Neurologic effects of exogenous saccharides: A review of controlled human, animal, and in vitro studies

Objectives Current research efforts are centered on delineating the novel health benefits of naturally derived saccharides, including growing interest in their abilities to influence neurologic health. We performed a comprehensive review of the literature to consolidate all controlled studies assessing various roles of exogenous saccharide compounds and polysaccharide-rich extracts from plants, fungi, and other natural sources on brain function, with a significant focus on benefits derived from oral intake. Methods Studies were identified by conducting electronic searches on PubMed and Google Scholar. Reference lists of articles were also reviewed for additional relevant studies. Only articles published in English were included in this review. Results Six randomized, double-blind, placebo-controlled clinical studies were identified in which consumption of a blend of plant-derived polysaccharides showed positive effects on cognitive function and mood in healthy adults. A separate controlled clinical study observed improvements in well-being with ingestion of a yeast beta-glucan. Numerous animal and in vitro studies have demonstrated the ability of individual saccharide compounds and polysaccharide-rich extracts to modify behavior, enhance synaptic plasticity, and provide neuroprotective effects. Discussion Although the mechanisms by which exogenous saccharides can influence brain function are not well understood at this time, the literature suggests that certain naturally occurring compounds and polysaccharide-rich extracts show promise, when taken orally, in supporting neurologic health and function. Additional well-controlled clinical studies on larger populations are necessary, however, before specific recommendations can be made.


Introduction
The increasing prevalence of debilitating neurodevelopmental, psychiatric, and neurodegenerative diseases continues to be of significant concern for the developed world. 1 Owing to the paucity of affordable, safe, and effective treatment options for neurologic disorders, there is considerable interest in preventative and therapeutic complementary and alternative medicines. According to a recent survey, 21% of American adults with common neurologic conditions (memory loss, back pain with sciatica, migraines, regular headaches, seizures, stroke, and dementia) use biologically based therapies, consisting primarily of herbal remedies. 2 Traditional Chinese, Ayurvedic, and African medicines have utilized an assortment of plants and herbal extracts to treat various central nervous system (CNS) dysfunctions. 3 Effective compounds from wellknown neurobiologically active plants include flavonoids from Gingko biloba and Hypericum perforatum (St John's wort) as well as alkaloids, quinones, tannins, and other phenolic compounds. To date, very little attention has been given, however, to exploring the efficacy of naturally derived complex carbohydrate compounds. (For the sake of this review, the term complex carbohydrates will be used interchangeably with the terms glycans, polysaccharides, fiber, and complex sugars or saccharides.) Saccharide molecules play a number of fundamentally important roles in the brain, where they are largely glycoconjugated to proteins or lipids to assist in structural development, synaptogenesis, and synaptic transmission. 4 Saccharides can also be used as a source for energy and neurotransmitter production. 5 An early review highlighted the potential role and impact of saccharides in both simple and complex glycoconjugated form for supporting brain and cognitive function. 6 Indeed, exogenously applied small sugar molecules, specifically monosaccharides, have been shown to impact functions within the brain related to cognitive benefits in human and animal studies. For example, consumption of glucose, a monosaccharide with wellestablished effects on brain function, has significant impacts on mood and cognition in human subjects. 7 Systemic and intracranial application of L-fucose have been shown to influence glycoprotein synthesis and enhance memory behavior and synaptic plasticity in rodents, 8,9 whereas sialic acid, another monosaccharide component of glycoproteins, has been shown to improve learning and memory following oral administration to piglets. 10 Given the high concentrations of sialic acid in both the brain and human breast milk, it has been hypothesized that this monosaccharide may be an important nutrient for infant brain development. 11 The exogenous application of more complex sugar compounds has also been studied with respect to impacts on the brain. However, there remains a limited understanding of the potential mechanisms by which complex saccharide molecules may be influencing neurologic function. Saccharides derived from natural sources are structurally heterogeneous, come in neutral and acidic varieties, and can contain as much as 10 different monosaccharide sugars. The diversity of saccharides in both form and source provides potential for applied research into the occurrence, structure, and health properties of saccharides. In particular, varieties of saccharide compounds have been shown to improve brain function in vitro and in human and animal studies following oral, systemic, and localized administration. To better understand the efficacy and possible mechanisms of action by which complex saccharides influence CNS function, we thus conducted this review of the available literature. It is anticipated that this information may be useful for guiding future research that will eventually provide a clear understanding of safe and effective dietary complex saccharides for specific neurologic health applications.
