Effects of a diet low in excitotoxins on PTSD symptoms and related biomarkers.

Post-traumatic stress disorder (PTSD) develops after trauma exposure and involves symptoms of avoidance, intrusive re-experiencing, mood and cognitive dysfunction, and hypervigilance. PTSD is often comorbid with Gulf War Illness (GWI), a neurological condition involving widespread pain, cognitive dysfunction, digestive problems, and other symptoms, in Gulf War veterans. PTSD tends to be more severe when comorbid with GWI. Low cortisol and elevated homocysteine levels have been found in PTSD, making them potential PTSD biomarkers. The low-glutamate diet, which aims to reduce excitotoxicity by eliminating the consumption of free glutamate and aspartate, has been shown to significantly reduce GWI and PTSD symptoms. This study examined whether changes in serum cortisol and homocysteine are associated with reduced PTSD severity in veterans with GWI after one month on the low-glutamate diet, and whether reducing the consumption of dietary excitotoxins was associated changes in PTSD and serum biomarkers. Data were analyzed for 33 veterans. No serum biomarkers significantly changed post-diet; however, cortisol increased as dietary excitotoxin consumption decreased, which held in a multivariable linear regression after adjustment for sex. Reduced dietary excitotoxin consumption was also associated with reduced hyperarousal symptoms, which held in a multivariable linear regression after adjustment for sex. Cortisol increase was associated with reduced avoidance symptoms after adjustment for change in BMI, and was marginally associated with overall PTSD reduction. Change in homocysteine was not significantly related to dietary adherence nor change in PTSD. Results suggest that reducing the consumption of dietary excitotoxins may normalize cortisol levels, which has been associated with alleviating PTSD.

Artificial food coloring affects EEG power and ADHD symptoms in college students with ADHD: a pilot study.

Objectives: Removing artificial food coloring (AFC) is a common dietary intervention for children with Attention-Deficit/Hyperactivity Disorder (ADHD), but has not been tested in young adults. This pilot study examined the effects of AFC on ADHD symptoms and electroencephalography (EEG) in college students with and without ADHD.Methods: At baseline, control and ADHD participants completed the Adult ADHD Self-Report Scale (ASRS), simple and complex attention measures, and resting-state EEG recordings. ADHD participants (n = 18) and a subset of controls (extended control group or EC, n = 11) avoided AFC in their diet for 2 weeks and then were randomized to a double-blind, placebo-controlled crossover challenge. Subjects received either 225 mg AFC disguised in chocolate cookies or placebo chocolate cookies for 3 days each week, with testing on the third day each week. Baseline comparisons were made using Student's t-test or Wilcoxon rank sum tests and challenge period analyses were run using General Linear Modeling.Results: The ADHD group had significantly greater scores on the ASRS (p < 0.001), confirming a symptom differential between groups; however, there were no differences in attentional measures or EEG at baseline. The AFC challenge resulted in an increase in posterior mean gamma power (p = 0.05), a decrease in posterior relative alpha power (p = 0.04), and a marginal increase in inattentive symptoms (p = 0.08) in the ADHD group. There were no effects of AFC in the EC group.Discussion: This study indicates that AFC exposure may affect brainwave activity and ADHD symptoms in college students with ADHD. Larger studies are needed to confirm these findings.

The low glutamate diet improves cognitive functioning in veterans with Gulf War Illness and resting-state EEG potentially predicts response.

