The Effect of Creatine Monohydrate on Persistent Post-concussive Symptoms

The purpose of this study, is to investigate whether creatine monohydrate as a supplement reduces the number and severity of symptoms in patients with persistent post-concussive symptoms through self-reported post-concussion symptoms questionnaires.

Mild traumatic brain injury (mTBI), which throughout the literature is used interchangeably with concussion, is a problem the media is drawing more and more attention to, which have made it a public concern too. It is estimated that between 0.6 % and 1.2 % of the general population will suffer an mTBI each year. Out of these, an estimated 10-30 % of the patients, will suffer from persistent post-concussive symptoms (PPCS). These symptoms typically includes headache, poor concentration, memory problems, fatigue, sleep difficulties, dizziness, irritability, feeling nervous or anxious. At the moment no single treatment option is available with guaranteed success, and therefore nutritional supplements are a possibility. The nutritional supplement Creatine Monohydrate (CrM) is one of the most popular ergogenic aids on the market among professional and amateur athletes. It is mostly used in the development of muscle mass, as creatine is primarily located skeletal muscle. Roughly five percent of the body's creatine is distributed in the brain and testicles. As mTBI's also see a change in the metabolism of the brain, creatine supplementation might be beneficial for patients with PPCS. This is further supported by a newly conducted study, that creatine supplementation may reduce the severity of mild concussion in animal models. Furthermore, as the enzyme Creatine Kinease (CK), which is involved in ATP energy system, also has a brain specific isoform (BB-CK), creatine may be a relevant part of the energy system of the central nervous system (CNS). In addition evidence points towards creatine supplementation can increase cellular energy availability. It has been reported to increase brain phosphocreatine content by as much as 15 %, which in turn improves the metabolic processes of the brain. CrM has been described to be a potent anti-inflammatory molecule. It has been shown to reduce the cytotoxic effects in oxidatively-injured cells without affecting antioxidant enzyme activities, and has been shown to inhibit reactive oxygen species-induced formation of mitochondrial permeability transition pores in the liver mitochondria of mice. At the same time, concussion seems to increase inflammation in the brain, and this inflammation has been hypothesized to correlate with the symptomatology and duration. And even though research in the area of recovery is still scarce, neuroinflammation seems to play a vital role in the pathophysiology of concussions. This warrants hopes of a decrease in post-concussive symptoms. Other studies have indicated an improvement of cognitive functions, including fatigue, working memory and mood state. All symptoms related to PPCS. Additionally evidence points towards creatine supplementation can help with chronic fatigue, depression and anxiety. All this points towards CrM being helpful in the treatment of PPCS. PPCS has proven to be not only a health problem, but also a socioeconomical problem. Data from Fallesen et al. showed that salary in Denmark five years after a concussion decreased 4.2 %, with an increased risk of losing ones job. Currently there is not viable treatment option for these patients, but if the intervention shows positive results, patients suffering from PPCS would be able to improve on their symptoms, relatively easy and cheap. They would have a go-to supplement, that would make it possible for them to get a normal day, without any of the symptoms connected to PPCS. The study will be performed as a randomized controlled study. The study is expected to include a convenience sample of 45 patients. The patients will randomly be allocated to either a control group (CG), placebo group (PLA) or intervention group (INT), with 15 patients in each. The study will be double blinded, i.e., the participants not knowing which group they will be allocated to. The study population consists of patients with persistent post-concussive symptoms between six and twelve months at start of participation. Participants will be recruited through social media and contact with neurological outpatient clinics throughout Denmark. At the start of the study, participants will have to be between 25 and 35 years of age. This will make the population a homogenous age group, and we will avoid physical and cognitive challenges related to early childhood and adolescents, as well as avoiding the degeneration in physical capacities that begin at approximately the age of 35 as well as the cognitive decline around the same time. Their anthropometrics will consist of: Age (years) Gender (male/female) Height (cm) Weight (kg) Period with PPCS (months) Concussion history (yes/no) If yes - how many (number) Training status (hours/week) Study procedure Baseline phase: Before inclusion in the study, participants have to sign a declaration of consent, to make them fully aware of what they agree to participate in, what risks there are and what they can gain from the study. When the declaration is signed, the participants have to have their height in cm and weight in kg measured, as well as answering how many concussions they previously suffered, along with their training status as hours/week. The baseline measurements concludes with participants answering the Rivermead Post-Concussion Symptom Questionnaire (RPQ). Study phase: The participants will randomly be allocated to either the CG, PLA or INT group. CG will not receive any treatment other than usual treatment. PLA and INT will both receive a powder, that has to be ingested. PLA will receive a powder similar in looks to CrM, but with no apparent nutritional value, while INT will receive CrM. oAs both PLA and INT are the interventions, they will follow the same protocol for ingestion 5 grams per day in seven weeks. All 5 grams will be ingested at once. This protocol has been chosen instead of the more common 0.3 g/day for the first week, ingested over five times during the day. In other studies on CrM and the brain, this have been the chosen strategy also. But studies on CrM in the muscles show, that both protocols illicit the same response with 28 days, and the loading phase is not required. Furthermore, some studies have used this protocol with creatine supplementation, and found increased cognitive function. Our reason for choosing 5 g/day in seven weeks, is to increase the chances of compliance, and decrease the risks of discomfort with to high an intake of CrM. An intake five times a day for the first week, is demanding, and will most likely get some participants to quit the study. At the mid phase of the study, all baseline measurements will be done again. End of study protocol: The length of the intervention is seven weeks. After the seven weeks, all baseline measurements will be done again. And a week after last ingestion, the measurements will be done one last time. At the week eight appointment, every participant will have to answer whether they thought they were getting placebo or CrM. This is done in order to figure out how big an effect placebo have on the results.

The control group will receive standard care. However, to our knowledge there is no common accepted description of a standard care in the literature. In general, these participants will be advised to keep themselves as asymptomatic as possible throughout the entire seven weeks, and besides that live as normal a life as they can.

As we are using a dietary supplement as our intervention, following participants body weight in kg throughout the intervention is necessary in order to know if changes in body weight have any effect on our results.

Inclusion Criteria: Have had PPCS for a minimum of six months and a maximum of 12 months at the start of the study. Being between 25 and 35 years of age Exclusion Criteria: Elite athletes, as well as people who in general is physical active for more than ten hours a week on average. Participation in other interventions/treatment than this study Have had PPCS in: <6 months >12 months Pregnant Other brain diseases or traumatic injuries Musculoskeletal diseases

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