Review

Hydration and Cognition: A Critical Review and Recommendations for Future Research
Harris R. Lieberman, PhD US Army Research Institute of Environmental Medicine, Natick, Massachusetts Key words: cognitive performance, mood, fatigue, dehydration, environment, heat, exercise
The limited literature on the effects of dehydration on human cognitive function is contradictory and inconsistent. Although it has been suggested that decrements in cognitive performance are present in the range of a 2 to 3% reduction in body weight, several dose-response studies indicate dehydration levels of 1% may adversely affect cognitive performance. When a 2% or more reduction in body weight is induced by heat and exercise exposure, decrements in visual-motor tracking, short-term memory and attention are reported, but not all studies find behavioral effects in this range. Future research should be conducted using dose-response designs and state-of-the-art behavioral methods to determine the lowest levels of dehydration that produce substantive effects on cognitive performance and mood. Confounding factors, such as caffeine intake and the methods used to produce dehydration, need to be considered in the design and conduct of such studies. Inclusion of a positive control condition, such as alcohol intake, a hypnotic drug, or other treatments known to produce adverse changes in cognitive performance should be included in such studies. To the extent possible, efforts to blind both volunteers and investigators should be an important consideration in study design.

Key teaching points:

Dehydration impairs cognitive performance and mood. Adverse effects of dehydration on cognitive function are present at a 2% or more reduction in hydration and may be present at a 1% level of dehydration. Most studies of the effects of dehydration on cognitive function have used heat and exercise to induce rapid dehydration. Studies of the effect of dehydration on cognitive function should employ dose-response designs. The specific behavioral functions most likely to be affected by dehydration have not been established; additional studies should be conducted using state-of-the-art performance tests and mood questionnaires. Double-blind procedures, or surrogates for these procedures, should be employed whenever possible in studies of cognitive function and dehydration.

INTRODUCTION
Adequate hydration is essential for human homeostasis and survival, including maintaining brain function. In a relatively brief period of time, failure to consume sufficient water will lead to deteriorating cognitive and neurologic function, organ failure, and death. However, the effects of dehydration on cognitive performance and brain function have not been thoroughly investigated. There are a variety of reasons for the lack research on the effects of dehydration on human brain function.

Dehydration is difficult to assess accurately (see Armstrong [1]). Its study requires considerable specialized physiologic expertise since producing reliable changes in hydration is complex and demanding. Attaining a precise level of dehydration is difficult to achieve, and even the best studies do not precisely reach the desired end point. Furthermore, there are many confounders associated with such studies, including the nature and duration of the stressors used to produce dehydration, typically heat and sustained aerobic exercise. In addition, since there are physiologically distinct categories of dehydration, such as

Address reprint requests to: Harris R. Lieberman, PhD, US Army Research Institute of Environmental Medicine, Natick, MA 01760. E-mail: harris.lieberman@us.army.mil Presented at the ILSI North America 2006 Conference on Hydration and Health Promotion, November 29 30, 2006 in Washington, DC. Conflict of Interest Disclosure: There are no conflicts of interest to declare in connection with this work.

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hypotonic and isotonic dehydration, it can be difficult to generalize results of specific studies. Assessing human cognitive function is also difficult and complex. There are hundreds of tests of cognitive performance and little agreement among psychologists as to which tests to use to assess specific functions, such as attention, learning, memory, and reasoning [2,3]. When examining an area as unique as the effects of dehydration on cognitive function, with limited published literature available, there are few established principals that can readily be applied by investigators working in the area. Perhaps the most closely related areas of investigation are psychopharmacology and nutritional neuroscience, for which many methodological issues have been resolved [3]. Since severe dehydration inevitably leads to delirium, coma, and death, there is no question that it will produce decrements in cognitive function before such severe consequences are present (Fig. 1) [4,5]. However, there is insufficient information available to determine the extent and duration of dehydration that will produce cognitive decrements and the cognitive functions that will be most impaired. Dehydration is a unique stressor with unique physiological effects that may or may not be similar to the effects of other stressors on cognitive performance. For example, dehydration, unlike other stressors, may produce shifts in electrolytes that could substantially alter brain neurotransmission since neuronal function is highly dependent on the physiological milieu of the central nervous system (CNS). For a discussion of possible physiological mechanisms that may be responsible for the adverse effects of dehydration on brain function, see Wilson and Morley [5] and Maughan [6]. Using the limited available literature in the area, this paper will attempt to provide some guidance as to the effects of dehydration on cognitive function, note some of the major methodological issues in the area, and suggest future research agendas.