Objectives: Gulf War Illness (GWI) is a chronic, multi-symptom disorder with underlying central nervous system dysfunction and cognitive impairments. The objective of this study was to test the low glutamate diet as a novel treatment for cognitive dysfunction among those with GWI, and to explore if baseline resting-state electroencephalography (EEG) could predict cognitive outcomes.Methods: Cognitive functioning was assessed at baseline, after one-month on the diet, and across a two-week double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG) relative to placebo.Results: Significant improvements were seen after one-month on the diet in overall cognitive functioning, and in all other domains tested (FDR p < 0.05), except for memory. Challenge with MSG resulted in significant inter-individual response variability (p < 0.0001). Participants were clustered according to baseline resting-state EEG using k-means clustering to explore the inter-individual response variability. Three distinct EEG clusters were observed, and each corresponded with differential cognitive effects during challenge with MSG: cluster 1 had cognitive benefit (24% of participants), cluster 2 had cognitive detriment (42% of participants), and cluster 3 had mild/mixed effects (33% of participants).Discussion: These findings suggest that the low glutamate diet may be a beneficial treatment for cognitive impairment in GWI. Future research is needed to understand the extent to which resting-state EEG can predict response to the low glutamate diet and to explore the mechanisms behind the varied response to acute glutamate challenge.

Post-traumatic stress disorder may set the neurobiological stage for eating disorders: A focus on glutamatergic dysfunction.

Post-traumatic stress disorder (PTSD) is a trauma and stress-related disorder which has been shown to be highly comorbid with, and commonly a precedent of, the eating disorders anorexia nervosa, bulimia nervosa, and binge eating disorder. The objective of this review is to discuss a potential overlapping neurobiological mechanism for this comorbidity. Alterations in glutamatergic neurotransmission have been observed in all four of the aforementioned disorders. Excessive excitation via glutamate contributes to excitotoxicity, and over-activation of the hypothalamic-pituitary-adrenal axis, both of which have implications for the deterioration of various brain structures. Prominent structures impacted include the hippocampus, hypothalamus, and prefrontal cortex, all of which are integral to the regulation of stress and eating. The current review suggests that altered glutamate function by trauma or extreme stress may facilitate PTSD and subsequent eating disorder onset, and that glutamatergic modulation may be a key treatment for individuals suffering from these conditions. This overlapping mechanism may help inform future research on individuals with comorbid PTSD and eating disorders, and it could also help inform ways to potentially prevent the onset of these conditions.

Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: A prospective investigation.

Early life predictors of attention-deficit/hyperactivity disorder (ADHD) are critically needed; they could inform etiological theory and may help identify new prevention targets. The current study examined prospectively whether maternal cytokine levels during pregnancy predict offspring ADHD symptoms at age 4-6 years. Secondarily, we evaluated maternal cytokine levels as a possible common pathway through which prenatal risks exert influence on child ADHD. Data came from a sample of women recruited during the 2nd trimester of pregnancy (N = 62) and followed postnatally until children were 4-6 years old. Maternal inflammation was assessed using 3rd trimester plasma concentrations of three indicators of nuclear factor kappa B signaling: interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 which were combined into a latent variable. Mothers and teachers reported on child ADHD symptoms, negative affect, and externalizing behaviors at 48-72 months of age. Maternal inflammation in the 3rd trimester predicted ADHD symptoms when children were 4-6 years old (ß = 0.53, 95% CI = 0.154, 0.905, p = 0.006). Further, maternal inflammation mediated the effect of prenatal distress on child ADHD (ß = 0.21, 95% CI = 0.007, 0.419, p = 0.04). The inflammation effect on ADHD was not explained by concurrent child negative affect, externalizing behavior, or familial ADHD status. This is the first human study to prospectively link maternal pregnancy cytokine levels and offspring ADHD symptoms, suggesting that cytokine levels are a possible marker of ADHD risk. Results also provide new evidence that maternal prenatal inflammation may be one common pathway by which prenatal risk factors influence offspring mental health outcomes.

Moving past antioxidant supplementation for the dietary treatment of multiple sclerosis.

Current research has demonstrated the definitive presence of oxidative stress in multiple sclerosis (MS). This finding has led to clinical trial research which has indicated that specific antioxidants have the ability to effectively reduce markers of oxidative stress. However, few interventions testing antioxidant supplements have shown efficacy for reducing the symptom burden in the disorder. This paper quickly reviews what is currently known about oxidative stress and antioxidants in MS, explains which nutrients are critical for the creation and maintenance of the myelin sheath, describes potential negative effectors in the diet which may be contributing to oxidative stress, and how these aspects of diet, combined with current knowledge on antioxidants, may be able to be combined into a whole food dietary intervention which can be tested for efficacy in MS.

