Abstract

The old saying “you are what you eat” is becoming increasingly important in the field of neuroscience these days. There is mounting evidence that nutritional factors are beginning to play a major role in cognitive status, or cognitive wellbeing. One of these emerging factors is magnesium (Mg²⁺). Although the physiological investigation of Mg²⁺ has a long history, its role in cognitive function is just starting to emerge. The focus of this chapter is to review the available literature on the effects of Mg²⁺ on cognitive function in the healthy and diseased/injured brain. In addition, data from our laboratory will be presented that has investigated the effects of Mg²⁺ manipulation on learning and memory tasks in rodents, as well as the ability of Mg²⁺ therapy to improve cognitive performance in the damaged brain.

Introduction

The purpose of this chapter is to provide a review of the literature on the role of Mg²⁺ in cognitive function. Although the research on this topic is generally sparse, there is an accumulating body of evidence suggesting that Mg²⁺ is vitally important. The role that micronutrients play in maintaining and promoting cognitive ability and neural plasticity has started to receive a good deal of attention. A recent paper has provided an excellent review on how various nutrients promote cognitive performance and neural plasticity (Gómez-Pinilla, 2008). Although this review does not specifically discuss the role of Mg²⁺, it is clear that this is a rapidly evolving area of research. Another review does address the role of Mg²⁺ and its relationship with other micronutrients on cognitive function and performance. It especially highlights the important role that Mg²⁺ has in interacting with other micronutrients (Huskisson et al., 2007). Recent evidence also suggests that Mg²⁺ plays an important role in age-related deficits in neurotransmitter release, neuronal excitability and synaptic plasticity related to cognition (Billard, 2006), and these topics will be reviewed in Chapter 6.

Additionally, there is ample evidence that Mg²⁺ plays an important role in the pathophysiological processes following traumatic brain injury (TBI) and that Mg²⁺ therapy is effective in promoting functional recovery in a variety of animal models (Hoane and Barth, 2001; Hoane, 2004; Sen and Gulati, 2010; van den Heuvel and Vink, 2004; Vink et al., 2009). Specifically, this chapter will focus on reviewing the literature on Mg²⁺ and cognitive function and review a series of studies conducted in our laboratory that have investigated the ability of Mg²⁺ therapy to alter cognitive function and to improve cognitive recovery following focal and traumatic brain injuries in the rat.

Introduction to rodent cognitive assessment

The Morris water maze (MWM) is a standard task for measuring cognitive/spatial performance in rodents. This task uses a water-filled tank with a submerged escape platform and many different aspects of memory can be assessed (Hoane et al., 2003; Hoane, 2005; Hoane et al., 2009; Kaufman et al., 2010; Lindner, 1997; Lindner et al., 1998; Quigley et al., 2009). Briefly, a reference memory trial consists of placing the rat into the water at one of 4 randomly chosen start locations. A computer-assisted video tracking system is used to measure the swim latency and distance to the submerged escape platform. On trials designed to measure working memory the escape platform is relocated to a new position in the tank every day. The first trial (in the new location) is considered an information trial and the subsequent 3 trials are test trials and are averaged to form the dependent variable. Additional paradigms can be used that incorporate various mazes or dividers that are placed into the tank that can test other aspects of learning and memory in the rodent.

Additionally, the Barnes spatial maze, a dry version of the MWM, can also be used to assess cognitive/spatial performance (Vink et al., 2003). Rats are placed on an elevated 1.2 m circular tabletop with 19 holes cut around the periphery. The rat learns the location of the hole that leads to an escape tunnel. The latency to find the correct hole is then analysed. Operant chambers (Skinner boxes) can be used to assess appetitive conditioning of learning ratios under various conditions. In general, rats are shaped to bar- press for a reinforcer and then are shifted to more complicated reward paradigms. Thus, there are many ways in which rodent cognitive assessments can be made and many of these have been utilized to examine the role of Mg²⁺ in cognition.