METHODOLOGICAL ISSUES
Inducing Dehydration
Inducing dehydration in a controlled, consistent manner is difficult. Most studies examining the effect of dehydration on cognitive function have used a combination of exposure to heat and controlled exercise (for a comprehensive review, see Sawka [7]). Unfortunately, there are inherent limitations to this procedure. Exposure to heat and exercise alone will invariably alter cognitive performance and mood state [8 10]. Investigators will usually attempt to control for these potentially confounding effects by using a fully-hydrated control condition with equivalent exposure to heat and exercise as the dehydrating test condition. However, this assumes that the effects of heat and exercise exposure will be identical regardless of the effects of hydration state. In fact, a combination of stressors may have complex, non-linear effects on cognitive performance. The sum of the effects of combining heat, exercise and dehydration may not be additive relative to heat exposure and exercise alone. This could lead to either over- or underestimation of the effects of dehydration per se, depending on the extent and direction of any non-linear interactions of the combination of stressors. For example, if dehydration amplifies the effects of heat and exercise then it will appear that dehydration has a greater effect on cognitive performance than would be observed if the only treatment condition is dehydration. Studies of heat- and exercise-induced dehydration should therefore not be considered as studies of pure dehydration. Another method to induce dehydration is withholding fluids and foods with high water content. Unfortunately, this technique has only apparently been employed in two recent studies, and they had significant limitations as discussed below [11,12].

Advantages of the Dose-Response Design

A standard, widely-employed design used in pharmacology research is to administer the compound of interest in a graded range of doses. Like the dosage of a drug, dehydration is a continuous variable and can be induced in a range of levels, within the bounds of volunteer safety, and has the capability to accurately assess hydration state. There are various advantages of dose-response studies, including a robust form of internal control. In addition to yielding information on a particular treatments parametric effects, if a studys results are systematically dose-related, this provides internal replication of its findings. Using a dose-response design to study the effects of dehydration on cognitive performance is a particularly appropriate strategy given the inherent complexity associated with the assessment of cognitive function. Since there are so many types of cognitive function, each governed by different brain regions and neurotransmitter systems, it is likely these will be differentially affected by dehydration. The

Fig. 1. Decline in function resulting from dehydration.

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internal, within-study replication provided by a dose-response study allows for much greater confidence that the studys results are correct. Dehydration is particularly wellsuited for study using a dose-response design since it appears to produce graded, monotonic changes in cognitive function, as indicated by several studies [13,14]. These studies suggest that, as the extent of dehydration increases, adverse effects on behavior increase. Pharmacologic and nutritional treatments do not always produce monotonic dose-response functions. With drugs and some dietary constituents, as the dose administered increases beyond optimal levels, beneficial effects will typically be reduced and adverse changes will occur. For example, low and moderate doses of caffeine have positive effects on cognitive performance and mood, but high doses have adverse effects [15,16]. markings. Trail-making assesses short-term memory, reasoning, and motor control. The volunteer is presented with a test sheet with 48 scattered symbols half are consecutive numbers and half are consecutive English-language letters. Volunteers must trace a trail for 60 seconds, alternating between a number and letter, as rapidly as possible, without lifting pencil from paper [14]. Fig. 2a presents the results from the serial addition test. The intended level of dehydration is plotted on the y-axis, and directly below it, in parentheses, the measured mean level of dehydration achieved is presented. In all cases the achieved level of dehydration exceeded the planned level. Dehydration at the planned 1, 2, 3 and 4% levels produced significant decrements in correct responses on this task. Furthermore, there was a consistent, dose-related decline in performance across all levels of dehydration. A similar pattern was present for the trail-making test, with speed to complete significantly increasing with increasing dehydration at the 2, 3 and 4% levels (Fig. 2b). The third test, word recognition, showed the same pattern, with percent correct words recalled decreasing with increasing