Evaluation of dietary intake in children and college students with and without attention-deficit/hyperactivity disorder.

Objectives: To evaluate dietary intake among individuals with and without attention-deficit hyperactivity disorder (ADHD), to evaluate the likelihood that those with ADHD have inadequate intakes. Methods: Children, 7-12 years old, with (n = 23) and without (n = 22) ADHD, and college students, 18-25 years old, with (n = 21) and without (n = 30) ADHD comprised the samples. Children's dietary intake was assessed by a registered dietitian using 24-hour recalls over 3 days. College students kept a detailed food record over three days. Dietary information for both groups was entered into the Nutrition Data Systems for Research database, and output was analyzed using SAS 9.4. Nutrient analyses included the Healthy Eating Index-2010, Micronutrient Index (as a measure of overall micronutrient intake), and individual amino acids necessary for neurotransmission. Logistic regression was used to model the association of nutrient intake with ADHD. Models were adjusted for age, sex, IQ (or GPA), and energy intake (or total protein intake) as appropriate. Significance was evaluated at P = 0.05, and using the Benjamini-Hochberg corrected P-value for multiple comparisons. Results: No evidence existed for reduced nutrient intake among those with ADHD compared to controls in either age group. Across both groups, inadequate intakes of vitamin D and potassium were reported in 95% of participants. Children largely met nutrient intake guidelines, while college students failed to meet these guidelines for nine nutrients. In regards to amino acid intake in children, an increased likelihood of having ADHD was associated with higher consumption of aspartate, OR = 12.61 (P = 0.01) and glycine OR = 11.60 (P = 0.05); and a reduced likelihood of ADHD with higher intakes of glutamate, OR = 0.34 (P = 0.03). Among young adults, none of the amino acids were significantly associated with ADHD, though glycine and tryptophan approached significance. Discussion: Results fail to support the hypothesis that ADHD is driven solely by dietary micronutrient inadequacy. However, amino acids associated with neurotransmission, specifically those affecting glutamatergic neurotransmission, differed by ADHD status in children. Amino acids did not reliably vary among college students. Future larger scale studies are needed to further examine whether or not dietary intake of amino acids may be a modulating factor in ADHD.

Early identification of ADHD risk via infant temperament and emotion regulation: a pilot study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is theorized to have temperamental precursors early in life. These are difficult to identify because many core features of ADHD, such as breakdowns in executive function and self-control, involve psychological and neural systems that are too immature to reliably show dysfunction in early life. ADHD also involves emotional dysregulation, and these temperamental features appear earlier as well. Here, we report a first attempt to utilize indices of emotional regulation to identify ADHD-related liability in infancy. METHODS: Fifty women were recruited in the 2nd trimester of pregnancy, with overselection for high parental ADHD symptoms. Measures of maternal body mass index, nutrition, substance use, stress, and mood were examined during pregnancy as potential confounds. Offspring were evaluated at 6 months of age using LABTAB procedures designed to elicit fear, anger, and regulatory behavior. Mothers completed the Infant Behavior Questionnaire about their child's temperament. RESULTS: After control for associated covariates, including maternal depression and prenatal stress, family history of ADHD was associated with measures of anger/irritability, including infant negative vocalizations during the arm restraint task (p = .004), and maternal ratings of infant distress to limitations (p = .036). In the regulation domain, familial ADHD was associated with less parent-oriented attention seeking during the still face procedure (p < .001), but this was not echoed in the maternal ratings of recovery from distress. CONCLUSIONS: Affective response at 6 months of age may identify infants with familial history of ADHD, providing an early indicator of ADHD liability. These preliminary results provide a foundation for further studies and will be amplified by enlarging this cohort and following participants longitudinally to evaluate ADHD outcomes.

