were four different groups as listed in the table at the bottom. So group A was a low dose vitamin C, 500 milligrams per day IV for seven days. Group B was a high dose vitamin C and they got 10 grams IV on the first day, another 10 grams on day four, and then four grams per day IV for the remaining three days. Group C was vitamin E, 400 internationally nits per day given intramuscularly for seven days and group D was just a placebo. And so the results had showed high dose vitamin C stabilized or reduced the diameter of perilesional edema in subsequent days in 68% of the patients. There was also a reduction in hospital mortality and improvements in long-term outcome for patients receiving vitamin E. And then Glasgow outcome scale scores that discharge involved were significantly better for the patients who were in the vitamin E group. And so looking at the high dose of vitamin C, again, affects perilesional edema, lesion size, and then vitamin E reduces mortality rate, improves GOS. There's less pronounced functional deficits serologically as well as a decreased inhibition of axonal regeneration. There was a study by Wu and colleagues that looked at pretreatment with vitamin E for four weeks prior to mild fluid percussion injury in rodents. And the results showed significant improvement in cognition, lower levels of oxidized proteins. And then these graphs are showing that there was a normalization of levels of BDNF which is implicated in cognition, synaptic plasticity, as well as calcium, calmodulin-dependent protein kinase two, or KAMK2 and hippocampus, levels of superoxide dismutase or SOD, and then silent information regulator two or SRV2. Another study had looked at various groups that were either group A was a non-TBI untreated group, group B was a TBI untreated, and then they separated into a low dose vitamin C in group C, a vitamin E low dose group D, and then a combination of the low doses in group E, and then higher doses of vitamin C in group F, high dose vitamin E in group G, and then a combination of the high doses in group H. And so for these patients, you see that serum vitamin C levels significantly increased in the treatment groups compared with the TBI untreated, with the exception of the group treated only with vitamin C. And then treatment with both the low dose and the high dose combinations increased the levels of vitamin E when compared with the TBI untreated group. And then supplementation in the second graph of the combined vitamin C and E increased vitamin C in the tissue compared with TBI untreated group. And then the groups that have a combination of both increased the tissue vitamin E compared with the TBI untreated group, as well as the group with the high dose vitamin E also showed a significant increase. And so pre and post-injury treatment of vitamin E has also been shown to reduce amyloidosis, improve cognitive function. Pre-injury treatments with vitamin E specifically can improve cognition, lower levels of oxidized proteins, and normalize BDNF levels as shown previously in this study. The combination can reduce oxidative stress, mortality rate, healing time. But specifically, there are no human trials that are examining the use of vitamin C or E in mild traumatic brain injury, even though the animal studies currently appear promising. So in summary, breaking it down on the far left, there are the different supplementations that I discussed in my talk, as well as separating it into where you might see the impact of these supplements, such as excitotoxicity. All of them are useful for oxidative stress seen in the animal studies or some of the more severe traumatic brain injury studies. Cell loss, brain edema, the plasticity neuromodulation, inflammation, lesion volume, and energy supplementation. And then these are the various references that you will see for the studies mentioned previously, as well as for the images. Thank you. So hello, my name is Ginger Polich, and I am an instructor in physical medicine and rehabilitation at Spaulding Rehabilitation Hospital. Today I'm going to be talking about use of curcumin, caffeine, and melatonin in brain injury. And I have no disclosures. So we'll first talk about curcumin, also known as turmeric. So curcumin is a polyphenolic bioflavonoid, and it comes from a root plant of the curcuma longa plant. It's similar in some characteristics to the ginger family, and it is commonly used in many different populations in culinary cuisines, including South Asian, Middle Eastern, and Indian. It has a very vibrant bright orange or yellow color, and also is very flavorful. On the supplement side, turmeric or curcumin is often taken in capsule form, where the powdered form of the curcumin is given in a gelatin capsule. And there are many different formulations that are out on the supplement market. Some supply curcumin just as the powdered form. Others are given in combination with black pepper extract, which may increase the bioavailability of the compound. When we look at the data for curcumin across neurologic populations or brain injury, we can talk a little bit about mechanisms. So here on the left, I have one figure that basically shows the curcumin as it enters the cell. There are a number of different purported mechanisms for why this might be beneficial across a range of populations. Primarily, though, the argument of anti-inflammatory effect is raised. So here you see a number of different mechanisms labeled, and in particular, the NF kappa B, or the PPAR gamma pathways are primarily involved. And these act on anti-inflammatory cytokines or decreased pro-inflammatory cytokines. On the right, there's a figure from a recent review by Tang and others in 2017 that look at the range of mechanisms of actions of curcumin. So an anti-inflammatory effect is the one that is most commonly discussed in the literature, though there are many