Improving Cognition With Neurodegradation Countermeasure

Study Overview
=================
Brief Summary
-----------------
The goal of this randomized, placebo-controlled, three-condition, double-blind, within-participants crossover clinical trial is to compare caffeine, TeaCrine plus caffeine, and a placebo condition in ROTC or tactical personnel. The main question it aims to answer is the effect of the condition on measures of cognitive performance, cardio-autonomic, and hemodynamic responses after a physically demanding protocol. The physiological function will be derived from metrics of heart rate variability, whilst cogntive performance will be evaluated using tasks that assess cognitive domains of executive function, reaction time, and memory. Participants will report to the lab 4 times, once for familiarization of cognitive measures and then 3 times for their experimental visits. Participants will consume their randomized condition an hour prior to the fatiguing interval exercise protocol. Following they will complete a series of cognitive tasks.

Detailed Description
-----------------
The purpose of this randomized, placebo-controlled, three-condition, double-blind, within-participants crossover clinical trial is to determine and compare the effects of the combination of TeaCrine® and caffeine to a placebo and a caffeine condition on measures of cognitive performance, cardio-autonomic, and hemodynamic responses after a physically demanding protocol. After giving informed consent, 20 ROTC members or tactical personnel will undergo baseline performance testing and familiarization and will then be randomly assigned to order of completion of the placebo (P), caffeine (C) condition, and caffeine + TeaCrine (CT) condition, with each session separated by at least 96 hours. In each condition, Participants will be given the condition pill assigned to them, the pill will be taken orally with water, and will wait 60 minutes. At this time, the Participant will complete a treadmill-based physically fatiguing interval protocol with select cognitive testing during the exercise recovery intervals. Participant measures of mental fatigue will be assessed pre- and post-testing, and following the interval bout participants will perform a series of cognitive tasks. Heart rate variability (HRV) and respiration will be assessed continuously though these tasks and blood pressure will be assessed at baseline, prior to the exercise bout, immediately following the exercise bout, and following the cognitive testing.

Official Title
-----------------
Improving Neuroprotection, Cognitive Function, and Mental Focus With Neurodegradation Countermeasure

