Patent Publication Number: US-2017367996-A1

Title: Use Of Xanthophyll Carotenoids To Improve Visual Performance And Neural Efficiency

Description:
RELATED APPLICATION 
     This application claims priority from U.S. Provisional Application No. 61/507,451, filed Jul. 13, 2011 and entitled “Use of Lutein and Zeaxanthin to Improve Visual Performance and Neural Efficiency”. The complete contents of U.S. Provisional Application No. 61/507,451 are hereby incorporated by reference in their entirety. 
    
    
     FIELD OF THE INVENTION 
     In one embodiment, the invention provides a method of improving reaction time and coincidence anticipation ability in a subject in need, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids. In additional embodiment, a method is further used to allow a subject in need, especially including the subject above, to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function Related compositions are also provided. 
     BACKGROUND OF THE INVENTION 
     Xanthophyll carotenoids lutein (L) and zeaxanthin (Z) are found in high concentration in human nervous tissue, such as retina and neocortex [1, 2]. In the retina, L and Z are located in the macula and are termed macular pigment (MP). Thus, MP is composed of the carotenoids lutein (L) and zeaxanthin (Z) and a product of their interconversion, meso-zeaxanthin (MZ). MP optical density can be measured non-invasively using established psychophysical techniques[3], and MP optical density relates strongly to L and Z concentrations in the brain. MP is thought to protect the retina from actinic damage and oxidative stress, and to improve visual function by two basic mechanisms: short-wave light absorption, and improving neural efficiency. 
     While high MP density may be beneficial for the population at large, athletes who play outdoor sports may receive extra benefit from maintaining high MP optical density (MPOD), as they are required to perform a number of visual and visual-motor tasks at extremely high speed in the very environmental and lighting conditions known to degrade visual function the most. 
     L and Z function in the retina is relatively well-understood. The following three basic hypotheses have been posed in past literature to explain what L and Z as MP may do to improve visual function. The first hypothesis is the protective hypothesis, which suggests that because L and Z are pigments that both absorb damaging short-wave “blue” light and serve as antioxidants, MP may be able to improve visual function by preventing acquired ocular diseases that degrade vision, such as age-related macular degeneration (AMD), the leading cause of blindness in the West. 
     The second hypothesis for MP function is based on optical properties of MP. Because L and Z absorb short-wave light, and because short-wave light scatters readily in the atmosphere and within the eyes, MP&#39;s ability to absorb short-wave light improves visual performance in short-wave dominant viewing conditions, and in those conditions where absorbing the short-wave portion of a relatively intense broad band light source improves vision. For example, individuals with higher MPOD tend to have improved visual function under glare conditions and in the presence of light stressors. Individuals with higher MP also have improved ability to detect the edge of an object when that object is presented in front of a short-wave background, such as a “blue” sky. 
     The third hypothesis for MP function is the neural efficiency hypothesis. The neural efficiency hypothesis suggests that MP, on the level of the neural retina and as a biomarker of cortical L and Z concentration, is capable of improving neural efficiency by reducing neural noise (random neural firing that is not correlated to the presence of a sensory stimulus), by improving processing speed, and by minimizing the amount of cortical area necessary to perform for any given cognitive task. 
     A relatively large body of literature has supported the first two hypotheses (the protective hypothesis and the optical hypotheses). Renzi and Hammond [4] posited the neural efficiency hypothesis in 2010 and have been collecting data to determine whether or not the neural efficiency hypothesis is correct. 
     Notwithstanding the aforementioned efforts to understand the role of cortical L and Z in optic health, the need continues to exist for treatments and pharmaceutical compositions that can utilize Xanthophyll carotenoids to improve visual performance and neural efficiency. 
     SUMMARY OF THE INVENTION 
     In one embodiment, the invention provides a method of enhancing a subject&#39;s macular pigment optical density, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids. Preferably, the Xanthophyll carotenoids are selected from the group consisting of lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), and enantiomers, metabolites, esters, pharmaceutically acceptable salts and derivatives thereof. In certain embodiments, the Xanthophyll carotenoids such as lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are each in substantially pure enantiomeric form. 
     Preferably, a pharmaceutically effective amount of one or more Xanthophyll carotenoids is administered topically to the subject (or by the subject to himself or herself) by application of an ocular solution, or is administered systemically through a solid or liquid dosage form comprising not less than about 200%, or not less than about 190%, or not less than about 180%, or not less than about 170%, or not less than about 160%, or not less than about 150%, or not less than about 140%, or not less than about 130%, or not less than about 120%, or not less than about 110% of the amount of xanthophyll carotenoids that might otherwise be metabolized by a subject as a result of eating food sources such as eggs, spinach, or corn. For example, using purely illustrative ranges, pharmaceutically effective amounts of lutein (L) and zeaxanthin (Z) could range from about 1,000 mg, or about 900 mg, or about 800 mg, or about 700 mg, or about 600 mg, or about 500 mg, or about 400 mg, or about 300 mg, or about 200 mg, or about 100 mg, or about 900 mg, or about 90 mg, or about 80 mg, or about 70 mg, or about 60 mg, or about 50 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 9 mg, or about 8 mg, or about 7 mg, or about 6 mg, or about 5 mg, or about 4 mg, or about 3 mg, or about 2 mg, or about 1 mg. In certain aspects of the invention, the composition is in the form of a food composition, including a food bar such as a sports bar or a liquid. 
     In another embodiment, the invention provides a method of improving reaction time and coincidence anticipation ability in a subject in need, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids. 
     In another embodiment, the invention provides a method of increasing the ability of a subject in need to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids. 
     In another embodiment, the invention provides a method of improving reaction time and coincidence anticipation ability in a subject who is required to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids. 
     In the methods of treatment described above, the subject may or may not suffer from an ocular disorder. 