Role of Mg2+ in health and cognition

The importance of Mg²⁺ in normal cellular functioning has been well documented, as has its importance in the pathophysiology following injury. Previously, several reviews have been written that address these issues (Hoane and Barth, 2001; Hoane, 2004; van den Heuvel and Vink, 2004) so only a brief synopsis will be provided in this paper. Mg²⁺ is involved in many critical cellular processes including cellular respiration, protein synthesis, membrane stability and regulation of vascular tone. A more detailed discussion on the physiology of Mg²⁺ is presented in several chapters within Section 1 of this book.

Although the main focus of this chapter is on animal models, there are some interesting human studies that have examined the role of Mg²⁺ in cognitive ability. A recent study examined the correlation between levels of several trace minerals (iron, Mg²⁺, potassium and zinc) in the hair of adolescent girls and their academic record. Although care must be taken with the interpretation of correlational studies of this nature, there was evidence that some trace minerals correlated more highly with increased academic performance. Specifically, it was found that Mg²⁺ and zinc demonstrated a strong positive correlation with academic performance (Wang et al., 2008). Furthermore, a recent case report of a patient presenting with anorexia nervosa and Wernicke-Korsakoff syndrome was found to have a low serum Mg²⁺ level (Saad et al., 2010). Although the main cause of this condition was thiamine deficiency, a major adjunct factor was believed to be Mg²⁺ deficiency. The results from this case study are supported by a review article on micronutrients and cognitive performance that details the inter- relationships between Mg²⁺ and other micronutrients such as the B-group vitamins and how deficiencies in these nutrients interact to produce cognitive deficits (Huskisson et al., 2007). Thus, there is an expanding literature that suggests that Mg²⁺ status plays an important role in cognitive performance.

A unique condition in which Mg²⁺ has been implicated is TBI. McIntosh and colleagues have shown that Mg²⁺ homeostasis is disrupted following CNS injury (McIntosh et al., 1988; Vink et al., 1988). Fluid percussion injury (FPI) produced a rapid and severe decline in intra- and extracellular Mg²⁺ levels, which correlated significantly with the severity of the behavioural deficits observed following injury (McIntosh et al., 1988; Vink et al., 1988). Additional research on the role of Mg²⁺ and neurological diseases will be presented in Section 2 of this book, while Mg²⁺ in cognitive function following TBI is addressed later in this chapter. These findings suggest that Mg²⁺ plays an important role in normal physiology and in the pathophysiological events that occur following injury to the nervous system.

Recent laboratory data

Mg²⁺ therapy and learning

From a purely pharmacological standpoint, administration of Mg²⁺ immediately prior to the acquisition of a learning task should have a detrimental effect on that task given the non- competitive antagonistic properties of Mg²⁺ at the NMDA receptor. It has been shown that administration of other NMDA antagonists such as MK-801 and PCP have been shown to disrupt spatial learning in rodents (Kesner et al., 1993; McLamb et al., 1990; Murray and Ridley, 1997); however, in some cases a facilitative effect can be shown (Pussinen and Sirvio, 1999). In order to examine the biological activity of Mg²⁺ administration on the acquisition of learning, a MgCl₂ solution was administered (1 mmol/kg or 2 mmol/kg, i.p.) prior to the acquisition of learning a reference memory task in the MWM (Hoane, 2007). Intact rats received daily injections of MgCl₂, 30 min prior to the start of their MWM session and were tested for 5 consecutive days for 4 trials per day with an intertrial interval (ITI) of 15 min. The reference memory acquisition paradigm was used in the MWM. In this paradigm, the submerged escape platform stayed in the same location for every trial and the animals were released from 1 of 4 different starting points in the maze. As can be seen in Figure 1, the vehicle-treated (0.9% saline, i.p.) group showed steady acquisition of the task. In comparison, the MgCl₂-treated animals showed a more varied response. The initial acquisition of the 2 mmol group was slightly lengthened on day 1 compared to the other groups. On day 4, both groups of MgCl₂-treated animals started to show a lengthening of their escape latencies compared to vehicle-treated animals. On the last 2 test days the comparison of swim latencies between the 2 mmol and saline group was significantly different (p < 0.01) indicating a possible learning impairment on the task.

Figure 1.