Dietary polysaccharides improve cognitive function and mood in healthy young and middle-aged adults A number of preliminary randomized, double-blind, placebo-controlled clinical trials have indicated that consumption of naturally sourced polysaccharides can benefit brain function in healthy young and middle-aged adults (Table 1). Supplementation with a baker's yeast beta-glucan product (Wellmune WGP ® ; Biothera, Eagan, MN, USA) for 4 weeks improved various measures of well-being in healthy adult marathon runners compared with placebo. 12 Specifically, profile of mood state scores of tension, fatigue, anger, and confusion were significantly decreased and scores of vigor were significantly increased following supplementation. Significant improvements in cognitive function and mood have also been found in healthy middle-aged adults with a mixed polysaccharide product (Ambrotose ® complex; Mannatech, Incorporated, Coppell, TX, USA). In a recent study, individuals supplemented their diets for 12 weeks with placebo or a blend of saccharide-rich extracts from plants including Aloe vera, Astragalus gummifer, and Anogeissus latifolia. When compared with placebo, those subjects who consumed the blend of plant polysaccharides performed significantly better on tasks of recall and recognition memory and reported significantly reduced scores for tension and low mood (depression-dejection scale). 13 Interestingly, acute effects on brain function have also been observed following intake of plant polysaccharides. A single dose of Ambrotose ® complex administered to healthy, middle-aged adults has been recently shown to improve recognition memory and working memory despite conditions of mental fatigue. 14 In this study, blood glucose-mediated effects on cognitive function were ruled out since no changes in blood glucose levels were observed before or during testing, at 30 and 105 minutes post-treatment, respectively. Earlier research in middle-aged adults showed that a single dose of Ambrotose ® complex had a tendency towards positive effects on memory tasks; however, these differences were not statistically significant, which may have been due to methodological differences in dose and time between supplementation and testing (10 minutes). 15 Two studies of young adults demonstrated improved performance on tasks of visual discrimination and working memory at 45 minutes following intake of Ambrotose ® complex. 16 The exact mechanisms of action behind these acute improvements in cognitive function and mood are unclear. However, in a separate study of young male adults, significant increases in electroencephalogram-recorded brain wave frequencies during focused attention were seen 30 minutes after consumption of Ambrotose ® complex relative to placebo. 17 The specific changes in brain wave frequencies observed are commonly associated with abilities such as concentration and arousal. Overall, supplementation with a blend of plant polysaccharides seems to benefit various aspects of neurologic function and suggests functional benefits in healthy young and middle-aged adults. It is important to note, however, that these clinical studies, although well-controlled, were performed on relatively small populations; larger study groups are needed to confirm the validity of these results.

Exogenous saccharides modulate memory-and mood-related behaviors in rodents
Given the mechanistic limitations associated with clinical research, rodent models are commonly utilized to study the effects of therapeutic interventions on the CNS. A variety of rodent behavioral tests can be significant indicators of human cognitive function, which, when combined with experimentation on tissues from specific brain regions, can help elucidate possible mechanisms of action. For studies looking at behavioral and neurobiological effects of natural saccharides, animals with neurologic impairments have been utilized, which serves to both study the efficacy for protection against impairment-induced functional deficits and increase the likelihood of observing positive results ( Table 2). For example, oral administration of isolichenan, an alpha-glucan from the lichen Cetrariella islandica, to ethanol-fed mice was able to reverse the ethanol-induced impairment in memory acquisition assessed by passive avoidance tests. 18 Furthermore, an attenuation of spatial memory deficits during testing in the Morris water maze were observed with isolichenan ingestion in rats exposed to beta-amyloid peptide (A-beta), a small protein associated with the neurologic deterioration of Alzheimer's disease. It is important to note that in both studies, naive animalsthose unexposed to either ethanol or A-betadid not display memory enhancements with isolichenan treatment.