     Thus, in one embodiment, the static and dynamic visual performance of a subject such as an athlete, pilot, or member of the military is enhanced by administration of a pharmaceutically effective amount of one or more Xanthophyll carotenoids. For example, the Xanthophyll carotenoids may be administered to or by such a subject before the subject encounters glare conditions. Thus, in one example, an athlete, before or during a night game in a lighted stadium, may be treated with or may self-administer one or more Xanthophyll carotenoids in accordance with the invention to enhance his or her static and dynamic visual performance, or in another example a pilot, before or during a night flight, may be treated with or may self-administer one or more Xanthophyll carotenoids in accordance with the invention to enhance his or her static and dynamic visual performance. 
     In certain embodiments of the invention, a fatty acid (e.g., an omega 3, omega 6 or an omega 9 fatty acid) is co-administered with one or more Xanthophyll carotenoids. 
     In another embodiment, the invention provides a method of preventing continued visual acuity deterioration in a subject who suffers from age-related macular degeneration, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids such as those described above. The age-related macular degeneration can be dry age-related macular degeneration or wet age-related macular degeneration. 
     In certain embodiments, the subject has not experienced visual loss and expresses drusen prior to treatment. In other embodiments, the subject suffers from geographic atrophy prior to treatment. 
     In another embodiment, the invention provides a method of preventing visual acuity deterioration in a subject who is at risk of developing age-related macular degeneration, the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids such as those described above. 
     In still another embodiment, the invention provides a composition as otherwise described herein comprising one or more active ingredients selected from the group consisting of Xanthophyll carotenoids such as lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), and enantiomers, metabolites, esters, pharmaceutically acceptable salts and derivatives thereof, and optionally one or more pharmaceutically acceptable excipients and/or other additives as described herein. 
     These and other aspects of the invention are described further in the Detailed Description of the Invention. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1 . Stimuli and timing characteristics for CAT, FRT and VRT as determined for healthy subjects in the experiment of Example 1. 
         FIG. 2 . Improvements for one subject, baseline MPOD of 0.7 at 30-min of eccentricity, 12-week MPOD of 0.77, as determined for healthy subjects in the experiment of Example 1. 
         FIG. 1A . Glare disability testing results determined in the experiment of Example 2; stimuli presented in three-channel Maxwellian-view optical system (1 kW xenon-arc light source): (a) 570 nm target (100% contrast, 5 cycles per degree—cpd); 10° inner, 12° outer diameter annulus comprised of broad-band xenon light. Contrast enhancement testing results determined in the experiment of Example 2: (b) 600 nm target (100% contrast grating, 5 cpd); 460 nm surround. 
         FIG. 2A . Dynamic visual performance results determined in the experiment of Example 2. 
         FIG. 3A . Temporal Contrast Sensitivity Function (TCSF) apparatus (a) and Free-view presentation (through an artificial pupil; see  FIG. 3 a   ) of 1°, 660 nm target centered within 10°, 660 nm surround (b); results determined in the experiment of Example 2. 
         FIG. 4A . Increases in MPOD and improvement in both static and dynamic visual performance after zeaxanthin supplementation results determined in the experiment of Example 2. 
         FIG. 1B . Schematic of CAT stimuli presentation; results determined in the experiment of Example 3. 
         FIG. 2B . Fixed and variable position reaction time; results determined in the experiment of Example 3. 
         FIG. 3B . MPOD was significantly related to decreased RT (r=−0.25, p&lt;0.05); results determined in the experiment of Example 3. 
         FIG. 1C . The relationship between MPOD and fixed position reaction time in young, healthy adults. (r=−0.21, p&lt;0.05); results determined using a protocol similar to that described in the experiment of Example 4. 
         FIG. 2C . The relationship between MPOD and variable position reaction time in young, healthy adults. (r=−0.22, p&lt;0.05); results determined using a protocol similar to that described in the experiment of Example 4. 
         FIG. 3C . The relationship between error in coincidence anticipation and MPOD in young, healthy adults. (r=−0.23, p&lt;0.05); results determined using a protocol similar to that described in the experiment of Example 4. 
         FIG. 4C . The relationship between MPOD and balance time in healthy elders. (r=0.29, p&lt;0.05); results determined using a protocol similar to that described in the experiment of Example 4. 
         FIG. 5C . The relationship between MPOD and judgment reaction time in healthy elders. (r-0.25, p&lt;0.05); results determined using a protocol similar to that described in the experiment of Example 4. 
         FIG. 6C . Schematic of the linear light array used to determine FRT, VRT and CAT in accordance with the experiment described in Example 4. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following terms, among others, are used to describe the present invention. It is to be understood that a term which is not specifically defined is to be given a meaning consistent with the use of that term within the context of the present invention as understood by those of ordinary skill. 
     It is noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” include plural referents unless expressly and unequivocally limited to one referent. Thus, for example, reference to “a compound” includes two or more different compound. As used herein, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or other items that can be added to the listed items. 
     “Improved reaction time and coincidence anticipation ability” and “enhanced static and dynamic visual performance” can be assessed in a variety of ways, e.g. using the methodologies described in Examples 1-4 herein. Relevant parameters indicative of improved reaction time and coincidence anticipation ability include but are not limited to:
     (1) an increase in MPOD of about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% compared to a subject&#39;s baseline MOPD level;   (2) an increase in MPOD associated with a decrease in photostress recovery time of about 10, or 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 or 1 seconds (e.g. decreased photostress recovery time associated with a MPOD increase of around 10% to around 15% of a baseline MPOD level);   (3) decreases in CAT, FRT, and/or VRT of about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% compared to a subject&#39;s baseline CAT, FRT, and/or VRT levels;   (4) a critical flicker fusion threshold increase of between around 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.4, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.8, 2.9, or 3.0 Hz; and   (5) a logarithmic increase in disability glare threshold (veiled glare threshold)) of around 0.01 to 0.25 over a period of around one to around six months;   