The effects of repeated pre-testing administration of MgCl₂ (1 or 2 mmol/kg) on the acquisition of a reference memory task in the MWM. Plotted are the mean (± SEM) swim latencies to find the submerged escape platform. The 2 mmol dose of MgCl₂ (more...)

Thus, it appears that daily dosing with the higher dose of MgCl₂ produced a significant degree of amnesia after 3 days. Unfortunately, testing was terminated after 5 days so it is unknown if this effect would have persisted or worsened with additional testing. It should be noted that, in general, the NMDA antagonists that work at the PCP site on the NMDA receptor (i.e., MK-801 and PCP) seem to have a greater amnesic effect than MgCl₂. This may raise some concerns for continued dosing regimens of Mg²⁺ therapy lasting more than a couple days. However, a longer window of time between administrations and testing may reveal different findings, because this effect is perceived to be state dependent. Thus, given these behavioural results it is clear that systemic injections of MgCl₂ did indeed exert behavioural effects in uninjured animals with an intact blood-brain barrier (BBB), and therefore give support to the ability of MgCl₂ to cross the BBB. This finding supports earlier research to this fact (Hallack et al., 1992).

We have also recently investigated the effect of dietary Mg²⁺ deficiency on learning acquisition in the MWM. Rats were placed on either a standard laboratory diet or a commercially available Mg²⁺- deficient diet for 14 days. Peripheral blood collect- ions were performed for determination of serum Mg²⁺ levels and all animals were placed back on to the standard diet. The serum analysis indicated a significant loss in serum Mg²⁺ in the deficiency group (p < 0.05). One week later, animals were tested for the acquisition of a reference memory task over 4 days (4 trials per day, 15 min ITI). As can be seen in Figure 2A, the 14 days of Mg²⁺ deficiency significantly impaired the initial acquisition of the task on the first day (p<0.05). The animals were then switched to a more challenging working memory assessment in the MWM. As can be seen in Figure 2B, the animals that experienced Mg²⁺ deficiency showed impaired learning on the task (p<0.05). Additionally, animals were trained to acquire a fixed ration (FR-10) schedule of reinforcement in an operant chamber. The total number of bar presses is shown in Figure 2C. The higher number of responses results in a greater number of reinforcers being delivered and can be equated to the learning of the reinforcement schedule. Animals on the Mg²⁺-deficient diet responded at a significantly lower level (p<0.05) than those animals on the Mg²⁺-normal diet, suggesting a learning impairment. A somewhat similar finding has been shown in mice exposed to a Mg²⁺-deficient diet (Bardgett et al., 2005; Bardgett et al., 2007). In this study, 10 days of Mg²⁺ deficiency resulted in impaired learning of a conditioned fear task. However, maze performance in the MWM was not impaired. Thus, these data suggest that even temporary Mg²⁺ deficiency may interfere with learning.

Figure 2.

The effects of dietary restriction of Mg²⁺ on cognitive performance in the MWM. Plotted are the mean swim latencies (± SEM) on the acquisition of reference memory task (A), working memory (B), and the acquisition of a FR-10 reinforcement schedule (more...)

A newly formulated form of Mg²⁺, magnesium-L- threonate (MgT) has been shown to increase cerebrospinal fluid levels of Mg²⁺ to a much greater degree than other Mg²⁺ preparations (e.g. MgCl₂) (Slutsky et al., 2010). Administration of MgT has also been shown to result in an enhancement of various forms of cognitive/ learning ability in rodents, including working memory. This effect was also evident in aged rats following which cognitive abilities were generally reduced. The beneficial behavioural effects were thought to be caused by beneficial changes in synaptic plasticity within the hippocampus (Slutsky et al., 2010).