A recent study looking at the effects of dietary fiber on sickness behavior demonstrated faster recovery from lipopolysaccharide (LPS)-induced social withdrawal with a pectin diet compared with a cellulose diet. 19 Although cellulose also falls within the complex saccharide category, this study was concerned with comparing the immunological benefits of soluble ( pectin) versus insoluble (cellulose) dietary fiber. Their results suggest that effects within the gastrointestinal tract following consumption of soluble, fermentable carbohydrates may be important for the neuroimmune recovery from LPS. Gastrointestinal fermentation effects were also proposed as one possible mechanism by which orally administered arabinoxylan from the yeast Triticum aestivum and beta-glucan from barley were able to preserve memory in a mouse model of vascular dementia. 20 Neurologic effects of polysaccharide-rich plant extracts have also been observed in rodents following systemic injection ( Table 2). The biological activity of Asian ginseng (Panax ginseng), a traditional Chinese medicine and popular natural product with touted cognitive health benefits, is typically attributed to its ginsenoside saponin content. 21 However, some  research suggests that ginseng's saccharide components may also play a role. A polysaccharide fraction of P. ginseng administered by daily intraperitoneal injections for 10 days seemed to enhance learning in healthy adult rats. 22 Possible mechanisms of action were not addressed by the authors of this study. Fu Zi, a preparation of the daughter root from the plant Aconitum carmichaeli Debeaux (Chinese Monkshood), is another traditional Chinese medicine that has been used for centuries to treat mood disorders. Intraperitoneal injections of an alpha-glucan isolated from Fu Zi (FPS) showed antidepressant-like effects in the forced swim test, similar to the tricyclic antidepressant imipramine, in healthy mice. 23 Surprisingly, FPS was also able to reverse the social avoidance behavior of defeated mice, a model of chronic stress, within just 2 weeks of intraperitoneal administration, whereas the effects of imipramine treatment were only observed after 4 weeks. The authors attributed these behavioral effects to increased brain-derived neurotrophic factor (BDNF) signaling and neurogenesis within the hippocampus, both known to be associated with an antidepressant-like response. 24 Alpha-and beta-glucans enhance hippocampal synaptic plasticity The hippocampus is an important brain structure that helps regulate many behaviors, including memory and mood, and contains one of only a few sites of adult neurogenesis, the dentate gyrus. Owing to its organized neuronal circuitry, the hippocampus is commonly utilized to measure various types of synaptic transmission, including a form of synaptic plasticitylong-term potentiation (LTP)that is believed to be the cellular basis for learning and memory. LTP is observed as an activity-dependent increase in synaptic strength that takes place when repeated presynaptic neurotransmitter release immediately precedes the generation of an action potential by the postsynaptic neuron, rendering the postsynaptic neuron hypersensitive to subsequent stimulation. It is thought that this repeated stimulation represents learning during exposure to a novel stimulus, which then strengthens specific synaptic connections for encoding long-term memories. Some of the first in vivo electrophysiological recordings of LTP, performed on anesthetized rabbits, were of the responses of hippocampal dentate gyrus neurons receiving synaptic inputs from the entorhinal cortex. 25 Utilizing a similar method of recording hippocampal LTP in rats, a number of studies have found significant effects of lichen-and fungal-derived glucans on synaptic plasticity (Table 3). Acute exposure (≤30 minutes) to the alpha-glucans PC-2 and PB-2 from the lichens Parmelia caperata and Flavoparmelia baltimorensis, respectively, enhanced the magnitude of LTP induction when administered either orally or intravenously. 26,27 Intravenous administration of another lichen-derived alpha-glucan, isolichenan from Cetariella islandica, also enhanced synaptic plasticity in the dentate gyrus. 18 In this case, these results correlated somewhat with isolichenan's ability to reduce memory impairments following oral administration (see Table 2). Interestingly, although the effects of PB-2 and PC-2 on synaptic plasticity were seen with both oral and intravenous administration, no changes were seen when the alpha-glucans were applied directly to the brain via intracranial ventricular injection. Owing to these results, the authors proposed a peripheral site of action for alpha-glucans, which then leads to unidentified centralized signaling mechanism(s) that can elicit the observed effects on synaptic activity. Additional studies suggest an involvement of norepinephrine, both centrally and peripherally. Co-intravenous injection or pretreatment with specific beta-1-adrenergic receptor antagonists, by either intracranial ventricular injection or direct infusion into the dentate gyrus, resulted in inhibition of PB-2's ability to enhance LTP. 28,29 These findings are further supported by the observation that PC-2 had no effects on synaptic plasticity in adrenalectomized rats. 26 Activation of brain interleukin-1 receptors (IL-1R) may also play a role, since intracranial ventricular injection of IL-1R antagonist prior to intravenous PB-2 application was shown to enhance the alpha-glucan's effects on LTP. 28 Like alpha-glucans, beta-glucans also appear to modulate synaptic plasticity (Table 3). Oral and intravenous administration of lentinan, a beta-1,3/1,6 glucan from the fungus Lentinula edodes, and oral administration of Hoelen, a beta-glucan from the fungus Poria cocos Wolf, resulted in increased magnitudes of LTP. 30,31 Altogether, there is a fair amount of in vivo evidence suggesting alpha-and beta-glucan consumption can lead to positive effects on synaptic activity in the dentate gyrus of the hippocampus. Additional research is needed to determine whether these saccharide-induced changes in synaptic plasticity convincingly lead to cognitive outcomes, and whether these functional and behavioral effects are mediated by norepinephrine or IL-1 receptor activation in the hippocampus.