Biomarkers Associated with Depression Improvement in Veterans with Gulf War Illness Using the Low-Glutamate Diet.

Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-γ, IL-6, IL-1ß, TNF-α) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression (p < 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), (p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (ß = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-γ was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), (p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-γ, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work.

Nutritional Criminology: Why the Emerging Research on Ultra-Processed Food Matters to Health and Justice.

There is mounting concern over the potential harms associated with ultra-processed foods, including poor mental health and antisocial behavior. Cutting-edge research provides an enhanced understanding of biophysiological mechanisms, including microbiome pathways, and invites a historical reexamination of earlier work that investigated the relationship between nutrition and criminal behavior. Here, in this perspective article, we explore how this emergent research casts new light and greater significance on previous key observations. Despite expanding interest in the field dubbed 'nutritional psychiatry', there has been relatively little attention paid to its relevancy within criminology and the criminal justice system. Since public health practitioners, allied mental health professionals, and policymakers play key roles throughout criminal justice systems, a holistic perspective on both historical and emergent research is critical. While there are many questions to be resolved, the available evidence suggests that nutrition might be an underappreciated factor in prevention and treatment along the criminal justice spectrum. The intersection of nutrition and biopsychosocial health requires transdisciplinary discussions of power structures, industry influence, and marketing issues associated with widespread food and social inequalities. Some of these discussions are already occurring under the banner of 'food crime'. Given the vast societal implications, it is our contention that the subject of nutrition in the multidisciplinary field of criminology-referred to here as nutritional criminology-deserves increased scrutiny. Through combining historical findings and cutting-edge research, we aim to increase awareness of this topic among the broad readership of the journal, with the hopes of generating new hypotheses and collaborations.

Targeting Glutamate Neurotoxicity through Dietary Manipulation: Potential Treatment for Migraine.

Glutamate, the main excitatory neurotransmitter in the central nervous system, is implicated in both the initiation of migraine as well as central sensitization, which increases the frequency of migraine attacks. Excessive levels of glutamate can lead to excitotoxicity in the nervous system which can disrupt normal neurotransmission and contribute to neuronal injury or death. Glutamate-mediated excitotoxicity also leads to neuroinflammation, oxidative stress, blood-brain barrier permeability, and cerebral vasodilation, all of which are associated with migraine pathophysiology. Experimental evidence has shown the protective effects of several nutrients against excitotoxicity. The current review focuses on the mechanisms behind glutamate's involvement in migraines as well as a discussion on how specific nutrients are able to work towards restoring glutamate homeostasis. Understanding glutamate's role in migraine is of vital importance for understanding why migraine is commonly comorbid with widespread pain conditions and for informing future research directions.

The low glutamate diet reduces blood pressure in veterans with Gulf War Illness: A CONSORT randomized clinical trial.

BACKGROUND: Gulf War Illness is a multi-symptom condition affecting veterans of the 1990 to 1991 Gulf War, which often presents with comorbid hypertension. The purpose of this study was to analyze the effects of the low glutamate diet, as well as an acute challenge of monosodium glutamate (MSG)/placebo, on resting heart rate, blood oxygenation level, and blood pressure (BP) in this population. METHODS: These data were measured at 4 time points: baseline, after 1 month on the low glutamate diet, and during each challenge week, where subjects were randomized into a double-blind, placebo-controlled, crossover challenge with MSG/placebo over 3 days each week. Pre-post diet changes were analyzed using paired t tests, change in the percentage of veterans meeting the criteria for hypertension was compared using chi-square or Fisher exact tests, and crossover challenge results were analyzed using general linear modeling in SAS® 9.4. RESULTS: There was a significant reduction in systolic BP (sitting and recumbent; both P < .001) and diastolic BP (sitting; P = .02) after 1 month on the diet. The percentage meeting the criteria for hypertension was also significantly reduced (P < .05). Challenge with MSG/placebo did not demonstrate an acute effect of glutamate on blood pressure. CONCLUSION: Overall, these findings suggest that the low glutamate diet may be an effective treatment for lowering blood pressure in veterans with Gulf War Illness. This dietary effect does not appear to be driven by reduced consumption of free glutamate, but rather, by an increase in consumption of non-processed foods.

