High-level cognitive processes:

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1 High-level cognitive processes: Attention can be selective (to be focused on only one thing e.g. phone call in a middle of open plan office), sustained (to be focused for a long time e.g. attend to a lesson) or divided (to be focused on different things in the same time e.g. attend to a lesson and write notes). During all his life, human needs to integrate information, adapt his behavior to situation and people, and acquire knowledge and skills. Those processes are achieved by brain using specific tools, known as cognitive functions. There are six cognitive functions which are deeply interconnected, interdependent and cannot work alone to achieve an intellectual task. Memory can be divided in two groups: The working memory implicates both short term memory and manipulation to achieve a mental task, such as mental calculation. Short term memory has a restricted capacity. During a short period of time, it stores data, used for instant interpretation. The long-term memory allows to save data and recall them after a period of time. For example, remind mother s birthday, last diner composition, etc. These six cognitive functions are divided into two levels: Low-level cognitive processes: Gnosis allows to recognize and identify what our senses feel (e.g. sight, hearing, taste, sense of smell and touch). Praxis coordinates different part of our body to perform a motor task (for example to run, to draw, to dress, to cook, etc.) Language is a cognitive function which implicates comprehension and expression. It includes both types of support: oral and written (e.g. listen, discuss, read and write). Executive function is probably the most complex and also the most interdependent with other cognitive functions. It describes adaptation (such as behavior) when you are facing to a new or unknown situation, in opposite with used and regular situation. 1

2 Many intellectual tasks require executive function: to plan, to determine a strategy, to change our mind, to adapt ourselves, to work in a team, to inhibit instinctive reaction, self-monitoring, etc. For example, how to find a new road the morning on the way to work, when an accident happens. All cognitive functions work in combination with other(s), in a coordinate manner. More specifically, Attention, Working memory and Long-term memory are deeply connected to achieve an intellectual task (as well as Executive function). Nowadays, information are going faster than ever. We are constantly solicited by an uninterrupted flow of data that we have to integrate, treat and memorize. Our cognitive functions, and likely more high-level processes, are endlessly recruited and challenged. In our fast moving society, a growing demand exists from active people who want to remain mentally performant and competitive. They are concerned of their memory in the office or their concentration on the sports pitch. Supplements supporting cognitive health can benefit to all people, from millennials to baby boomers. Sports people use them to remain concentrate while practicing. Older people want to stay mentally sharp (for 94% of adults over 50 years old, staying mentally sharp is everything they need (AAARP, 2011)). 20% young people, such as students, are using psychic tonics to enhance apprenticeship during exams (Passeport Santé, 2016). Finally, working persons consume cognitive supplements to help them staying active and performant. In this context, try to extend Long-term memory (and the recall process), improve or facilitate Attention and Working memory, is an interesting approach to adapt and perform in modern life. Who is concerned by cognitive performance? For healthy persons, exercising and having a balanced nutrition helps to remain healthy. However, having a healthy lifestyle could be challenging. This is why consumers turn to supplements market. With the number of people over 60 expected to double between 2000 and 2050 (WHO, 2017), concerns over cognitive health is growing worldwide. Dementia is the first fear in older adults who are a huge audience for cognitive health products. However, their cognitive disorders, if classified in age-related decline, are out of the field of supplements. The booming cognitive market According to Innova, between 2011 and 2015, the cognitive market incredibly increased: +235% on the Supplements category and +113% on the Food & Beverage category (in terms of new product launches)! However, on the Food & Beverage market, cognitive ingredients still represent a minority with less than 1% of the NPL. Mainly used in supplements, cognitive health is a booming category (11 to 13% of the NPL) and has reached $2.7 billion in 2015 (Euromonitor International, 2016) 2