STUDIES OF DEHYDRATION INDUCED BY HEAT AND/OR EXERCISE

Most studies examining effects of dehydration on cognitive performance have employed heat, exercise, or the combination of these factors to produce hypohydration. For such studies to be interpretable, it is essential they include a fully hydrated control condition where equivalent exposure to heat and/or exercise is studied [7]. One of the most comprehensive studies conducted using this design assessed the effects of dehydration levels ranging from approximately 1 to 4% in 1% increments in 11 healthy males aged 20 to 25 years [14]. The volunteers were acclimated to heat prior to starting the study and each was tested in all five experimental conditions. Volunteers performed continuous moderate work by stepping up and down on a 38 cm platform at a rate of 15 steps/min, stopping when the desired level of dehydration was reached. The chamber where they were dehydrated was maintained at 45C with 30% relative humidity (RH). In addition to a fully hydrated control condition with heat and exercise exposure, the investigators also included a thermoneutral, no exercise control condition. The behavioral tests employed were a serial addition test, word recognition test and trail-making test. Serial addition is an auditory test that assesses short-term memory and reasoning. Sixty random single digit numbers are grouped into 12 sets of five numbers; numbers from each set are read to the volunteer at a rate of one number every two seconds. The volunteer must add the five consecutive numbers and write down the sum. The score is percent correct answers. Word recognition is an auditory test in which 15 words from a 52 word list are read at a rate of one every two seconds. After hearing the 15 words, the volunteer is given the written list and required to mark as many of the 15 words as can be recalled. Score is percent of correct

Fig. 2. a) Percent of correct responses on the serial addition test. Results are reported at thermoneutral, 0, 1, 2, 3 and 4% dehydration conditions. The actual levels of dehydration are shown in parentheses below the desired target levels (*p 0.05; ***p 0.001). Data re-plotted from Gopinathan et al. [14]. b) The mean speed (sec) on the trail-making test at thermoneutral, 0, 1, 2, 3 and 4% dehydration conditions. Actual levels of dehydration reached are shown in parentheses below the desired target levels (***p 0.001). Data re-plotted from Gopinathan et al. [14].

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dehydration. The effects were statistically significant at the 1, 2, 3 and 4% levels [14]. The results of this study are particularly robust because all three administered tests detected consistent dose-related deterioration in cognitive performance. In addition, the inclusion of a second control condition, in which volunteers were exposed to thermoneutral conditions without exercise during the period when dehydration would have been induced, provided an additional baseline test session for comparison. For each cognitive task, performance during this condition was nearly equal to the other control condition (Fig. 2) providing additional support for the validity and accuracy of the findings. A similar study was conducted by Sharma et al. [13] at the same laboratory as the previously discussed study. This study assessed the effects of dehydration at levels from 1 to 3% in eight males, 21 to 24 years old. In this study, moderate exercise in the heat was the principal method used to induce dehydration and behavioral testing was conducted in three different conditions: thermoneutral (37C, 50% RH), hot dry (45C, 30% RH) and hot humid (39C, 60% RH). Three levels of dehydration were induced approximating 1, 2 or 3%. The behavioral tests employed were a symbol substitution test, concentration test, and an eye-hand coordination test. In the symbol substitution test, a volunteer is presented a sample code where 10 letters are associated each with one of 10 designs. The volunteer is then presented with several horizontal rows of the geometric designs in random order. The volunteer has three minutes to write the correct letter from the code under as many symbols as possible. The concentration test assessed working memory. Ten series of numbers were read aloud at a rate of one per second. At random intervals, the series was stopped and the volunteer attempted to write down the last five numbers read in reverse order [17]. The eye-hand coordination test used a metal plate with a 0.5 cm wide groove cut into an eight-cornered star pattern. The volunteer was required to move a stylus in the groove without touching the edge. Score is based on time to complete and number of errors [13]. Significant dose-related effects of dehydration were noted in two of three tests administered. In one of the tests, symbol substitution, significant effects of dehydration were only observed at the 3% level of dehydration (p .05) (Fig. 3a), but for another, eye-hand coordination, significant effects were observed at all three levels of dehydration in at least one of the environmental conditions tested (p .01) (Fig. 3b). The results of this study are robust and internally consistent since testing was conducted at three levels of hydration and in three different environmental conditions. Across all environmental parameters, graded dose-related changes in cognitive performance were observed (Fig. 3) [13]. Although these two studies provide insight into the effects of dehydration on cognitive performance, they do not provide an indication as to which behavioral functions are most affected by dehydration. The tests employed did not adequately differentiate the general effects of dehydration from effects specific