     “Lighting conditions that are known to be detrimental to visual function” include but are not limited to lighting conditions in which blue light (e.g. “blue haze”) is a major factor in limiting outdoor vision (e.g. light at wavelengths of around 400 nm to around 550 nm), and disability glare conditions associated with xenon-white light at log energy (μW/cm 2 ) values of around 2 to around 4. 
     “Increases in MPOD” can be measured over a wide variety of time points, including but not limited to one or more days, weeks, or months (e.g. around a 50% increase in MPOD over a period of around 120 days). 
     “Preventing continued visual acuity deterioration in a subject who suffers from age-related macular degeneration” includes but is not limited to improving standardized visual acuity, optical coherence tomography (OCT), macular thickness and volume, and intraocular pressure, decreasing central foveal thickness from around 400 to around 300 or around 250 microns as measured by OCT, fluorescein angiography and OCT demonstrated cessation of vascular leakage, resolution of hemorrhage and subretinal fluid in the treated eye, improved scores on the National Eye Institute Vision Function Questionnaire (NEI VFQ), the Activities Inventory (AI), and the Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-48) or Targeted vision Test, or in a sample protocol achieving the following results: test corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of a patient with Stargardt&#39;s macular dystrophy, and vision also improves in a patient with dry age-related macular degeneration (from 21 ETDRS letters to 28). 
     “Preventing visual acuity deterioration in a subject who is at risk of developing age-related macular degeneration” can entail preventing increases in macular thickness and volume in a subject who is around fifty years of age of older, as well as decreasing such a subject&#39;s intraocular pressure and central foveal thickness, and preventing an accumulation in the subject&#39;s eye of sub-RPE deposits that contain molecular constituents of human drusen, decreased segmentation of atrophic areas in the subject&#39;s eye as confirmed by Fundus autofluorescence imaging, decreased GA enlargement in the subject&#39;s eye, and confirmation of a lack distinct micro structural alterations related to GA as visualized using high-resolution spectral-domain optical coherence tomography. 
     “Xanthophyll carotenoids” generally refers to a naturally occurring or synthetic 40-carbon polyene chain with a carotenoid structure that contains at least one oxygen-containing functional group. The chain may include terminal cyclic end groups. Exemplary, though non-limiting, xanthophyll carotenoids include astaxanthin, zeaxanthin, lutein, echinenone, lycophyll, canthaxanthin, and the like. Isomerism around carbon-carbon double bonds yields distinctly different molecular structures that may be isolated as separate compounds (known as Z (“cis”) and E (“trans”), or geometric, isomers). Xanthophyll carotenoids therefore include but are not limited to (3R,3′R,6′R)-lutein, (3R,3′R,6′R)-zeaxanthin, the (E/Z) isomers of (3R,3′R,6′R)-lutein and (3R,3′R,6′R)-zeaxanthin, the metabolites (3R,3′S,6′R)-lutein (3′-epilutein) and 3-hydroxy-β,ε-caroten-3′-one, (3R,3′S-meso)-zeaxanthin (meso-zeaxanthin (MZ)), 3′-oxolutein, 3-methoxyzeaxanthin (3-MZ), β-cryptoxanthin, epsilon-lycopenes, 5-Z-lycopenes, and apo-carotenoid products including 3-OH-β-ionone, 3-OH-α-ionone, β-ionone, 3-OH-α-apo-10′-carotenal, 3-OH-β-apo-10′-carotenal, and β-apo-10′-carotenal. 
     “Substantially pure enantiomeric form” as used herein comprises greater than about 80% by weight of a particular enantiomeric form of xanthophyll carotenoid (e.g. (3R,3′R,6′R)-zeaxanthin) and less than about 20% by weight of another enantiomeric form of that xanthophyll carotenoid, more preferably greater than about 90% by weight of the particular enantiomeric form of the xanthophyll carotenoid and less than about 10% by weight of another enantiomeric form of that xanthophyll carotenoid, even more preferably greater than about 95% by weight of the particular enantiomeric form xanthophyll carotenoid and less than about 5% by weight of another enantiomeric form of that xanthophyll carotenoid, and most preferably greater than about 99% by weight of particular enantiomeric form of xanthophyll carotenoid and less than about 1% by weight of another enantiomeric form of that xanthophyll carotenoid. A “substantially pure xanthophyll carotenoid derivative” is defined similarly with respect to the relative amounts of its enantiomers. 
     The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, optical isomers (e.g. enantiomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds as well as diastereomers and epimers, where applicable in context. The term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. 
     “Fatty acids” include but are not limited to essential fatty acids, omega-3, omega-6, and omega-9 fatty acids, and trans fatty acids. 
     The term “patient” or “subject” is used throughout the specification within context to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment (prophylaxis), with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal. 
     The term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result, whether that result relates to the enhancement of a subject&#39;s macular pigment optical density, improving the static and dynamic visual performance of a subject, improving reaction time and coincidence anticipation ability in a subject who is required to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function, inhibition of the effects of an ocular disorder such as macular degeneration (e.g. preventing continued visual acuity deterioration in a subject who suffers from age-related macular degeneration), or preventing visual acuity deterioration in a subject who is at risk of developing age-related macular degeneration. This term subsumes all other effective amount or effective concentration terms (including the term “therapeutically effective”) which are otherwise described in the present application. 
     The terms “treat”, “treating”, and “treatment”, etc., as used herein, include improving the static and dynamic visual performance of a subject, improving reaction time and coincidence anticipation ability in a subject who is required to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function, inhibiting the effects of an ocular disorder such as macular degeneration (e.g. preventing continued visual acuity deterioration in a subject who suffers from age-related macular degeneration), or preventing visual acuity deterioration in a subject who is at risk of developing age-related macular degeneration. Treatment, as used herein, encompasses both prophylactic and therapeutic treatment and also includes self-treatment (e.g. a subject without the assistance of any intermediary ingests or applies a Xanthophyll carotenoid to himself or herself). 
     The term “pharmaceutically acceptable salt” or “salt” is used throughout the specification to describe a salt form of one or more of the compositions herein which are presented to increase the solubility of the compound in saline, most preferably in order to promote dissolution and the bioavailability of topically applied or orally ingested compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. Sodium and potassium salts may be preferred as neutralization salts of carboxylic acids and free acid phosphate containing compositions according to the present invention. The term “salt” shall mean any salt consistent with the use of the compounds according to the present invention. In the case where the compounds are used in pharmaceutical indications, the term “salt” shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents. 
     The term “co-administration” shall mean that at least two compounds or compositions or treatment regimens are administered to the patient at the same time, such that effective amounts or concentrations or effects of each of the two or more compounds or treatment regimens may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents or treatment regimens at the same time or at different times, including sequential administration. Preferably, effective concentrations of all co-administered compounds or compositions or regimens are found in the subject at a given time. In the treatment of macular degeneration, co-administered compounds or treatment regimens include anti-angiogenesis, anti-VEGF therapy, bevacizumab (Avastin®) and ranibizumab (Lucentis®), laser surgery (laser photocoagulation), zinc, copper, and vitamin C. 
     The term “ester”, as used herein, refers to a group —C(O)O-substituent wherein the substituent represents, for example, a hydrocarbyl or other substitutent as is otherwise described herein. 
     Compositions, including pharmaceutical compositions, comprising combinations of an effective amount of at least one Xanthophyll carotenoids according to the present invention, and one or more of the compounds otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present invention. 
     The compositions used in methods of treatment of the present invention, and pharmaceutical compositions of the invention, may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, Salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. 
     The compositions used in methods of treatment of the present invention, and pharmaceutical compositions of the invention, may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally or topically. Oral compositions also may be presented in the form of a food product or liquid drink. 
     Sterile injectable forms of the compositions used in methods of treatment of the present invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. 
     The compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added as well as a food base, especially to provide a food or liquid composition, for example, in the form of a sports bar or sports drink. 
     Alternatively, the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. 
     The compositions of this invention may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-acceptable transdermal patches may also be used. 
     For topical applications, the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. 
     Alternatively, the compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. 
     For topical ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. 
     The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. 
     The amount of compound in a composition of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration. Preferably, the compositions should be formulated to contain between about 0.05 milligram to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one additional active ingredient which may be used to improve one or more of the static and dynamic visual performance of a subject and improve reaction time and coincidence anticipation ability in a subject, including a subject who is required to perceive and react to temporally varying stimuli under lighting conditions that are known to be detrimental to visual function, inhibit the effects of an ocular disorder such as macular degeneration (e.g. prevent continued visual acuity deterioration in a subject who suffers from age-related macular degeneration), or prevent visual acuity deterioration in a subject who is at risk of developing age-related macular degeneration. 
     It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated. 
     The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. 
     The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1 mg, 1 mg to 3,000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25-250 mg is often convenient. 
     In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. 
     Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. 
     Representative compositions of the invention include, but are not limited to the following. 
     A composition (e.g. a topically-applied ophthalmic composition or an orally ingestable composition, including a food composition or liquid drink) comprising: 
     (a) about 1,000 mg, or about 900 mg, or about 800 mg, or about 700 mg, or about 600 mg, or about 500 mg, or about 400 mg, or about 300 mg, or about 200 mg, or about 100 mg, or about 900 mg, or about 90 mg, or about 80 mg, or about 70 mg, or about 60 mg, or about 50 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 9 mg, or about 8 mg, or about 7 mg, or about 6 mg, or about 5 mg, or about 4 mg, or about 3 mg, or about 2 mg, or about 1 mg of at least one Xanthophyll carotenoid; and optionally
 