3 Consumers are mainly looking for benefits on memory (72%): this positioning represents 50% of the sales. Secondly, they seek to maintain healthy brain functions (59%), prevent memory loss (57%) and help with concentration (55%). Finally, focus is seeking by 48% consumers. Plant-based product is a growing trend in the supplement industry and begins to appear on the cognitive category. According to Innova, in 2016, 4.5% more botanical and herbal supplements claiming to promote cognitive health were launched compared to This means that consumers needs on cognitive plant-based products are not satisfied yet. General concern also exists over a lack of sleep, stress, mood which can affect the cognitive health. In the USA, the market for cognitive and brain supplements is represented by three main ingredients: fish & animal oils, multivitamins and Ginkgo biloba (Nutrition Business Journal). Salvia, a sacred story telling Sage, or Salvia which means save or heal in Latin, belongs to the Lamiaceae family. Garden Sage is also called the sacred grass: it's not a surprise that its 900 species are used throughout the world since time immemorial. Vegetable products benefit from a more natural and healthier image than those from animals. This vegetable trend is true both in Food & Beverage and in Supplement markets. On the supplement market, the botanical and herbal category is growing much faster than total supplements. In 2016, this category represents 16% of the new product launches (Innova, 2016). Salvia is considered as one of the oldest cultivated herbs. Historically, Sage was used in food and by traditional medicines in Europe and China. Previously called Salvia salvatrix, Sage is well-known for its health benefits. Today, Nexira has chosen the best varieties of Sages that have a synergistic effect to create a unique and innovative ingredient. 3

4 What is Cognivia? Cognivia is a water-dispersible powder, suitable for numerous dietary supplements applications. Cognivia is the first organic ingredient to combine two species of Sage: Spanish Sage (Salvia lavandulifolia) and Garden Sage (Salvia officinalis). To develop this unique ingredient, Nexira worked with different parts of the herb. First, the essential oil is extracted from Salvia lavandulifolia. For many years, Nexira has developed an expertise in micro-encapsulation with acacia gum. This know-how, applied to organic Spanish Sage essential oil with Fibregum Bio, insures a protection from oxidation and drying process. This process also enhances the powder water dispersibility. On the other side, the organic Salvia officinalis provides an aqueous leaf extract. These two sage species have a synergistic effect and can help consumers to improve naturally their cognitive health. Cognivia is a natural and safe ingredient with a full traceability control. Clinical studies with Sage Most in vivo trials were done using Salvia officinalis as an aqueous, ethanolic or hydroethanolic extract and sometimes with the essential oil. It was demonstrated on animal model that these extracts have two actions. First, they show an inhibitory activity on acetylcholine esterase. Secondly, they limit the noxious effect of oxidative stress. The result is an improvement of the rodent memory process. Negative effect of the chemical agents used to induce amnesia or neurodegeneration is also limited. Clinical studies use common and recognized tests to measure the quality of memory and cognitive performance: Immediate word recall: 15 common words are presented one second each to the participants. Right after they have to write down as many words as possible. Delayed word recall: the participants are tested 20 minutes after the words have been presented. Once again they have to write down as many right words as possible. Delayed word recognition: the participants are presented with 15 words from an original list, plus 15 novel distractor words. They answer yes or no as to whether each word was in the original word list. Correctness and speed are measured. Cognivia, an innovative natural & organic phytoingredient for cognitive performance Delayed picture recognition task: the participants are presented with the 15 original pictures, plus 15 distractors. They answer yes or no as to whether each picture was one of those presented earlier. Correctness and speed are measured. Spatial working memory test: participants are presented a pictorial representation of a 4