Investigation of the low glutamate diet as an adjunct treatment for pediatric epilepsy: A pilot randomized controlled trial.

INTRODUCTION: Current dietary therapies for epilepsy have side effects and are low in nutrients, which would make an alternative dietary treatment, which addresses these issues, advantageous. One potential option is the low glutamate diet (LGD). Glutamate is implicated in seizure activity. Blood brain barrier permeability in epilepsy could enable dietary glutamate to reach the brain and contribute to ictogenesis. OBJECTIVE: to assess the LGD as an adjunct treatment for pediatric epilepsy. METHODS: This study was a nonblinded, parallel, randomized clinical trial. The study was conducted virtually due to COVID-19 and registered on clinicaltrials.gov (NCT04545346). Participants were eligible if they were between the ages of 2 and 21 with ≥4 seizures per month. Baseline seizures were assessed for 1-month, then participants were allocated via block randomization to the intervention month (N=18), or a wait-listed control month followed by the intervention month (N=15). Outcome measures included seizure frequency, caregiver global impression of change (CGIC), non-seizure improvements, nutrient intake, and adverse events. RESULTS: Nutrient intake significantly increased during the intervention. No significant differences in seizure frequency were observed between intervention and control groups. However, efficacy was assessed at 1-month compared to the standard 3-months in diet research. Additionally, 21% of participants were observed to be clinical responders to the diet. Overall health (CGIC) significantly improved in 31%, 63% experienced ≥1 non-seizure improvements, and 53% experienced adverse events. Clinical response likelihood decreased with increasing age (0.71 [0.50-0.99], p=0.04), as did the likelihood of overall health improvement (0.71 [0.54-0.92], p=0.01). DISCUSSION: This study provides preliminary support for the LGD as an adjunct treatment before epilepsy becomes drug resistant, which is in contrast to the role of current dietary therapies in drug resistant epilepsy.

Beyond Plants: The Ultra-Processing of Global Diets Is Harming the Health of People, Places, and Planet.

Global food systems are a central issue for personal and planetary health in the Anthropocene. One aspect of major concern is the dramatic global spread of ultra-processed convenience foods in the last 75 years, which is linked with the rising human burden of disease and growing sustainability and environmental health challenges. However, there are also calls to radically transform global food systems, from animal to plant-derived protein sources, which may have unintended consequences. Commercial entities have moved toward this "great plant transition" with vigor. Whether motivated by profit or genuine environmental concern, this effort has facilitated the emergence of novel ultra-processed "plant-based" commercial products devoid of nutrients and fiber, and sometimes inclusive of high sugar, industrial fats, and synthetic additives. These and other ingredients combined into "plant-based" foods are often assumed to be healthy and lower in calorie content. However, the available evidence indicates that many of these products can potentially compromise health at all scales-of people, places, and planet. In this viewpoint, we summarize and reflect on the evidence and discussions presented at the Nova Network planetary health meeting on the "Future of Food", which had a particular focus on the encroachment of ultra-processed foods into the global food supply, including the plant-sourced animal protein alternatives (and the collective of ingredients therein) that are finding their way into global fast-food chains. We contend that while there has been much uncritical media attention given to the environmental impact of protein and macronutrient sources-meat vs. novel soy/pea protein burgers, etc.-the impact of the heavy industrial processing on both human and environmental health is significant but often overlooked, including effects on cognition and mental health. This calls for a more nuanced discourse that considers these complexities and refocuses priorities and value systems towards mutualistic solutions, with co-benefits for individuals, local communities, and global ecology.

The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms.