Examination of Mg2+ therapy following focal injury

In our laboratory we have examined recovery of cognitive function in a bilateral focal cortical ablation model. Rats were given small (4 mm²) electrolytic lesions aimed at the bilateral anterior medial cortex (bAMC) of the frontal lobe (Hoane et al., 2003). Administration of Mg²⁺ therapy occurred 15 min following injury with rats receiving either injections of MgCl₂ (1 or 2 mmol/kg, i.p.) or saline (1 ml/kg). This regimen was repeated again 24 and 72 hrs later, so that each rat received 3 injections within the first 72 hrs following injury. Behavioural testing began 5 days after injury and included the assessment of cognitive function. The MWM was used to investigate the acquisition of reference and working memory. In addition, the MWM tank was also used to examine spatial ability using a delayed matching-to-sample (DMTS) task, a very sensitive measure of spatial working memory.

As can be seen in Figure 3A & 3B, the results of the behavioural testing indicated that bAMC lesions produced severe deficits in cognitive function on both the reference and working memory tasks in the MWM. Mg²⁺ therapy with either the 1 or 2 mmol dose did not significantly facilitate the acquisition of reference memory in the MWM. However, the mean swim latencies for both MgCl₂ groups were greatly improved compared to saline in the last 2 blocks of trials. Although Mg²⁺ therapy did not demonstrate a statistically significant improvement on reference memory performance in the present study, it did improve working memory performance in the MWM. Administration of the 2 mmol dose of MgCl₂ significantly reduced the working memory deficit compared to saline treatment on the first 2 days of testing. The 1 mmol dose of MgCl₂ also reduced the working memory impairments on the first day of testing and significantly improved working memory performance on day 2 of testing. Severe cognitive impairments were also seen on the DMTS spatial memory test following injury. The 2 mmol dose of MgCl₂ significantly reduced the number of trials needed to reach the criterion of 80% correct choices compared to saline- treated rats, while the 1 mmol dose of MgCl₂ did not, although the number of trials was greatly reduced. Thus, Mg²⁺ therapy was effective in a task and dose-dependent manner in this study.

Figure 3.

The effects of a regimen of MgCl₂ (1 or 2 mmol/kg) administered following bAMC focal lesions on cognitive performance in the MWM. Plotted are the mean swim latencies (± SEM) during the acquisition phase of a working memory task (A) and the mean (more...)

Mg2+ therapy in the traumatically injured brain

To examine the ability of Mg²⁺ therapy following TBI, groups of rats were prepared with a cortical contusion injury (CCI) or sham procedure and then assigned to either MgCl₂ (1.0 mmol/kg, i.p.) or saline treatment conditions (Hoane, 2005). Mg²⁺ therapy was administered 15 min and 24 hr following injury. Rats were then examined for cognitive/spatial performance in the MWM, investigating the acquisition of reference and working memory. Administration of MgCl₂ following CCI significantly reduced some of the behavioural impairments observed following injury (see Figure 3C & 3D). The acquisition of reference memory in the MWM was significantly improved compared to saline-treated rats. In contrast, MgCl₂ did not improve working memory performance.

In a second study, the ability of Mg²⁺ therapy to improve cognitive/spatial performance following unilateral CCI was examined. Groups of rats were given unilateral CCIs or sham surgeries of the left sensorimotor motor/frontal cortex. One hr following injury, rats were administered 1 mmol/kg MgCl₂ or saline. They were then tested for their ability to acquire a reference memory task in the MWM on 4 consecutive days (4 trials/day) starting 11 days after CCI. Their working memory performance was measured on days 16 and 17. It was found that the single 1 mmol/kg dose of MgCl₂ effectively facilitated the acquisition of the reference memory task compared to treatment with saline (see Figure 4). In a similar manner, the working memory performance was greatly enhanced following CCI in the Mg²⁺-treated rats compared to the saline-treated rats. In fact, the working memory performance of the Mg²⁺- treated rats could not be distinguished from the sham controls on either day of working memory testing (see working memory graph in Figure 4). Mg²⁺ treatment appeared to have prevented the occurrence of the working memory deficit following unilateral frontal injury.

Figure 4.

The effects of MgCl₂ (1 mmol/kg) administration 1 hr following unilateral CCI of the sensorimotor/frontal cortex. Plotted are the mean swim latencies (± SEM) on the acquisition of reference memory and working memory tasks in the MWM. Administration (more...)