Neuroprotective effects of plant-derived saccharides
Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's, are devastating disorders that result from progressive loss of neurons in various brain regions that control motor and cognitive function. Aging is the greatest risk factor for these diseases. Identifying treatments to prevent neuronal loss  has proven a daunting task, and as the average life expectancy of the human population continues to increase, the need for successful therapies intensifies. An encouraging number of animal and in vitro studies have demonstrated neuroprotective effects of plant-derived saccharides and saccharide-rich extracts ( Table 4).
Effects of the disaccharide trehalose, found in baker's yeast, have been studied in a mouse model of Huntington's disease, R6/2 transgenic mice. Following oral administration for 12 weeks, trehalose improved motor dysfunction and reduced brain atrophy and the number of ubiquitin-positive aggregates in the motor cortex and striatum. 32 A comparative glucose feeding was found to be ineffective, leading the authors to conclude that the beneficial activities of trehalose could be attributed to the trehalose molecule itself and not to its glucose subunits. Indeed, trehalose was found in measurable amounts in brain homogenates. In vitro treatment utilizing a cellular model for Huntington's revealed that trehalose, as well as the oligosaccharide N-acetylgalactosamine tetramer, the disaccharide maltitol, and the monosaccharide mannose, each decreased the amount of polyglutamine aggregates and/or improved cell survival, with trehalose proving to be the most effective. 32 A number of additional sugar molecules showed no beneficial effects, including glucose, N-acetylneuraminic acid, sucrose, turanose, cellobiose, melibiose, and melezitose. In a second study, significant improvements in motor function as well as memory performance were seen in R6/2 mice when treated with a combination of orally administered trehalose along with intracranial ventricular injections of neural progenitor cells. 33 The authors of both studies hypothesize that trehalose may be acting by directly binding to polyglutamine proteins in the brain and inhibiting aggregation. Trehalose consumption has also been shown to be beneficial in a mouse model of tauopathy with Parkinsonism by improving motor function and anxiety-related behavior and decreasing tau pathology through an apparent increase in autophagic processes. 34 The polysaccharide fucoidan may be another candidate for neurodegenerative disease therapies. In an in vitro model of Parkinson's disease, fucoidan from the brown alga Laminaria japonica protected mouse dopaminergic MN9D cells from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. In an MPTP-exposed mouse model of Parkinson's, daily intraperitoneal injections of Laminaria fucoidan reduced locomotor deficits, prevented striatal depletion of dopamine, enhanced brain antioxidant activity, and protected against the loss of dopaminergic neurons in the substantia nigra. 35 In acutely dissociated rat basal forebrain neurons from the diagonal band of Broca, treatment with fucoidan from Fucus vesiculosus (Bladderwrack) protected cells from A-beta-induced apoptosis. 36 Preliminary research suggests that fucoidan may also protect against brain damage associated with ischemic stroke. Compared with control animals, rats receiving intravenous infusion of Bladderwrack fucoidan for 7 days following intracerebral hemorrhage induction showed improved motor function and memory retention in a passive avoidance test, despite an increase in hematoma size. 37 The authors hypothesized that these effects were due to fucoidan's antiinflammation or hemodilation activities, although these possible mechanisms of action were not investigated in this study. Bladderwrack fucoidan, when administered through intraperitoneal injection, was also able to attenuate the extent of hypoxia-ischemiainduced neural damage in the rat cortex, hippocampus, and striatum. 38 Additional in vitro studies have examined possible neuroprotective effects of crude plant extracts rich in complex saccharides (Table 4). Four different polysaccharide fractions from Nerium indicum (Oleander) reduced A-beta peptide-induced apoptosis of primary rat cortical neurons, whereas three of the extract fractions also improved survival during serum-deprivation. 39,40 Similar protection against A-beta toxicity occurred in cultured cortical neurons treated with various polysaccharide-rich extracts of Lycium barbarum (Wolfberry). [41][42][43] Polysaccharide fractions from Wolfberry also reduced the amount of glutamate excitotoxicity and homocysteine-induced cell death in cortical cultures. 