OBJECTIVES: To examine the effects of a challenge with monosodium glutamate (MSG) as compared to placebo on the symptoms of fibromyalgia (FM), in participants who initially experienced >30% remission of symptoms on an excitotoxin elimination diet. METHODS: Fifty-seven FM patients who also had irritable bowel syndrome (IBS) were placed on a 4-week diet that excluded dietary additive excitotoxins including MSG and aspartame. Thirty-seven people completed the diet and 84% of those reported that >30% of their symptoms resolved, thus making them eligible to proceed to challenges. Subjects who improved on the diet were then randomised to a 2-week double-blind placebo-controlled crossover challenge with MSG or placebo for 3 consecutive days each week. The primary outcome measure was total symptom score. Secondary outcome measures included visual analogue pain scales (VAS for FM and IBS), an IBS Quality of Life Questionnaire (IBS QOL) and the Fibromyalgia Impact Questionnaire-Revised (FIQR). Repeated measures ANOVA was used to analyse crossover challenge results. RESULTS: The MSG challenge, as compared to placebo, resulted in a significant return of symptoms (total symptom score, p<0.02); a worsening of fibromyalgia severity as determined by the FIQR (p<0.03); decreased quality of life in regards to IBS symptoms (IBS QOL, p<0.05); and a non-significant trend toward worsening FM pain based on visual analogue scale (VAS, p<0.07). CONCLUSIONS: These findings suggest that dietary glutamate may be contributing to FM symptoms in some patients. Future research on the role of dietary excitotoxins in FM is warranted.

The Effect of the Low Glutamate Diet on the Reduction of Psychiatric Symptoms in Veterans With Gulf War Illness: A Pilot Randomized-Controlled Trial.

The objective of this pilot study was to examine the effects of the low glutamate diet on anxiety, post-traumatic stress disorder (PTSD), and depression in veterans with Gulf War Illness (GWI). The low glutamate diet removes dietary excitotoxins and increases consumption of micronutrients which are protective against glutamatergic excitotoxicity. This study was registered at ClinicalTrials.gov (NCT#03342482). Forty veterans with GWI completed psychiatric questionnaires at baseline and after 1-month following the low glutamate diet. Participants were then randomized into a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG; a dietary excitotoxin) vs. placebo over three consecutive days per week, with assessments on day three. Data were analyzed across the full sample and with participants categorized by baseline symptom severity. Pre-post-dietary intervention change scores were analyzed with Wilcoxon signed-rank tests and paired sample t-tests across the full sample, and changes across symptom severity categories were analyzed using ANOVA. Crossover challenge results were analyzed with linear mixed modeling accounting for challenge material (MSG v. placebo), sequence (MSG/placebo v. placebo/MSG), period (challenge week 1 v. week 2), pre-diet baseline symptom severity category (minimal/mild, moderate, or severe), and the challenge material*symptom severity category interaction. A random effect of ID (sequence) was also included. All three measures showed significant improvement after 1 month on the diet, with significant differences between baseline severity categories. Individuals with severe psychological symptoms at baseline showed the most improvement after 1 month on the diet, while those with minimal/mild symptoms showed little to no change. Modeling results from the challenge period demonstrated a significant worsening of anxiety from MSG in only the most severe group, with no significant effects of MSG challenge on depression nor PTSD symptoms. These results suggest that the low glutamate diet may be an effective treatment for depression, anxiety, and PTSD, but that either (a) glutamate is only a direct cause of symptoms in anxiety, or (b) underlying nutrient intake may prevent negative psychiatric effects from glutamate exposure. Future, larger scale clinical trials are needed to confirm these findings and to further explore the potential influence of increased micronutrient intake on the improvements observed across anxiety, PTSD, and depression.

The association between heightened ADHD symptoms and cytokine and fatty acid concentrations during pregnancy.

Objective: Previous research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD. Methods: Data (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake. Results: The group with heightened ADHD symptoms had higher n-6:n-3s (ß = 0.30, p < 0.01) and higher TNF-α concentrations (ß = 0.35, p < 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample. Conclusion: Pregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake.