5 house with some of its windows illuminated. Other presentations of the house are then presented with only one lighted window. The participants have to answer as quickly as possible whether yes or no the window was already lighted in the original presentation. Numeric working memory: the participants are presented five digits. A series of 30 digits are then presented and the participant have to answer by yes or no whether the digit was in the original series. Digit vigilance task: the participants have to press yes every time a target digit appears among series of digits on the screen. Accuracy and speed are measured. Serial substraction task: the participants have to count backwards during two minutes from a given number as fast and accurately as possible. In this case the numbers they have to serially substract were either three (3) or seven (7). Simple reaction time: the participants have to press the yes button as fast as possible each time it is presented on a screen. Stroop color word task: words describing one of four colors are presented in different colored fonts. The participants have to click on color panels corresponding to the color font and without being confused with the color written down. Perceived Alertness : using the Bond-Ladder mood scale Five recent clinical studies, using these cognitive measures, have established the efficiency of Salvia lavandulifolia essential oil (E.O.) and Salvia officinalis leaf after only one intake. Three studies focus on Salvia lavandulifolia essential oil: In 2003, Tildesley and his team established in two trials that the acute ingestion of 50 µl and 100 µl of Salvia lavandulifolia essential oil enhanced the memory process of healthy young adults. 50 µl was the most efficient. The test used was part of the Cognitive Drug Research (CDR) computerized assessment battery. The trials demonstrated an impressive improvement among young healthy adults in immediate and delayed word recall at 1 and 2,5h after ingestion. In 2005, Tildesley and al. went further with a more exhaustive tailored version of the CDR using 25 µl and 50 µl of EO. They measured subjective mood testing and serial subtraction tasks. Once again they tested healthy young adults. They confirmed that the essential oil improved the memory of the participants starting at 25 µl even though 50 µl is the most efficient intake. It appeared that their mental mathematical skills increased and volunteers felt more alert. Finally, Kennedy and al. in 2011 used other batteries of tests: Computerized Mental Performance Assessment System (COMPASS) and Cognitive Demand Battery (CDB). The results confirmed the previous studies ingesting 50 µl on healthy young adults. The participants improved their score at the memory tests and felt more alert. These studies on Salvia lavandulifolia essential oil indicate that the effects on memory come quickly and seem to last during several hours on alertness and mental skills. Salvia officinalis leaves, whole dried or extracted, were also studied: Kennedy and his team in 2006 demonstrated that the ingestion of dried leaf increased the cognitive performance of healthy young participants using the Defined Intensity 5

6 Stressor Simulation (DISS) computerized battery. These effects were also confirmed by participants who felt more alert. Finally, Scholey et al., in 2008, demonstrated that the activity of a hydro-ethanolic extract of S. officinalis was efficient among older participants (average of 73 years old). Using several tasks from the CDR they established that different quantities of leaf extract increased cognitive performance and improved the memory of the participants. Thus demonstrating that S. officinalis turns out to be efficient for adult young and old. All those five clinical studies (table1) demonstrated and confirmed several times the benefits of Spanish sage essential oil and Garden sage leaves, on cognitive functions notably Attention, Working memory, Longterm (secondary) memory and Executive function. Those benefits has been highlighted on young persons, few hours after only one intake. Those botanical sources represent a really interesting opportunity for healthy and active people looking for an improvement of their cognitive functions. Publication Product tested Use level Participants Significant and noticeable effects of Sage Tildesley S. lavandulifolia 50 µl, 100 µl Group 1 of µl was the most efficient intake and al. essential oil and 150 µl young healthy tested: 2003 Or Placebo (1 and 2.5 hours after a single intake) adults (av.: 19 y.o) Immediate word recall score: Grp1: +8 to 13% / Grp2: +12% Delayed word recall score : Group 2 of 24 young healthy adults Grp1: +18% Tildesley and al Kennedy and al Kennedy and al Scholey and al S. lavandulifolia essential oil Or Placebo S. lavandulifolia essential oil Or Placebo S. officinalis dried leaves Or Placebo S. officinalis hydro-ethanolic (70%) extract Or Placebo 25 or 50 µl (1, 2.5, 4 and 6 hours after a single intake) 50 µl (1 and 4 hours after a single intake) 300 or 600 mg (1 and 4 hours after a single intake) 167, 333, 666 or 1332 mg (1, 2.5, 4 and 6 hours after a single intake) (av.: 23 y.o) 24 young healthy adults (av.: 23.2 y.o) 30 young healthy adults (av.: 24.4 y.o) 20 older adults (av.: 73 y.o) Quality of memory: +8% Secondary memory: +15% Speed of memory: +5 to 6%. Perceived alertness: +11 to 12% Speed of mental calculation: +9 to 15% Accuracy of mental calculation: +26 to 97% Delayed word recall: +22% Simple reaction time: +7% Delayed word recognition: +12% Delayed picture recognition: +7 to 8% Perceived alertness: +5%. 600 mg was the most efficient intake tested: Stroop color test: +18% to 36% Perceived alertness: +7 to 11% 333 mg was the most efficient intake tested: Delayed word recognition: +22 to 33% Immediate word recall: +18 to 19% Delayed word recall: +25 to 27% Table1: Summary of Sage effects on cognitive functions, demonstrated in human studies 6