44,45 Finally, an aqueous extract of Verbena officinalis Linn. (Verbena), containing 30% w/w carbohydrates, protected primary rat cortical neurons from the cytotoxic effects of A-beta and dithiothreitol. The verbena extract had no protective effects against tunicamycin, hydrogen peroxide, or ultravioletradiation, leading the authors to speculate that components of this extract may act as antioxidants and/or bind directly to putative cell surface receptors that can detect extracellular A-beta. 46 In this collection of studies of saccharide-rich extracts, treatments appeared to improve neuronal survival by either inhibiting intracellular signaling molecules involved in cell death or activating survival pathways.

Towards a mechanistic understanding of dietary saccharide-induced neurologic effects
Given the wide range of sugar compositions and structures of the saccharide compounds discussed in this review, common mechanisms of action that take place within the brain following oral consumption can be difficult to ascertain. Direct effects on the CNS would have to overcome the significant barriers of entry for complex carbohydrates that exist between the gastrointestinal tract and blood stream    and then across the blood-brain barrier. Although such direct mechanisms cannot be ruled out, it is perhaps more likely that initial changes are occurring peripherally or within the digestive tract itself that ultimately result in cognitive outcomes. To elucidate possible mechanisms of action that allow ingested saccharides to affect brain function, one must have an understanding of how these compounds are processed in the gut.
Human enzymes capable of digesting carbohydrates are largely limited to alpha-amylases that are able to hydrolyze the glycosidic bonds found in starches and certain disaccharides such as maltose and sucrose. Glucose and other monosaccharide subunits are then released and absorbed into the bloodstream, with general consensus that the majority of these monosaccharides travel on to the liver to be used as energy. The disaccharide trehalose can also be hydrolyzed into its two glucose subunits by the enzyme trehalase expressed in cells along the brush border of the small intestine. 47 Here, we have presented animal and in vitro studies suggesting trehalose may be a viable dietary candidate for treatment of neurodegenerative disorders associated with protein misfolding (tauopathies), although no relevant testing has yet been performed on human subjects. A comparative study of the effects of trehalose versus glucose in a mouse model of Huntington's disease appeared to rule out the possibility that trehalose provides protective benefits via an increase in blood glucose levels, since trehalose was found present within the brain and glucose administration did not show the same effects. 32 Additional research is needed to completely rule out whether changes in blood glucose levels are occurring following consumption of trehalose or other naturally derived complex saccharides and whether these changes are responsible for the observed alterations in brain function. Recent noteworthy evidence from a human intervention study with the mixed polysaccharide supplement, Ambrotose ® complex, demonstrated beneficial effects of acute saccharide treatment on brain function, in terms of memory and cognitively demanding tasks, independent of any change in blood glucose response. 14 When consumed, the vast majority of plant-derived, non-starch complex carbohydrates are considered indigestible by human enzymes and will either pass through the digestive tract intact or may be broken down and fermented by species of colonic bacteria. Many are known to have prebiotic effects, meaning they can stimulate the growth and/or activity of beneficial bacteria that reside in the digestive tract. For example, beneficial alterations in intestinal bacteria have been demonstrated in in vitro and animal studies of beta-glucan and Ambrotose ® complex. 48,49 New and exciting research has begun to demonstrate how alterations in gut bacteria can affect animal behaviors, such as anxiety and stress-induced changes in learning and memory, as well as hippocampal BDNF levels. [50][51][52][53] Therefore, it seems plausible that consumption of complex saccharides may bring about alterations in intestinal bacteria that result in cognitive benefits. Complex interactions between the digestive, immune, and nervous systems may be responsible for some of the mechanisms by which this can occur.