(b) a pharmaceutically acceptable excipient.
 
     In the compositions described herein, the at least one Xanthophyll carotenoid can be in substantially pure enantiomeric form. 
     Another illustrative composition comprises: 
     (a) about 1,000 mg, or about 900 mg, or about 800 mg, or about 700 mg, or about 600 mg, or about 500 mg, or about 400 mg, or about 300 mg, or about 200 mg, or about 100 mg, or about 900 mg, or about 90 mg, or about 80 mg, or about 70 mg, or about 60 mg, or about 50 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 9 mg, or about 8 mg, or about 7 mg, or about 6 mg, or about 5 mg, or about 4 mg, or about 3 mg, or about 2 mg, or about 1 mg of at least one Xanthophyll carotenoid selected from the group consisting of (3R,3′R,6′R)-lutein, (3R,3′R,6′R)-zeaxanthin, the (E/Z) isomers of (3R,3′R,6′R)-lutein and (3R,3′R, 6′R)-zeaxanthin, (3R,3′S,6′R)-lutein (3′-epilutein) and 3-hydroxy-β,ε-caroten-3′-one, (3R,3′S-meso)-zeaxanthin (meso-zeaxanthin (MZ)), 3′-oxolutein, 3-methoxyzeaxanthin (3-MZ), β-cryptoxanthin, epsilon-lycopenes, 5-Z-lycopenes, 3-OH-β-ionone, 3-OH-α-ionone, β-ionone, 3-OH-α-apo-10′-carotenal, 3-OH-β-apo-10′-carotenal, and β-apo-10′-carotenal; and optionally (b) a pharmaceutically acceptable excipient. 
     Another illustrative composition constitutes an ophthalmic solution or gel comprising at least one active ingredient selected from the group consisting of: 
     (a) substantially enantiomerically pure (3R,3′R,6′R)-lutein, substantially enantiomerically pure (3R,3′R,6′R)-zeaxanthin, or a substantially enantiomerically pure (E/Z) isomer of (3R,3′R,6′R)-lutein or (3R,3′R,6′R)-zeaxanthin; and
 
(b) a pharmaceutically acceptable excipient.
 