7 Proprietary study and Cognivia benefits Nexira, in collaboration with Nutribrain (Adera/INSERM Bordeaux University France) investigated Cognivia benefits on cognitive functions in an in vivo study. Because of lack of consciousness and language skills in rodent study, explicit (declarative) memory is not assessable. Specific models on mice have been developed to measure memory function by reducing it into basic experimental paradigms (Sharma 2010). In these behavioral paradigms, we can assess impacts on memory by observation of animal behavior in response of a two-step process: a Learning Phase where animal is recording data; then a Recall Phase (restitution test) where animal facing to multiple solutions can express a choice through his behavior and based on recalled information. In this study on normal adult mice, we assessed three ingredients compared to control conditions: Cognivia Essential oil of Spanish sage (Salvia lavandulifolia) contained in Cognivia Aqueous leaves extract of Garden sage (Salvia officinalis) contained in Cognivia We can conclude that this association of both sage remains effective to improve cognitive function. Prolonged administration: In the Morris water maze model, we assessed administration of our three ingredients during 14 days. The first step is an adaptation to the environment during 4 days. The learning phase lasted from the 5th day to the 11th day. It consists in learning the position of the submerged platform, ie the localization of the target quadrant. Then, there are 2 days of forgetting process, without intervention. The last step is the restitution test, performed on the 14th day: the platform is removed and we observed the mice behavior. The behavioral paradigm of mice assessed was the distance travelled in the target quadrant (where the platform is supposed to be), compared to the time spent in remaining quadrants. Higher distance in the target quadrant indicates that the mice haven t forgotten (or less forgotten) that the platform is supposed to be there. Morris water maze is related to working memory and long-term (reference) memory. Single intake: In this part, we confirmed that a single intake of Cognivia (as well as both sources of sage individually) has a significant positive impact on memory in the Y-maze model, 2 hours after administration. The Y-maze model is more related to working memory (Sharma 2010). This observation is in accordance with benefits observed in clinical studies described above and regarding both sources of sage included in Cognivia. 7

8 Difference of distance travelled in target vs remaining quadrants (%) After 14 days of intake, Cognivia is the only ingredient to have a significant (p value < 0,01) positive impact (Graph1). After the same period of administration, the two Sage sources, tested individually, haven t demonstrated any significant results. Graph 1: Morris water maze model: restitution test after 14 days of intake. Difference of distance travelled in between the target and remaining quadrants The combination of both sources in Cognivia allows a synergistic action responsible of the improvement of the behavioral paradigm related to working and long-term memory. Thanks to these trials results, we concluded that Cognivia represents a specific Sage based ingredient to improve working and long-term memory. Cognivia inspired by nature and science: Clinical studies performed on both sources of Sage included in Cognivia Single intake efficacy (from 1 hour to at least 6 hours after intake) Improvements of high cognitive level processes (Attention, Working memory, long-term memory, executive function) Description of most effective intake in human as proposed in Cognivia s recommended level of use Proprietary study: in vitro study performed on Cognivia Confirmation of single intake efficacy Demonstration of the specific advantage of Cognivia for prolonged intake Possible claims: EFSA pending claims on Salvia lanvandulifolia: Helps maintaining optimal mental well-being, eg maintaining concentration, attention and memory Organic certified Suitable for young and healthy adults 8