Conditions
-----------------
Hemodynamics, Caffeine, TeaCrine, Cognitive Change

Intervention / Treatment
-----------------
* Dietary Supplement: TeaCrine and Caffeine
* Dietary Supplement: Caffeine
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is in good health and able to participate in high-intensity exercise. Participant is physically active: participating in resistance and/or endurance exercise ≥4 d/wk and ≥150 min/wk for ≥6 mo. Participant habitually consumes ≤240 mg caffeine/d (the equivalent of 3 cups of coffee). Participants will be asked about dietary supplementation use within the past 6 months. (If Participant began taking a supplement within the past month, the Participant will be asked to discontinue supplement use followed by a 2-week washout prior to participation. In all other cases, supplement use will be asked to be maintained throughout the study). Exclusion Criteria: Participant currently taking any prescription stimulants (i.e., Adderall, Ritalin, Vyvanse, etc.) Participant with any metabolic disorder including known electrolyte abnormalities, diabetes, thyroid disease, adrenal disease or hypogonadism. Participant with any inborn error of metabolism. Participant with a history of hepatorenal, musculoskeletal, autoimmune, or neurologic disease. Participant with sickle cell trait. Participant with a personal history of heart disease, high blood pressure (systolic >140 mm Hg & diastolic >90 mm Hg), psychiatric disorders, cancer, benign prostate hypertrophy, gastric ulcer, reflux disease, or any other medical condition deemed exclusionary by the medical staff. Participant currently taking thyroid, hyperlipidemic, hypoglycemic, anti-hypertensive, or anti-coagulant medications. Participant who has a known allergy to any of the ingredients in the supplement or the placebo. Participant who has migraines. Participant with a history of caffeine sensitivity.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a crossover intervention, in which participants will partake in all 3 conditions with at least 96 hours of washout between conditions.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TeaCrine and caffeine<br>150mg of Teacrine and 150mg of caffeine | Dietary Supplement: TeaCrine and Caffeine<br>* Participants will take Teacrine and caffeine then an hour later perform an intense interval exercise protocol followed by cognitive tests.<br>|
| Active Comparator: Caffeine<br>300mg of caffeine | Dietary Supplement: Caffeine<br>* Participants will take caffeine then an hour later perform an intense interval exercise protocol followed by cognitive tests.<br>|
| Placebo Comparator: Placebo<br>300mg of cellulose | Other: Placebo<br>* Participants will take the placebo cellulose pill and than an hour later perform an intense interval exercise protocol followed by cognitive tests.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in blood lactate | Changes in blood lactate across the experimental visit | On the experimental visit days: Min 0 prior to the exercise protocol, minutes 10, 22, and 30 during the exercise protocol, 5 min after the protocol (min 35), 10 minutes post exercise (min 40) | 
| Changes in Autonomic Nervous System Function (ANS) by linear metrics | To determine if the intervention impacts ANS function by measuring heart rate variability represented by linear time domain metrics. | On the experimental visit days, this will be measured on a second by second basis from the beginning to the end of the visit (approximately 2 hours) | 
| Changes in Autonomic Nervous System Function (ANS) by nonlinear metrics | To determine if the intervention has an impact on ANS function by measuring heart rate variability represented by nonlinear (ApSaEn) time domain metric. | On the experimental visit days, this will be measured on a second by second basis from the beginning to the end of the visit (approximately 2 hours) | 
| Changes in Autonomic Nervous System Function (ANS) by frequency domain metrics | To determine if the intervention has an impact on ANS function by measuring heart rate variability represented by frequency domain metrics. | On the experimental visit days, this will be measured on a second by second basis from the beginning to the end of the visit (approximately 2 hours) | 
| Changes in Inhibitory Control by reaction time (Go/No go) | To determine if the intervention has an impact on inhibitory control by measuring reaction time to Go targets (hits). | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Inhibitory Control by reaction time by errors(Go/No go) | To determine if the intervention has an impact on inhibitory control by measuring errors of commission representing incorrect responses to the target NoGo (false alarm). | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Attention (Go/No go) | To determine if the device has an impact on attention by measuring errors of omission to the target Go (misses). | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Inhibitory Control by accuracy scores (Flanker Task) | To determine if the intervention has an impact on inhibitory control measured by the accuracy scores (% of correct answers) for compatible-congruent, incompatible-congruent, compatible-incongruent, and incompatible-incongruent Flanker Task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Inhibitory Control by average response time (Flanker Task) | To determine if the intervention has an impact on inhibitory control measured by the average response time to incongruent flanker task trials irrespective of compatible or incompatible rule sets. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Inhibitory Control by commission errors (Flanker Task) | o determine if the intervention has an impact on inhibitory control measured by the commission errors when an individual fails to respond correctly to a flanker task trial, and commission error runs when an individual fails to respond correctly to multiple successive trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Attention by accuracy (Flanker Task) | To determine if the intervention has an impact on attention measured by the accuracy scores for congruent-compatible Flanker task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Attention by average response time (Flanker Task) | To determine if the intervention has an impact on attention measured by the overall average response time (milliseconds) to compatible and incompatible Flanker task trails irrespective of trial congruency. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Attention by omission errors (Flanker Task) | To determine if the intervention has an impact on attention measured by the omission errors when an individual fails to respond to a flanker task trial, and omission error runs when an individual fails to respond to multiple successive trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Cognitive flexibility by accuracy (Flanker Task) | To determine if the intervention has an impact on cognitive flexibility by the accuracy scores for incongruent-incompatible Flanker task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Cognitive flexibility by average response time (Flanker Task) | To determine if the intervention has an impact on cognitive flexibility measured by the average response time to incongruent-incompatible flanker task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Cognitive control by post-error accuracy (Flanker Task) | To determine if the intervention has an impact on cognitive control measured by post-error accuracy on Flanker task trials following an error. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Cognitive control by sequential congruency effect (Flanker Task) | To determine changes in cognitive control measured by sequential congruency effect when lower interference occurs following an incongruent relative to a congruent flanker task trial reflecting a consciously controlled narrowing of attention to the central target. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Cognitive control by inverse efficiency (Flanker Task) | To determine if the intervention has an impact on cognitive control measured by inverse efficiency a metric of a speed-accuracy trade-off for Flanker task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Attentional Inhibition (Flanker Task) | To determine if the intervention has an impact on attentional inhibition measured by congruency interference representing the costs associated with the interference demands associated with incongruent vs congruent flanker task trials. | On the experimental visit days: minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in Rating of Perceived Exertion | To determine if the intervention has an effect on perceived exertion, measured by Borg's Rating of Perceived Exertion scale from 6 to 20. Higher measures indicate more exertion. | On the experimental visit days: baseline at minute 0, minutes 10, 22, and 30 during the exercise protocol, and 30 minutes after the exercise protocol | 
| Changes in mood Brunel University Mood Scale (BRUMS). | To determine if the intervention has an effect on mental fatigue and mood. | On the experimental visit days: baseline at minute 0, immediately after completion of the exercise protocol at approximately 90 minutes into the visit, and 30 minutes after the exercise protocol approximately 120 minutes into the visit | 
| Changes in Object Hit and Avoid | To determine the effects of the intervention on rapid response execution and inhibition during complex continuous task performance. | On the experimental visit days: Immediately after and 30 minutes after the completion of the exercise protocol. | 
| Changes in Anti-Saccade Task | To determine the effects of the intervention on higher level processes, assessing response inhibition, working memory, and visuospatial attention. | On the experimental visit days: Immediately after and 30 minutes after the completion of the exercise protocol. | 
| Changes in Modified Trail Making Task | To determine the effects of the intervention on visuomotor processing and executive function. | On the experimental visit days: Immediately after and 30 minutes after the completion of the exercise protocol. | 
| Changes in 2-Back Task | The determine the effects of the intervention on working memory capacity. | On the experimental visit days: Immediately after and 30 minutes after the completion of the exercise protocol. |