Low glutamate diet improves working memory and contributes to altering BOLD response and functional connectivity within working memory networks in Gulf War Illness.

Gulf War Illness is a chronic multi-symptom disorder with severe cognitive impairments which may be related to glutamate excitotoxicity and central nervous system dysfunction. The low glutamate diet has been proposed as a comprehensive intervention for Gulf War Illness. We examined the effects of the low glutamate diet on verbal working memory using a fMRI N-back task. Accuracy, whole-brain blood oxygen level dependency (BOLD) response, and task-based functional connectivity were assessed at baseline and after 1 month on the diet (N = 24). Multi-voxel pattern analysis identified regions of whole-brain BOLD pattern differences after the diet to be used as seeds for subsequent seed-to-voxel functional connectivity analyses. Verbal working memory accuracy improved after the diet (+ 13%; p = 0.006). Whole-brain BOLD signal changes were observed, revealing lower activation within regions of the frontoparietal network and default mode network after the low glutamate diet. Multi-voxel pattern analysis resulted in 3 clusters comprising parts of the frontoparietal network (clusters 1 and 2) and ventral attention network (cluster 3). The seed-to-voxel analyses identified significant functional connectivity changes post-diet for clusters 1 and 2 (peak p < 0.001, cluster FDR p < 0.05). Relative to baseline, clusters 1 and 2 had decreased functional connectivity with regions in the ventral attention and somatomotor networks. Cluster 2 also had increased functional connectivity with regions of the default mode and frontoparietal networks. These findings suggest that among veterans with Gulf War Illness, the low glutamate diet improves verbal working memory accuracy, alters BOLD response, and alters functional connectivity within two networks central to working memory.

Micronutrients May Be a Unique Weapon Against the Neurotoxic Triad of Excitotoxicity, Oxidative Stress and Neuroinflammation: A Perspective.

Excitotoxicity has been implicated in many neurological disorders and is a leading cause of oxidative stress and neuroinflammation in the nervous system. Most of the research to date has focused on each of these conditions individually; however, excitotoxicity, oxidative stress, and neuroinflammation have the ability to influence one another in a self-sustaining manner, thus functioning as a "neurotoxic triad." This perspective article re-introduces the concept of the neurotoxic triad and reviews how specific dietary micronutrients have been shown to protect against not only oxidative stress, but also excitotoxicity and neuroinflammation. Future dietary interventions for neurological disorders could focus on the effects on all three aspects of the neurotoxic triad.

Brain concentrations of glutamate and GABA in human epilepsy: A review.

An imbalance between excitation and inhibition has been a longstanding proposed mechanism regarding ictogenesis and epileptogenesis. This imbalance is related to increased extracellular glutamate in the brain and/or reduction in GABA concentrations, leading to excitotoxicity, seizures, and cell death. This review aims to summarize the microdialysis and magnetic resonance spectroscopy (MRS) literature investigating glutamate and GABA concentrations in epilepsy patients, present limitations, and suggest future directions to help direct the search for novel epilepsy treatments. The majority of microdialysis studies demonstrated increased glutamate in epileptic regions either compared to control regions or to baseline levels; however, sample sizes were small, with some statistical comparisons missing. For the MRS research, two of six studies reported significant changes in glutamate levels compared to controls, though the results were mixed, with one reporting increased and the other reporting decreased glutamate levels. Eleven of 20 studies reported significant changes in Glx (glutamate + glutamine) or Glx ratios, with most reporting increased levels, except for a few epilepsy syndromes where reduced levels were reported. Few studies investigated GABA concentrations, with one microdialysis and four spectroscopy studies reporting increased GABA levels, and one study reporting decreased GABA in a different brain region. Based on this review, future research should account for medication use; include measurements of GABA, glutamate, and glutamine; use high-tesla strength MRI; and further evaluate the timing of microdialysis. Understanding the importance of brain glutamate and GABA levels in epilepsy may provide direction for future therapies and treatments.