     Another illustrative composition comprises: 
     (a) about 1,000 mg, or about 900 mg, or about 800 mg, or about 700 mg, or about 600 mg, or about 500 mg, or about 400 mg, or about 300 mg, or about 200 mg, or about 100 mg, or about 900 mg, or about 90 mg, or about 80 mg, or about 70 mg, or about 60 mg, or about 50 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 9 mg, or about 8 mg, or about 7 mg, or about 6 mg, or about 5 mg, or about 4 mg, or about 3 mg, or about 2 mg, or about 1 mg of at least one Xanthophyll carotenoid selected from the group consisting of (3R,3′S,6′R)-lutein (3′-epilutein), 3-hydroxy-β,ε-caroten-3′-one, (3R,3′S-meso),-zeaxanthin (meso-zeaxanthin (MZ)), 3′-oxolutein, 3-methoxyzeaxanthin (3-MZ), β-cryptoxanthin, epsilon-lycopenes, and a 5-Z-lycopene; and optionally
 
(b) a pharmaceutically acceptable excipient.
 
     Another illustrative composition constitutes an ophthalmic solution, ointment or gel comprising: 
     (a) substantially enantiomerically pure (3R,3′S,6′R)-lutein (3′-epilutein), substantially enantiomerically pure 3-hydroxy-β,ε-caroten-3′-one, substantially enantiomerically pure (3R,3′S-meso)-zeaxanthin (meso-zeaxanthin (MZ)), substantially enantiomerically pure 3′-oxolutein, substantially enantiomerically pure 3-methoxyzeaxanthin (3-MZ), substantially enantiomerically pure β-cryptoxanthin, a substantially enantiomerically pure epsilon-lycopene, and a substantially enantiomerically pure 5-Z-lycopene; and
 
(b) a pharmaceutically acceptable excipient.
 
     Each of the compositions described above may be formulated as a solid or liquid food composition for oral ingestion. Thus, the active compounds described above may be formulated as a sports bar or sports drink and packaged for consumption by the subject, for example, at the site of an athletic event or other location. 
     In one embodiment, a method of treatment of the invention comprises administering lutein and/or zeaxanthin to a subject or patient, in particular, an athlete engaging in a sports activity, a driver, including a long distance driver or a night driver, military personnel or aviation personnel, especially including pilots of aircraft in need of enhanced visual performance and/or neural efficiency. In one aspect of the invention, the method comprises enhancing visual performance and neural efficiency, thus making the performance of the subject engaging in the activity more effective. It is an unexpected result that effective amounts of lutein and/or zeaxanthin, preferably both lutein and zeaxanthin and optionally fatty acids especially including omega 3 fatty acids, would provide a significant enhance in the visual performance and neural efficiency of the subject. The use of the composition to provide a substantially non-toxic means of enhancing visual and neural efficiency (which can include physical performance including hand and eye coordination) is a further aspect of the present invention. 
     Notable aspects of the invention include the following:
         Exploiting a link between macular pigment measurement and sports performance;   Supplementation of zeaxanthin and lutein to build macular pigment;   Supplementation of zeaxanthin, lutein and Omega-3s to improve sports and other physical performance;   Measuring sports performance using macular pigment measurement and other visual performance tests;   Supplement delivery methods including pills, food, drinks, sports bars and powders;   Specific performance improvements including reaction time, hand and eye coordination, contrast sensitivity and others   The link between visual performance and sports performance       

     The use of the present invention in a patient or subject results in enhanced visual performance and/or neural efficiency takes the form of one or more of enhanced visual contrast sensitivity, enhanced cognitive performance, enhanced visual efficiency, enhanced motion sensitivity, enhanced spatial memory, enhanced choice reaction, enhanced integration of visual motion (reduction of time), enhanced choice reaction time (reduced), enhanced hand and eye coordination of that individual in the performance of a task or the engagement in an activity for that patient or subject. 
     The invention is illustrated further in the following non-limiting examples. 
     Example 1 
     The Effects of Macular Carotenoids Lutein and Zeaxanthin on Visual Performance and Neural Efficiency in Young, Healthy Subjects and College Athletes 
     The purpose of this pilot study was to describe visual performance differences between athletes and other young, healthy adults, and to determine whether or not increasing MP density resulted in performance increases in athletes. 
     Methods 
     1. Cross-Sectional Study 
     Subjects: 78 young, healthy adults (M=20.6±2.6 years), including 16 college baseball players, participated in the cross sectional study. Visual function was measured using MPOD. Neural efficiency was measured as shown in  FIG. 1 . The following additional parameters were also measured: Fixed Reaction Time (FRT); Variable Reaction Time (VRT); and Coincidence Anticipation Timing (CAT). 
     Results: 
     Cross-Sectional Study: 
     MPOD did not differ significantly between athletes and non-athletes. FRT did not differ significantly between athletes and non-athletes. VRT was significantly lower in athletes. Athletes were significantly more accurate on CAT than non athletes at high velocities. 
     2. Supplementation Study 
     Subjects: Seven college baseball players (M=20.3±0.58 years), supplemented with 20 mg/Z/day for 3-months, participated in this study. The visual function parameters MPOD, disability glare, photostress recovery time, and contrast enhancement were determined.
 
The neural efficiency parameters Fixed Reaction Time (FRT); Variable Reaction Time (VRT); and Coincidence Anticipation Timing (CAT) were determined.
 
     Results: 
     Supplementation Study: 
     Three subjects completed the study. MPOD increased in supplemented subjects (see sample subject,  FIG. 2 ). Photostress recovery time decreased in supplemented subjects. Early improvements in glare and contrast enhancement were observed. FRT and VRT improved and
 
CAT accuracy improved at the highest frequency
 
     Conclusions 
     Supplementation to increase MPOD is especially beneficial in athletes who perform outdoors. 
     Example 2 
     Static and Dynamic Measures of Visual Performance in Athletes 
     Baseball performance requires the ability to perceive and react to temporally varying stimuli under lighting conditions that are known to be most detrimental to visual function (i.e., short-wave light). Macular pigment (MP) lutein (L) and zeaxanthin (Z) in the retina—is known to improve performance under such conditions and may also improve neural efficiency. The purpose of this study was to assess static and dynamic visual performance in college baseball players in order to:
         a) Define performance ability in athletes and non-athletes matched for age and MP (N=18); and,   b) Improve athletes&#39; performance via supplementation.       

