BRAIN METABOLITE AND EEG-PROFILE SPECIFIC EFFECTS OF THE LOW GLUTAMATE DIET ON COGNITIVE FUNCTIONING IN GULF WAR ILLNESS

<p>Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder with underlying central nervous system (CNS) dysfunction and cognitive impairments. Neurotoxic exposures during the Gulf War are thought to have caused over activation of glutamatergic receptors, leading to neuroexcitotoxicity and symptoms associated with GWI. Glutamate has a dual role as an excitatory neurotransmitter and a non-essential dietary amino acid, with the potential to be an excitotoxin. While the blood-brain barrier (BBB) should prevent dietary glutamate from entering the CNS, Gulf War specific stressors may have increased BBB permeability among veterans with GWI allowing dietary glutamate to enter the CNS. Increased availability of glutamate in the CNS from dietary exposures may be contributing to excitotoxicity and the continuation of symptoms of GWI decades after the conflict. Therefore, the current clinical trial investigated a low glutamate diet as a novel treatment for GWI. Participants were assessed at baseline for CNS dysfunction using magnetic resonance spectroscopy (MRS), resting-state electroencephalography (EEG), and computerized cognitive functioning testing using CNS Vital Signs® (CNSVS) software. After intensive dietary training, all participants were on the low glutamate diet for one month before returning for post-diet assessments of MRS, EEG, and cognitive functioning. Participants were then randomized to a two-week double-blind placebo-controlled crossover challenge period where participants received either five grams of glutamate (as monosodium glutamate or MSG) or five grams of a sugar/salt mixture as a placebo (with an equal amount of salt as the MSG) over three days to test whether glutamate induced changes in EEG and CNSVS outcomes. After one month on the low glutamate diet, a majority of participants (72.5%) reported overall improvement based on the global impression of change scale. Overall cognitive functioning measured by the neurocognitive index (NCI) significantly improved (p=0.002), and the majority of the domain-specific cognitive outcomes showed significant improvement as well. A decrease in glutamine (p=0.074) and glutamate plus glutamine (Glx) (p=0.070) approached significance in the left hippocampus after one month on the low glutamate diet, and the change in glutamine was associated with improvements in the NCI (p=0.034). Changes in resting-state EEG included decreases in central and posterior delta (p<0.01) and increases in central and posterior alpha (p<0.01). Challenge with MSG relative to placebo did not show differences in cognitive functioning measured by NCI or any other cognitive domains tested in the population as a whole. However, there were significant increases in global theta (p<0.001) and beta (p<0.05) power during challenge with MSG relative to placebo. To examine if certain profiles of brainwave activity at baseline could predict response in cognitive functioning after the low glutamate diet and during challenge with MSG, baseline EEG frequency bands were clustered, resulting in three distinct groups (cluster 1 n=8, cluster 2 n=14, cluster 3 n=11). Cluster 2 (lowest in delta and theta power, highest in alpha and high gamma power at baseline) showed the most improvement in cognitive functioning across domains after one-month on the diet, as well as the worst performance across domains when challenged with MSG relative to placebo. This would suggest that individuals with GWI having baseline EEG profiles with decreased power in low frequency bands and increased power in mid and very high frequency bands are the most sensitive to glutamate in the diet. Future larger scale research of GW veterans will help to confirm if specific EEG profiles and changes in brain glutamate levels could be used to predict cognitive improvement from the low glutamate diet.</p>