9 Although NEXIRA has used diligent care to ensure that the information provided herein is accurate and up to date, NEXIRA makes no representation or warranty of the accuracy, reliability, or completeness of the information. This document only contains scientific and technical information for business to business use. Country or region-specific information should also be considered when labelling or advertising to final consumers. This publication does not constitute or provide scientific or medical advice, diagnosis, or treatment and is distributed without warranty of any kind, either expressly or implied. In no event shall NEXIRA be liable for any damages arising from the reader s reliance upon, or use of, these materials. The reader shall be solely responsible for any interpretation or use of the material contained herein. CDB: Cognitive Demand Battery CDR: Cognitive Drug Research COMPASS: Computerized Mental Performance Assessment System DISS: Defined Intensity Stressor Simulation EO: Essential Oil INSERM: Institut National de la Santé Et de la Recherche Médicale NPD: New Product Development NPL: New Product Launch Dinel, A. L., C. Andre, A. Aubert, G. Ferreira, S. Laye, N. Castanon. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS One, 2011, 6: e Dinel, A. L., C. Joffre, P. Trifilieff, A. Aubert, A. Foury, P. Le Ruyet, S. Laye. Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood." J Neuroinflammation, 2014, 11: 155. Eidi M., Eidi A, Bahar M. Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in rats. Nutrition, 2014, 22, El-Kholy, W. M., El-Habibi, E. M., Mousa, A. T. Oxidative stress in brains of male rats intoxicated with aluminium and the neuromodulating effect of some forms of sage (Salvia officinalis). Journal of American Science, 2010, 6(12), Horvathova, E., A. Srancikova, E. Regendova-Sedlackova, M. Melusova, V. Melus, J. Netriova, Z. Krajcovicova, D. Slamenova, M. Pastorek, K. Kozics. "Enriching the drinking water of rats with extracts of Salvia officinalis and Thymus vulgaris increases their resistance to oxidative stress." Mutagenesis, 2016, 31: Jadad, A. R., R. A. Moore, D. Carroll, C. Jenkinson, D. J. Reynolds, D. J. Gavaghan, H. J. McQuay. "Assessing the quality of reports of randomized clinical trials: is blinding necessary?" Control Clin Trials, 1996, 17: Kennedy D.O., Pace S., Haskell C., Okello E.J., Milne A., Scholey A.B. Effects of Cholinesterase Inhibiting Sage (Salvia officinalis) on Mood, Anxiety and Performance on a Psychological Stressor Battery. Neuropsychopharmacology, 2006, 31,

10 Kennedy D.O., Dodd F.L., Robertson B.C., Okello E.J., Reay J.L., Scholey A.B., Haskell C.F. Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults. J Psychopharmacol, 2011, 25, Kishore, S., Anitha, K., Nettem, S., Pratima, K., Shobana, K. Evaluation of nootropic activity of Salvia officinalis L. extract using different experimental models in rats. JGTPS, 2014, 5 (4) Miroddi, M., M. Navarra, M. C. Quattropani, F. Calapai, S. Gangemi, G. Calapai. "Systematic review of clinical trials assessing pharmacological properties of Salvia species on memory, cognitive impairment and Alzheimer's disease." CNS Neurosci Ther, 2014, 20: Morris, R. "Developments of a water-maze procedure for studying spatial learning in the rat." J Neurosci Methods,1984, 11: Perry, N. S., P. J. Houghton, P. Jenner, A. Keith, E. K. Perry. "Salvia lavandulaefolia essential oil inhibits cholinesterase in vivo." Phytomedicine, 2002, 9: Perry, N. S., P. J. Houghton, A. Theobald, P. Jenner, E. K. Perry. "In-vitro inhibition of human erythrocyte acetylcholinesterase by Salvia lavandulaefolia essential oil and constituent terpenes." J Pharm Pharmacol, 2000, 52: Savelev, S., E. Okello, N. S. Perry, R. M. Wilkins, E. K. Perry. "Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil." Pharmacol Biochem Behav, 2003, 75: Scholey A.B., Tildesley N.T.J., Ballard C.G., Wesnes K.A., Tasker A., Perry E.K., Kennedy D.O. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology, 2008, 198, Sharma, S., Rakoczy, S., Brown-Borg, H. Assessment of spatial memory in mice. Life sciences, 2010, 87(17), Smach, M. A., Hafsa, J., Charfeddine, B., Dridi, H., Limem, K. Effects of sage extract on memory performance in mice and acetylcholinesterase activity. Annales Pharmaceutiques Françaises, 2015, Vol. 73, No. 4, pp Tildesley N.T.J., Kennedy D.O., Perry E.K., Ballard C.G., Wesnes K.A., Scholey A.B. Salvia lavandulaefolia (Spanish Sage) enhances memory in healthy young volunteers. Pharmacology Biochemistry and Behavior, 2003, 75, Tildesley, N. T. J., Kennedy, D. O., Perry, E. K., Ballard, C. G., Wesnes, K. A., & Scholey, A. B. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiology & behavior, 2005, 83(5),