     Method: Static Visual Performance 
     Stimuli presented in three-channel Maxwellian-view optical system (1 kW xenon-arc light source). 
     Glare Disability (GL) 
     
         
         
           
             570 nm target (100% contrast, 5 cycles per degree—cpd); 10° inner, 12° outer diameter annulus comprised of broad-band xenon light (see  FIG. 1   a ). 
             Threshold: intensity of annulus required to completely veil target. 
           
         
       
    
     Contrast Enhancement (CE) 
     
         
         
           
             600 nm target (100% contrast grating, 5 cpd); 460 nm surround (see  FIG. 1A (b)). 
             Threshold: intensity of background required to obscure edge between target and surround. 
           
         
       
    
     Photostress Recovery Time (PR) 
     
         
         
           
             570 nm target (100% contrast; 5 cpd). 
             5 second exposure to bleaching photostressor (5° diameter disk; xenon-white light of log 2.5 μW/cm2 intensity). 
             Threshold: time to recover visibility of target. 
           
         
       
    
     Method: Dynamic Visual Performance 
     Coincidence Anticipation Timing (CAT) 
     
         
         
           
             Task: button press to indicate when a light bar (traveling along 120 LED linear track) reached a specified point. 
             Velocity randomly varied between 5, 10, 15, and 20 MPH (15 trials for each speed, randomly presented; inter-trial intervals randomly varied between 1000-3000 ms). 
           
         
       
    
     Fixed and Variable Position Reaction Time (FRT/VRT) 
     
         
         
           
             Task: button press in response to LED repeatedly presented at same position (FRT) or random location (VFT) along the 120 LED linear track. 
             60 trials; inter-trial intervals varied between 1000-3000 ms 
           
         
       
    
     Temporal Contrast Sensitivity Function (TCSF) 
     
         
         
           
             Free-view presentation (through an artificial pupil; see  FIG. 3A (a)) of 1°, 660 nm target centered within 10°, 660 nm surround (see  FIG. 3A (b)). 
             Threshold: depth of modulation required to detect movement of target presented at frequencies of 1.5, 1.4, 1.0, and 0.4 log Hz. 
           
         
       
    
     Critical Flicker Fusion Thresholds (CFF) 
     
         
         
           
             Threshold: frequency (Hz) at which the 1°, 660 nm target presented at 100% modulation appeared to fuse. 
           
         
       
    
     Method: Macular Pigment Optical Density 
     Heterochromatic Flicker Photometry 
     
         
         
           
             Customized HFP [3]—Macular Metrics Corp., Providence, R.I., 
           
         
       
    
     Results 
     Athletes Vs. Non-Athletes
         Average MPOD at 30′ eccentricity: 0.50.   Average age: 20 years.       

     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Static visual performance of athletes (no significant difference  
               
               
                 from non-athletes). 
               
            
           
           
               
               
               
               
            
               
                   
                 GL 
                 CE 
                 PR 
               
               
                   
                 (log energy) 
                 (log energy) 
                 (seconds) 
               
               
                   
                   
               
               
                   
                 0.84 
                 0.72 
                 20.8 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Dynamic visual performance of athletes (*significantly different from  
               
               
                 non-athletes, p &lt; 0.05). 
               
            
           
           
               
               
               
               
            
               
                 Velocity 
                 CAT 
                 FRT 
                 VRT 
               
               
                   
               
               
                  5 mph 
                 100% 
                 (ms) 
                 (ms) 
               
               
                 10 mph 
                  98% 
                 217.44 
                 225.52 
               
               
                 15 mph 
                  88% 
                 No significant 
                 No significant 
               
               
                   
                   
                 differences in TCSF 
                 differences in TCSF 
               
               
                   
                   
                 or CFF measures 
                 or CFF measures 
               
               
                 20 mph 
                  62% 
                 No significant 
                 No significant 
               
               
                   
                   
                 differences in TCSF 
                 differences in TCSF 
               
               
                   
                   
                 or CFF measures 
                 or CFF measures 
               
               
                   
               
            
           
         
       
     
     Zeaxanthin Supplementation 
     
         
         
           
             20 mg/d supplementation ongoing. 
             Preliminary data indicate increases in MPOD and improvement in both static and dynamic visual performance (see  FIG. 4A  for sample data from a subject who completed the 12 week intervention, MPOD change from 0.70 to 0.77). 
           
         
       
    
     Conclusions 
     Supplementation to increase MPOD may be especially beneficial for baseball players, given the tasks performed and outdoor lighting conditions. 
     Example 3 
     Macular Pigment: Relations to Fixed and Variable Reaction Time and Coincidence Anticipation Across the Lifespan 
     Introduction 
     High macular pigment optical density (MPOD) relates to improved critical flicker fusion thresholds [1] and temporal contrast sensitivity [2]. Whether improved ability to detect flicker translates to functional changes such as improved reaction time (RT) and coincidence anticipation timing (CAT) is unknown. Three studies were conducted to determine these relations in individuals across the lifespan. 
     Study 1: MPOD &amp; Standard Judgment RT 
     Study 2: MPOD &amp; CAT 
     Study 3: MPOD &amp; Fixed/Variable RT (FRT/VRT) 
     Subjects: 
     Study 1: N=49; Mean Age=54.76±11.97 years
 
Studies 2 and 3: N=62; Mean Age=20.71±2.80 years
 
     Macular Pigment Optical Density: 
     MPOD was assessed with customized heterochromatic flicker photometry at 30 minutes retinal eccentricity. 
     Reaction Time Paradigm: 
     A standard judgment RT paradigm was used, in which subjects responded with a key press that corresponded to the location of a randomly presented, computerized target appearing in one of four screen quadrants. 
     Timing Device (CAT, FRT, VRT): 
     A novel device was constructed for the CAT and FRT/VRT tasks based on studies using the Bassin Anticipation Timer [3]. The linear track consisted of 120 LEDs spaced 2.02 cm apart along a 10.07 foot linear track. The device utilized a custom-made software program. 
     Method 
     Coincidence Anticipation Timing: 
     Individual LEDs along the linear 120 LED track were lit in sequence. This created the appearance of a small, moving light bar. See  FIG. 1B . Subjects were asked to press a button to stop the light bar at a specified point along the track. Bar speed was randomly varied between 5, 10, 15, and 20 MPH across 60 trials. Inter-trial intervals were varied between 1000 ms and 3000 ms. 
     