others that also have some developing literature. And in particular, this article talked about a number of studies that discussed the potential role in amyloid beta inhibition, tau inhibition, as well as effects of acetylcholinesterase inhibition. So here, I'm going to highlight a couple studies that are in animal models, and then we'll also talk about a range of clinical studies in neurologic populations. So this is one study. There are many out there that look at immediate supplementation of curcumin for brain injury models in animals. So one such study here by Hung in 2017 shows a series of rats that were given middle cerebral artery occlusions, and shortly thereafter, within a matter of about 30 minutes, also giving curcumin extracts. On the left, you see a number of pictures of the actual lesion volume in each of these experimental arms. So some were given a vehicle or placebo, some were given curcumin, and two other experimental arms were given various substances, including an antibiotic, that interrupted the biosynthetic pathway of curcumin. And you can see the different lesion sizes in all these different groups. So on the right, we see the graph here that looks at infarct volume. And if you compare the middle cerebral artery group to those who received the curcumin, you see a significant change in infarct volume size. And when you look at the other experimental arms that provided a variety of molecules that disrupt that biosynthetic pathway, you see a larger infarct size. As another example of a variety of studies that are available for curcumin in brain injury, there are additional post-injury supplementation studies in animals. Here's an example where curcumin was given to rats who received fluid percussion injuries. And after that, the rats were sacrificed. And the degree of BDNF protein and mRNA in the cervical and lumbar spinal cord were assessed. And you see here, again, that individuals who received the curcumin extract versus those who were just given a regular diet had changes in the degree of BDNF. So BDNF might be one other potential mechanism of action here. On the right, there are a series of experimental arms of these animals given, again, regular diet or the curcumin diet across sham and experimental arms. And you can see the differences, again, in those who received the curcumin diet. There are also some human studies, none specifically in traumatic brain injury. But there are a number of human studies across a range of other neurologic diseases. Most prominent are those in individuals who are aging and individuals who have Alzheimer's disease as well as those with schizophrenia. And on the left here, there is a plot that shows, basically, when you look at these studies as a meta-analysis and aggregate, you see that generally those that are receiving the curcumin extract, again, have a more favorable outcome. We talked about some of the potential mechanisms a few slides ago. And I'm going to highlight one other study here on the right that's talking about an actual primate study, but that looks at some changes when these primates are given curcumin extract over a period of time, here 12 to 14 months. And the study showed that over a period of time, these primates had changes in the functional connectivity in a variety of brain regions, as well as gray matter density in the limbic system, the cerebellum, and a variety of brainstem regions, as well as in the basal forebrain. Next, we'll talk about caffeine. So caffeine is the most widely used psychostimulant in the world. It is an alkaloid that occurs naturally in about 60 plant species, most commonly for coffee, cocoa beans, tea leaves. Regarding mechanisms of actions here, caffeine is an adenosine receptor antagonist, and adenosine, again, is a receptor that regulates synaptic transmission and neural excitability throughout the brain. There are adenosine 1 and adenosine 2 receptors throughout the brain. The adenosine 1 receptors are primarily in the hippocampus, and adenosine 2 receptors primarily in the striatum, but also the amygdala, hippocampus, and prefrontal cortex. In human populations, the general recommendations for caffeine is not to exceed more than 400 to 450 milligrams per day, though on average about 30% of the U.S. population does exceed this limit. Caffeine can have a number of positive and sometimes negative effects as well. On the positive side, it can increase wakefulness, increase perception of stimuli, increase attention and alertness, discrimination, and reward system activity. But when used in excess over the recommendation limits, it can also cause an increase in fatigue and sleep. Here's a picture here of neonatal rats who were pre-treated with caffeine and then exposed to hypoxic injury. In this animal study, it was shown that the caffeine-treated animals had reduced oxidative stress, had a reduced overall anti-oxidative response, and had a decrease in pro-inflammatory cytokines. Regarding human studies, there's really no literature that particularly or specifically look at neurologic populations, including traumatic brain injury, but we all have, you know, a general sense of where caffeine is used and consumed on a general layperson basis. So I'm going to highlight one study here on the left. That is a study that includes adults ages 20 to 60 who had single one-time use of caffeine intake, and after that were asked to perform a series of neurocognitive tests. And in this study, adults were shown to have slight though modest improvements in sustained attention and on a specific driving task actually had improved break time. However, it's not so simple as just caffeine being a, you know, across the board cognitive enhancer. There's a lot of different studies that have looked at caffeine in adults with intakes across a range of neuropsychological batteries, some that show a benefit, some that show no