Many plant-derived polysaccharides have been shown to regulate the immune system as they pass through the intestinal tract. 54 For example, various beta-glucans demonstrate immune stimulating effects, 55 whereas saccharides such as those found in Ambrotose ® complex show anti-inflammatory effects within the gut. 56 In the study of dietary pectin on endotoxin-induced social withdrawal presented in Table 2, the authors suggested that pectin consumption improved intestinal barrier function thereby reducing the entry of LPS into the blood stream and the subsequent influence of systemic inflammation on the brain. 19 Once thought to be 'immune' to systemic inflammatory responses, it is now being discovered that the brain can be influenced by even low levels of peripherally circulating cytokines. 57 Neuroinflammation can lead to cognitive dysfunction and is thought to be involved in the etiology of many neurologic disorders, including Alzheimer's, multiple sclerosis, and depression. 58 Therefore, the effects of saccharide consumption on mood and cognitive function presented here may conceivably be attributed to immune signaling. Additional studies are needed, however, to determine whether immunomodulating effects of oral polysaccharides are in any way responsible for their influence on neurologic function.
Dietary polysaccharides may also impact brain function via the digestive tract due to the activation of parasympathetic nerve fibers, hormonal signaling, or additional brain-gut axis pathways. 59 For example, the transport of indigestible fibers through the colon is largely controlled by the vagus nerve, which projects directly from the viscera to the brain stem and can indirectly activate limbic and cortical regions of the brain involved in regulating mood and cognition. Vagus nerve stimulation has been proven as a successful therapy for a wide variety of neurologic disorders, including epilepsy, depression, and dementia. 60 Interestingly, activation of vagal afferents in rats has been shown to enhance LTP in the dentate gyrus 61 and increase norepinephrine levels in the hippocampus, 62 which was one suggested underlying mechanism for the effects of ingested alpha-glucans on hippocampal synaptic plasticity. 28,29 Repeating some of the oral studies presented in this review on vagotomized animals or human subjects may help elucidate the involvement of the vagus nerve in dietary saccharide-induced neurologic effects. Up to this point, no studies have focused on the neuroprotective effects of consuming fucoidan or any of the other polysaccharide-rich plant extracts discussed in Table 4. Although it seems unlikely that these systemically or centrally applied saccharides are acting in a similar manner to those administered orally, we found it pertinent to include them as part of our review. Often, neuroprotective compounds are first tested in vitro before going on to show benefits following oral administration. Heparin-derived, low-molecular weight glycosaminoglycans, which are mixtures of polysulfated oligosaccharides, have indeed shown neuroprotective effects both in vitro and in animal studies. 63 Interestingly, some evidence exists that such compounds may pass through the blood-brain barrier when administered peripherally. Del Bigio et al. 37 speculated that systemically applied fucoidan, a sulfated heteropolysaccharide, may provide protection against stroke-induced neurologic damage in part through its anti-inflammatory effects, which have been observed following fucoidan ingestion in animal studies. 54 Future research is needed to explore whether fucoidan and other natural sulfated sugar molecules can provide neuroprotective and other cognitive benefits following oral administration.

Conclusion
There is growing evidence that naturally derived saccharides have beneficial effects on brain function, demonstrated as both cellular and functional effects in terms of neuroprotection and improvements in cognition and mood. The purpose of this review was to consolidate studies on the brain-specific effects of these sugar compounds to help foster research in the area of natural complex carbohydrates and neurologic function. At present, an understanding of the efficacy and mechanisms of action for specific saccharides and saccharide-rich extracts is limited. The most promising human clinical research indicates that supplementation with a blend of plant polysaccharides can have beneficial effects on brain function related to cognitive performance and mood. In animals, various alphaglucans have shown the most significant effects on behavior and synaptic plasticity, whereas trehalose shows significant promise for neuroprotective benefits. Encouragingly, the general safety profiles of many of these dietary polysaccharides for human consumption are positive, with few reported adverse side effects. 54 Before recommendations can be made regarding their specific beneficial, preventative, or therapeutic applications, more robust well-controlled clinical trials are needed. Additional basic research is also warranted to better understand the range of effects of dietary glycans on brain function and behavior and to help elucidate the mechanisms behind which they may be occurring.