       
         
           
               
             
               
                 TABLE 1A 
               
             
            
               
                   
               
               
                 Timing information for each bar speed. 
               
            
           
           
               
               
               
            
               
                 Speed 
                 Time to End of Track 
                 Perfect Anticipation 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 5  
                 MPH 
                 135 ms 
                 102 ms 
               
               
                 10  
                 MPH 
                  68 ms 
                  51 ms 
               
               
                 15  
                 MPH 
                  45 ms 
                  34 ms 
               
               
                 20  
                 MPG 
                  34 ms 
                  25 ms 
               
               
                   
               
            
           
         
       
     
     Fixed and Variable Position Reaction Time: 
     The fixed task required a button press in response to one of the LEDs, repeatedly presented at the same position on the track. The varied task required a button press in response to one of the LEDS presented at a random location along the 120 LED track. See  FIG. 2B (a),  FIG. 2B  (b), 
     Results 
     Study 1: MPOD &amp; Standard Judgment RT 
     MPOD was significantly related to decreased RT (r=−0.25, p&lt;0.05). See  FIG. 3B   
     
       
         
           
               
             
               
                 TABLE 2A 
               
             
            
               
                   
               
               
                 Pearson product-moment correlation coefficients (r) and  
               
               
                 significance values (p) for the relation between MPOD and absolute  
               
               
                 error CAT and missed trials for each speed. 
               
            
           
           
               
               
               
            
               
                   
                 Absolute Error 
                 Missed Trials 
               
            
           
           
               
               
               
               
               
            
               
                 Speed 
                 r 
                 p 
                 R 
                 p 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                  5 MPH 
                 −0.17 
                 0.09 
                 — 
                 — 
               
               
                 10 MPH 
                 0.18 
                 0.09 
                 −0.20 
                 0.06 
               
               
                 15 MPH 
                 −0.01 
                 0.46 
                 −0.23 
                 0.04 
               
               
                 20 MPH 
                 −0.03 
                 0.40 
                 −0.16 
                 0.10 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3A 
               
             
            
               
                   
               
               
                 CAT performance for each speed at 15 trials in terms of average  
               
               
                 accuracy, anticipated (ANT) and lag responses. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 # 
                   
                   
                   
               
               
                 Speed 
                 Miss 
                 Accuracy 
                 % ANT 
                 % 1 ag 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                  5 MPH 
                 0 
                 100% 
                 42% 
                 58% 
               
               
                 10 MPH 
                 1.5 
                  90% 
                 57% 
                 33% 
               
               
                 15 MPH 
                 5 
                  69% 
                 37% 
                 32% 
               
               
                 20 MPG 
                 9.5 
                  39% 
                 10% 
                 29% 
               
               
                   
               
            
           
         
       
     
     Study 3: MPOD and Fixed/Variable Position RT: 
     MPOD was significantly related to FRT (r=−0.21, p&lt;0.05) and VRT (r=−0.22, p&lt;0.05). 
     Conclusions 
     MPOD and Reaction Time: 
     MPOD is significantly related to reaction time in middle-age and older adults (Study 1) and in college-aged adults (Study 3). MPOD is significantly related to reaction time as assessed via multiple methods, designed to capture earlier and later stages of visual processing. Study 1: Judgment paradigm, later visual processing; participant must not only see the stimulus, but also make a judgment about where the stimulus is located in space. Study 3: Fixed and variable simple reaction time, early visual processing; participant simply presses a button when the stimulus appears. No judgment necessary. 
     These results lend support to the neural efficiency hypothesis of macular pigment function [2]. 
     Coincidence Anticipation: 
     MPOD was significantly related or trending toward significance to absolute error ion low speed trials, and to number of trials missed on high speed trials. These relationships are complex. MP likely accounts for a small proportion of variance in CAT performance, but CAT performance is likely subject to practice. 
     REFERENCES FOR EXAMPLE 3 
     
         
         [1] Hammond, B R &amp; Wooten B R. (2005).  Ophthal Physiol Opt,  25, 315-319. 
         [2] Renzi, L M &amp; Hammond B R (2010).  Ophthal Physiol Opt,  30, 351-357. 
         [3] Millslagle, D. G. (2000).  Perceptual  &amp;  Motor Skills,  90, 498-504. 
       
    
     Example 4 
     Macular Pigment and Visual Motor Function in Young, Healthy Adults 
     Our experimental results presented below suggest that one result of improved neural efficiency (present in those with higher MP optical density, MPOD) is increased visuomotor performance, including improved fixed ( FIG. 1C ) and variable ( FIG. 2C ) reaction times and increased accuracy in the ability to anticipate and coordinate a motor action with a rapidly appearing visual stimulus ( FIG. 3C ). These pilot data were collected in a cross-section of young, healthy adults, who were not actively taking a Z supplement. Additional pilot data from our laboratory suggests that MPOD relates to balance time ( FIG. 4C ), as well as reaction time using a judgment paradigm ( FIG. 5C ) in healthy, supplement naïve elders. 
     Experiments are conducted to expand upon this pilot work, collected over a number of years. Improving MPOD via Z supplementation is shown to improve neural efficiency and, consequently, visual motor (“visuomotor”) performance, in young, healthy adults. 
     Methods 
     Participants 
     A total of 60 young, healthy adults, aged 18-30 years, are recruited. 
     Inclusion and Exclusion Criteria 
     
         
         
           
             Must not have taken lutein or Z supplements in the last 6-months 
             Must have best corrected visual acuity (Snellen notation) of 20:40 or better 
           
         
       
    
     Specific Methods 
     Macular Pigment Optical Density (MPOD): 
     MPOD will be measured psychophysically via customized heterochromatic flicker photometry (Stringham 2008). A spatial profile highlighting the fovea (loci at 7.5-minutes, 15-minutes, 30-minutes and 90-minutes, using targets of 15-minutes, 30-minutes, 1-degree and 1.75-degrees in diameter, respectively) will be collected at baseline and at the conclusion of the supplementation period, using a 7-degree parafoveal reference.
 