difference, some that actually show a decrement. Here on the right is an interesting study that's looking at a group of an adult population ages 60 to 85 who were also given a single time caffeine use and then asked to perform a series of neuropsychological tests. What's interesting in this study is that individuals who are younger, closer to 60 years in age, showed an improvement in their response time on a dual task. And those who are older actually showed a decrement in performance, suggesting that it's, you know, there's a potential that there's actually an age difference across how people's bodies and overall functioning is impacted by caffeine. The other area in which caffeine is often talked about is whether or not it has an impact on performance enhancement in the physical realm. So here's a meta-analysis that looks at caffeine intake and athletic performance across a number of different studies in a number of different categories. And on the whole, caffeine does seem to have a favorable response, and this includes an aerobic endurance activities, muscle strength, muscle endurance, anaerobic power, jump height, exercise speed, and one's ability to do short-term high-intensity exercise. Another area of relevance of caffeine in the brain injury population relates to its potential impact on headaches. And here's there's no particular studies that really have looked at this in an experimental way, but I want to highlight a few points of consideration that have been shown, at least in this one review study highlighted here. So one, when we think about taking a headache history with individuals with TBI, caffeine intake questions are often a part of this. And there is a likelihood that individuals who have high usage of caffeine, right, when they stop using caffeine at that high level, will develop caffeine withdrawal headaches. This is usually amongst individuals who are taking in at least 200 milligrams per day for over two weeks of caffeine. And if you abruptly withdraw the caffeine, a headache can ensue, but the headache typically decreases over a period of seven days, so it should not persist. A second question in relation to headaches, caffeine, and brain injury is whether or not caffeine can have a role in medication overuse headaches. So here's there's some theories that are thrown out there regarding cortical hyperexcitability, peripheral, and central desensitization. There's also questions of whether caffeine can be associated with a migraine transformation, whereas an individual consumes this substance for a repeated period of time over an extended period of time, and their migraine then develops into this daily chronic headache. So these are things that are often discussed with other type of as-needed medications in the migraine population, you know, such as taking any type of tryptan drug or the sort. And there is a question out there of whether or not caffeine should be on this list. So the last supplement I'm going to talk about today is melatonin. So melatonin is something that, again, is widely used in the general population, a common over-the-counter supplement. Melatonin is secreted by the pineal gland, and it regulates circadian rhythm via the suprachiasmatic nucleus of the hypothalamus. It acts as an internal synchronizer to daily rhythm, so our day and sleep-wake cycles. It can also actually act on seasonal sense of rhythm, so over the course of a year, one's seasonality sense. On a mechanism of action level, it acts as an anti-inflammatory. It can regulate cytokine production. It also can act as an antioxidant and scavenge-free radicals. Regarding literature on melatonin in brain injury, there are a few studies in animal models, and I'll highlight one here. So in this study, rats were given melatonin within hours of an experimental traumatic brain injury, and a number of different assessments were made thereafter that were looking at some of the physiology and also some of the behavioral responses. So the animals that received melatonin showed overall decreased brain water content, decreased ICP. They also had an improved score on the VCS, which is the veterinary coma scale. And so overall, there's some suggestion of whether this might have a role in acute TBI. But on a clinical sense, where we really see this much more often is the question of impact in subacute or chronic periods on sleep, and there's very few studies here in the actual brain injury population. When we talk about melatonin at large, of course, there's many studies out there that suggest that it can help with circadian rhythms. It can improve the onset, duration, and quality of sleep across a range of different sleep disorders. For dosage in those studies, speaking broadly, the dosages are often very highly variable and can range from 0.1 milligram to more than 10 milligrams. There's one study that was an RCT published in about two years ago that was an RCT crossover study involving individuals with mild to severe TBI. In this study, 33 participants received four weeks of a delayed release melatonin, two milligrams, versus placebo. And they did find an overall statistically significant benefit on improved Pittsburgh Sleep Quality Index, which was the primary outcome measurement, as well as sleep efficiency. Individuals in this study also showed reduced anxiety and fatigue scores, which were probably indirectly related to the improved overall sleep. So this is one study, single study for a single clinical use. And again, this study, we had the delayed release melatonin at two milligrams. So it might not tell us as much about dosage, but it's at least a start. All right. So that concludes my part of the presentation. Thank you again to everyone for tuning in for our talk today.

nutraceutical therapies

brain disorders

CDP-choline

N-acetylcysteine

cannabinoids

omega-3 fatty acids

resveratrol

curcumin

melatonin