Fig. 3. a) Results from the symbol substitution test at 0, 1, 2 and 3% dehydration levels at three environmental conditions; thermoneutral, hot-dry, and hot-humid. Mean levels of actual dehydration for only hot-dry and hot-humid conditions are shown in parentheses below the target levels. Actual dehydration levels for the thermoneutral condition were not reported. (*p .05; this value has been computed from the original data as the authors did not test significance below the p 0.01 level) Data re-plotted from Sharma et al. [13]. b) Results from the eye-hand coordination test at 0, 1, 2 and 3% dehydration levels at three environmental conditions -thermoneutral, hot-dry, and hot-humid. Mean levels of actual dehydration for hot dry and hot humid conditions are shown in parentheses below the target levels. Levels for the thermoneutral condition were not reported. (**p 0.01; ***p 0.001) Data re-plotted from Sharma et al. [13].

to particular cognitive functions, such as learning, memory, or vigilance [13,14].

STUDIES OF DEHYDRATION INDUCED BY WATER DEPRIVATION ALONE

Few studies have examined the effects of dehydration on cognitive performance induced by water deprivation alone. One recent study of 16 healthy men and women aged 20 to 34 assessed the effects of 28 h of self-monitored water deprivation resulting at a mean dehydration level of 2.6% [12]. Each volunteer participated in a control and dehydration testing session in random order. On the morning of day one, baseline data were collected after volunteers abstained from all caffeinated beverages that morning. All fluids were withdrawn during

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the dehydration treatment session and volunteers selected meals from foods containing less than 75% water by weight for the 28 h of the study. During the control session, volunteers could consume any nonalcoholic beverage, except coffee. The behavioral tests employed were a choice reaction time task, a manual tracking task, paced auditory serial addition task, and the Stroop word-color conflict test. Choice reaction time is a five-minute test where a random sequence of colored lights is presented and the volunteer responds by pressing corresponding buttons. In the manual tracking task, volunteers were required to follow, with a pointer, a white circle moving on a computer monitor for three minutes. The paced auditory serial addition task is similar to the serial addition task used by Gopinathan et al. [14], however this was a computerized version where numbers were presented at 2.5 s intervals and volunteers added the last two digits as rapidly as possible and responded verbally. The Stroop word-color conflict test assessed response time to conflicting stimuli. Color words were presented on screen but written in a different color (for example, green appeared on screen in a red font). Volunteers were required to name the font color in one portion of the task and name the color as written in another. Questionnaires assessed self-reported tiredness and alertness, as well as the perceived effort and concentration required to complete the behavioral tests [12]. No significant effects of 2.6% dehydration on cognitive performance were detected. However, there were effects of dehydration on self-reported levels of tiredness, alertness, effort, and concentration (p 0.05). There were some flaws with the conduct of this study. First, volunteers lost weight and were therefore somewhat dehydrated during the control (0.75%), as well as the dehydrated condition (2.56%). Also, caffeine was not adequately controlled. Only coffee consumption was restricted, but it appears that other caffeinated beverages were accessible to the free-living volunteers during both conditions. Since withdrawal from caffeine produces adverse effects on cognitive performance and mood [18], the dehydrated condition may have induced caffeine withdrawal not present in the control condition. Another study using water deprivation alone to produce dehydration did not evaluate cognitive performance, but did assess mood at several time periods during a 37-hour period of self-monitored water deprivation resulting in a 2.7% mean level of dehydration [11]. Fifteen volunteers with a mean age of 30 participated in two conditions, fluid restriction and euhydration. For both conditions, volunteers arrived at the laboratory after refraining from alcohol consumption and strenuous exercise for 24 hours and having fasted for four hours. After baseline measurements were taken, the volunteers were allowed to leave the laboratory. During the euhydration condition, volunteers were instructed to consume their normal diet and fluid intake. During fluid restriction, volunteers were asked to refrain from all fluid intake and to select foods with a low water content from a provided list. Volunteers reported back to the laboratory at 24-h and 37-h for measurements identical to those taken at baseline [11]. At each assessment session, an eight-item self-report questionnaire was administered using 100 mm visual analog scales. The scales assessed thirst, hunger, dry mouth, mouth taste, head soreness, concentration, tiredness, and alertness. Ratings of thirst and dry mouth were significantly greater during fluid restriction condition than in euhydration (p 0.05). Feelings of head soreness were significantly greater in the fluid restriction state versus euhydration at 24-h (p 0.005) and 37-h (p 0.05) (Fig. 4a), 1.8% and 2.6% dehydration, respectively (Fig 4c). There was also a significant reduction in concentration (Fig. 4b) and alertness at 13-h (1% dehydration), 24-h (1.8% dehydration) and 37 h (2.6% dehydration) in the fluid restriction state compared to euhydration (p 0.05), and fluid restricted volunteers reported feeling more tired at 24-h (p 0.001) [11]. It does not appear that caffeine intake was controlled in this study, a significant weakness since the adverse effects of dehydration may have been the result of caffeine withdrawal. Caffeine withdrawal can result in headache in susceptible individuals, increase tiredness and decrease alertness, symptoms that were all observed in this study [18].

CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH

Due to the lack of data, definitive conclusions regarding the effects of fluid restriction on cognitive performance are not possible. However, it is clear that dehydration induced by heat exposure, exercise, and fluid restriction impairs cognitive performance and mood. Adverse effects are present with levels of dehydration at 1.3% body weight loss and may be present when less dehydration is present. Since the few published doseresponse studies did not employ state-of-the-art behavioral tests known to be sensitive to the effects of experimental treatments on cognitive performance, they may underestimate the adverse effects of hypohydration. For discussions of the importance of test sensitivity in behavioral studies of nutritional factors or sleep deprivation, see Balkin et al. [19] and Lieberman [3]. In addition, the tests used did not permit determination of the specific behavioral functions affected by dehydration. Future studies should be conducted using both heat/exercise-induced dehydration and fluid restriction alone. A battery of behavioral tests known to be sensitive to various nutritional and environmental factors, and that can assess specific behavioral functions, should be employed in such studies [3]. As discussed above, the optimal design for such studies would assess dehydration at a graded range of levels. In addition, a positive control should be included in such studies, such as alcohol ingestion or treatment with a drug with hypnotic properties, such as diphenhydramine or a benzodiazepine [20 22]. A positive control will provide a metric for relating any effects

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could be used to maintain hydration. In the dehydrating condition, no fluid would be provided through the line [23].

ACKNOWLEDGEMENTS
This work was supported by the U.S. Army Medical Research and Materiel Command (USAMRMC). The views, opinions, and/or findings in this report are those of the authors, and should not be construed as an official Department of the Army position, policy, or decision, unless so designated by other official documentation. Citation of commercial organization and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.