Discussion

The results of these studies have demonstrated a wide range of conditions in which Mg²⁺ therapy regulates cognitive function. It was first shown that daily injections of MgCl₂ administered 30 mins prior to training on the task worsened acquisition of the reference memory task. It was also demonstrated that a two-week regimen of dietary Mg²⁺ deficiency impaired learning on 3 different cognitive tasks. This finding is especially interesting because the animals had been placed back onto a normal laboratory diet prior to the assessment phase of the study.

Mg²⁺ therapy in several models of cortical ablation and TBI have demonstrated positive effects on cognitive recovery. However, these effects occurred in a task and dose-dependent manner. Following focal ablation of the bAMC, MgCl₂ improved working memory performance on several measures and slightly improved reference memory performance. The CCI studies performed in our laboratory have shown that MgCl₂ administration following injury improved cognitive performance in a task-dependent manner. Previous studies that have examined the ability of Mg²⁺ therapy to improve cognitive performance following injury have shown mixed results. For example, administration of MgCl₂ following FPI has been shown to improve cognitive outcome by reducing memory loss in the MWM (Smith et al., 1993), but administration of MgCl₂ failed to improve the acquisition of a reference memory task in the MWM following injury (Bareyre et al., 1999). Thus, in a similar manner the current series of studies has shown similar mixed results. That is, significant effects were seen in some cases and non-significant effects were seen in others. However, in general we saw significant improvements in cognitive function by MgCl₂ in each of our studies. The discrepant results mainly varied based on dose and task-dependent properties of the studies.

From a mechanistic standpoint, Mg²⁺ therapy has multiple routes by which it can disrupt the pathophysiological processes that occur following injury and enhance cognitive recovery. In addition to offsetting injury-induced Mg²⁺ depletion (McIntosh et al., 1988; Vink et al., 1988) and preventing excitotoxic neuronal death (Nowak et al., 1984) mediated by the NMDA receptor, Mg²⁺ has been shown to have several other effects. For instance, administration of MgSO₄ has been shown to limit the generation of injury-induced edema following closed-head injury (Feldman et al., 1996) and it has been more recently shown that MgSO₄ (30 mg/kg) reduced aquaporin-4 immunoreactivity, thus contributing to edema reduction following injury (Ghabriel et al., 2006). Administration of MgCl₂ has also been shown to reduce the expression of p53 mRNA, a gene associated with the induction of cell death, following lateral FPI (Muir et al., 1999). In this study it was found that 750 μmol/kg of MgCl₂ reduced the expression of p53 mRNA in the injured cortex compared to saline-treated controls (Muir et al., 1999). High concentrations of Mg²⁺ (3 mM) have been shown to inhibit lipid peroxidation (Regan et al., 1998). Regardless of the mechanisms of action, the data presented in this review has shown that MgCl₂ has strong biological activity, appears to cross the BBB, and can improve cognitive performance following cortical ablation or TBI.

Conclusion

The studies presented in this book chapter have demonstrated a wide range of activities for Mg²⁺ therapy in relationship to cognitive function in the rodent. Daily injections of MgCl₂ prior to the acquisition of a learning task blocked the acquisition of a reference memory task and dietary deficiency of Mg²⁺ impaired learning on a number of different tasks. Using the damaged brain as a model to examine the ability of Mg²⁺ therapy to improve cognitive performance also demonstrated significant advantages with the therapy. Thus, it does appear that Mg²⁺ status and therapy have significant effects on cognitive performance in the brain and that further research is warranted. In addition, an accumulating body of research suggests that Mg²⁺ also plays an important role in human cognitive performance. Given the reported rates of magnesium deficiency in humans it is likely that this could impair cognitive performance (Barbagallo and Dominguez, 2010; Elin, 2010). In addition, the most intriguing factor related to Mg²⁺ therapy for cognitive wellbeing may reside in the use of Mg²⁺ as a co-therapy with other vital nutrients, which may produce the strongest effects.

Acknowledgements

A special thanks is given to Alicia Swan for critical reading of an earlier draft of this chapter. Partial support provided by ARRA funds from NINDS grant NS045647-04

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