Temporal Contrast Sensitivity Function (tCSF):
 
The tCSF will be measured using a custom made desktop device (Wooten, Renzi et al. 2010).
 
The depth of modulation necessary to enable flicker detection will be measured at 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.8, 0.6, and 0.4 log Hz, following procedures outlined by Renzi and Hammond (2010).
 
     Fixed and Variable Reaction Time (FRT and VRT) and Coincidence Anticipation Timing (CAT): 
     FRT, VRT, and CAT will be determined using a custom made, wall-mounted, linear light array (see  FIG. 6C  for a schematic). The array consists of 120 LEDs, spaced equally at approximately 1.3 cm apart on a 3.05 meter track. The researcher can isolate and illuminate a single LED at a time in the array (for FRT and VRT testing), or the speed at which the LEDs are illuminated in a sequence, which creates the percept of a rapidly moving light bar (CAT testing).
         FRT. For FRT testing, participants will be asked to stand at a distance of 2.5 meters from the linear light array, so that the entire array is easily visible. The researcher will select a specific LED on the light array to use as a test stimulus. The LED chosen will not vary across participants and will be given a white surround on the linear light array, in order to help participants maintain fixation on the correct LED. Participants will be asked to press a button on a keypad as soon as the pre-determined LED is illuminated. The interval between trials will be varied randomly between 1000 and 3000 ms, for 60 total trials.   VRT. For VRT testing, the same procedure and apparatus as FRT testing will be used, with one procedural variation: instead of repeatedly illuminating a single, predetermined LED for each trial, any LED within the entire linear light array may be chosen, and the same LED is not illuminated each trial. Instead, a different LED will be randomly chosen for illumination from trial to trial   CAT testing. In order to measure CAT, the same linear light array described previously will be used. LEDs will be illuminated and then turned off rapidly in sequence, which creates the percept of a rapidly moving light bar. Both the amount of time between trials will be varied (between 1000 and 3000 cosec), as well as the velocity of the light bar. Participants will be asked to make a button press coincide with the arrival of the moving light bar to a specific, pre-determined LED on the array, positioned at 2.29 meters on the 3.05 meter track. The specific LED will be given a white surround on the linear light array, in order to help participants keep the ending spot within sight while tracking the light bar. The light bar&#39;s velocity will be randomly varied between 5 mph (1.02 sec between onset and the button press for perfect anticipation), 10 mph (0.51 sec between onset and the button press for perfect anticipation), 15 mph (0.34 sec between onset and the button press for perfect anticipation), and 20 mph (0.25 sec between onset and the button press for perfect anticipation) between trials. A total of 60 trials will be completed.       

     Design 
     The general design of this study is a randomized, double-masked, placebo-controlled trial. Participants will be randomized into two groups: the supplement group (n=50) and the placebo group (n=10). The supplement group will be divided into 2 groups. One group (n=25) will be supplemented with 20 mg of zeaxanthin per day. The second group (n=25) will be supplemented by a formula (to be provided by ZeaVision) that will contain a mixture of zeaxanthin, lutein and Omega-3s. Randomization will be conducted by the researcher overseeing the trial, who will be the only member of the research team who knows supplement status (placebo vs. active supplement). Consequently, the researcher will not be actively collecting data on these participants. The rest of the research team will be masked to supplementation status. When the analyses have been conducted and the data are unmasked, participants in the placebo group will be given a four month&#39;s supply of Z supplements and will be encouraged to return to the Human Biofactors and Vision Sciences Laboratories for free follow-up testing should they wish to see if active supplementation is benefitting them. 
     REFERENCES FOR EXAMPLE 4 
     
         
         Renzi, L. M. and B. R. Hammond, Jr. (2010). “The relation between the macular carotenoids, lutein and zeaxanthin, and temporal vision.”  Ophthalmic  &amp;  Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians  ( Optometrists ) 30(4): 351-357. 
         Stringham, J. M., Hammond, B. R., Nolan, J. M., Wooten, B. R., Mammen, A., Smollon, W., Snodderly, D. M. (2008). “The utility of using customized heterochromatic flicker photometry (cHFP) to measure macular pigment in patients with age-related macular degeneration.”  Experimental Eye Research  87: 445-453. 
         Wooten, B. R., L. M. Renzi, et al. (2010). “A practical method of measuring the human temporal contrast sensitivity function.”  Biomed Opt Express  1(1): 47-58. 
       
    
     REFERENCES FOR BACKGROUND OF THE INVENTION 
     
         
         1. Snodderly D M, Auran J D, Delori F C: The macular pigment. II. Spatial distribution in primate retinas.  Investigative Ophthalmology  &amp;  Visual Science  1984, 25(6):674-685. 
         2. Craft N E, Haitema, T. B., Garnett, K. M., Fitch, K. A., Dorey, C. K.: Carotenoid, tocopherol, and retinol concentrations in elderly human brain.  J Nutr Health Aging  2004, 8(3): 156-162. 
         3. Wooten B R, Hammond, B. R., Land, R. I., Snodderly, D. M.: A practical method for measuring macular pigment optical density.  Investigative Ophthalmology and Visual Science  1999, 40:2481-2489. 
         4. Renzi L M, Hammond B R, Jr.: The relation between the macular carotenoids, lutein and zeaxanthin, and temporal vision.  Ophthalmic  &amp;  Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians  ( Optometrists ) 2010, 30(4):351-357.