REFERENCES
1. Armstrong L: Assessing hydration status: the elusive gold standard. J Am Coll Nutr, in press, 2007. 2. Lieberman HR: Nutrition, brain function and cognitive performance. Appetite 40:245254, 2003. 3. Lieberman HR: Human nutritional neuroscience: fundamental issues. In Lieberman HR, Kanarek R, Prasad C (eds.): Nutritional Neuroscience. Boca Raton, FL: CRC Press LLC, pp 310, 2005. 4. Maughan RJ: Impact of mild dehydration on wellness and on exercise performance. Eur J Clin Nutr 57:S19S23, 2003. 5. Wilson MM, Morley JE: Impaired cognitive function and mental performance in mild dehydration. Eur J Clin Nutr 57:S24S29, 2003. 6. Maughan RJ: Exercise, heat, hydration and the brain. J Am Coll Nutr, in press, 2007. 7. Sawka MN: Water. In Panel on Dietary Reference Intakes for Electrolytes and Water (eds.) Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate. Washington, DC: National Academies Press, pp 73185, 2004. 8. Hygge S: Heat and Performance. In Smith AP, Jones DM (eds): Handbook of Human Performance: Volume 1. San Diego, CA: Academic Press, INC, pp 79104, 1992. 9. Ramsey JD: Task performance in heat: a review. Ergonomics 38:154165, 1995. 10. Hancock PA, Vasmatzidis I: Effects of heat stress on cognitive performance: the current state of knowledge. Int J Hyperthermia 19:355372, 2003. 11. Shirreffs SM, Merson SJ, Fraser SM, Archer DT: The effects of fluid restriction on hydration status and subjective feelings in man. Br J Nutr 91:951958, 2004. 12. Szinnai G, Schachinger H, Arnaud MJ, Linder L, Keller U: Effect of water deprivation on cognitive-motor performance in healthy men and women. Am J Physiol Regul Integr Comp Physiol 289: R275R280, 2005. 13. Sharma VM, Sridharan K, Pichan G, Panwar MR: Influence of heat-stress induced dehydration on mental functions. Ergonomics 29:791799, 1986. 14. Gopinathan PM, Pichan G, Sharma VM: Role of dehydration in

Fig. 4. a) Ratings for the question, How sore does your head feel now? in the fluid restriction and euhydration conditions. (**p 0.01 compared to the euhydration condition). Data re-plotted from Shirreffs et al. [11]. b) Ratings for the question, How well can you concentrate just now? in the fluid restriction and euhydration conditions (**p 0.01 compared to the euhydration condition). Data re-plotted from Shirreffs et al. [11]. c) Changes in body mass over time for fluid restriction and euhydration conditions (*p 0.05 compared to euhydration). Data re-plotted from Shirreffs et al. [11].

of hypohydration to a factor with a known ability to impair cognitive performance. In addition, all studies should attempt to disguise the treatment condition from the volunteers and the investigators. Inclusion of a positive control condition, and matched placebo treatment for that treatment, will help to disguise the dehydration condition as placeboes could be administered in all arms of the study. Alternatively, an intravenous line (IV) with the flow rate hidden from the volunteer and the investigators responsible for conducting behavioral testing

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heat stress-induced variations in mental performance. Arch Env Health 43:1517, 1988. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS, Shader RI: Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol 37:693703, 1997. Lieberman HR, Tharion WJ, Shukitt-Hale, B, Speckman KL, Tulley R: Effects of caffeine, sleep loss and stress on cognitive performance and mood during US Navy SEAL training. Psychopharmacology 164:250261, 2002. Eysenck HJ: The Scientific Study of Personality. London: Routledge & Kegan Paul, 1952. Silverman K, Evans SM, Strain EC, Griffiths RR: Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 327:11091114, 1992. 19. Balkin TJ, Bliese PD, Belenky G, Sing H, Thorne DR, Thomas M, Redmond DP, Russo M, Wesensten NJ: Comparative utility of instruments for monitoring sleepiness-related performance decrements in the operational environment. J Sleep Res 13:219227, 2004. 20. Penetar DM, Belenky G, Garrigan JJ, Redmond DP: Triazolam impairs learning and fails to improve sleep in a long-range aerial deployment. Aviat Space Environ Med 60:594598, 1989. 21. Curran HV: Benzodiazepines, memory and mood: A review. Psychopharmacology 105:18, 1991. 22. Fine BJ, Kobrick JL, Lieberman HR, Riley RH, Marlowe B, Tharion WJ: Effects of caffeine or diphenhydramine on visual vigilance. Psychopharmacology 114:233238, 1994. 23. Montain SJ: Personal communication. December, 2006.

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