Low-grade inflammation as mediator between diet and behavioral disinhibition:A UK Biobank study

BACKGROUND: Dietary patterns have been associated with variations in behavior. However, evidence has been limited and mixed, and the underlying mechanism remains unclear. OBJECTIVE: Extend a previous study reporting significant associations between food patterns and behavioral disinhibition and explore whether low-grade inflammation is linked to behaviors and mediates the association between diet and behavioral disinhibition. DESIGN: Among participants of the UK Biobank (UKB) we extracted a single behavioral disinhibition principal component using the UKB touchscreen questionnaire, Mental Health Questionnaire (MHQ), and registered diagnoses. We identified four dietary patterns (prudent diet, elimination of wheat/dairy/eggs, meat-based diet, full-cream dairy consumption) by using the Food Frequency Questionnaire (FFQ). Immune biomarkers and an aggregated inflammation score (INFLA-score) were used to characterize low-grade inflammation. Associations between dietary patterns and immune biomarkers, between immune biomarkers and disinhibition were assessed, with adjustment for demographics, lifestyle factors, and somatic health conditions. Next, mediation analyses were run to examine whether the association between dietary patterns and disinhibition was partially explained by inflammatory levels. We also conducted subgroup analyses to explore whether associations and the mediation effect differed by sex, age, ethnicity/race, body-mass-index (BMI), and socioeconomic status (SES). RESULTS: The prudent diet was negatively, and the meat-based diet was positively associated with several pro-inflammatory biomarkers. Most immune biomarkers were positively associated with disinhibition (numbers of lymphocytes (βstandardized = 0.082, p < 0.001), monocytes (βstandardized = 0.043, p < 0.001), neutrophils (βstandardized = 0.071, p < 0.001), platelets (βstandardized = 0.022, p < 0.001), leukocytes (βstandardized = 0.093, p < 0.001), C-reactive protein (βstandardized = 0.051, p < 0.001), and for INFLA-score (βstandardized = 0.074, p < 0.001). In the mediation model, the INFLA-score mediated the association between prudent diet and meat-based diet and disinhibition score, with a significant indirect effect of low-grade inflammation for the prudent diet-disinhibition association (βstandardized = -0.007, p < 0.001) and for meat-disinhibition association (βstandardized = 0.001, p < 0.001)). Although all effects were small, covariates and interaction term adjustments did not attenuate the effects, and neither did most subgroup-only analyses. CONCLUSIONS: The prudent diet was associated with a lower disinhibition score and this effect was partially mediated by the lower inflammation. Reversely, the meat-based diet was linked to more inflammation, which was associated with more disinhibition. Our findings suggest mediating effects of immune function in the relationship between diet and behavioral disinhibition. However further alternative designs such as interventional trials are needed to establish causal effects

Dose-dependent effects of oral tyrosine administration on plasma tyrosine levels and cognition in aging

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60–75 years) received a single administration of 100, 150, or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18–35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210, and 240 min after tyrosine intake. Working memory was assessed using the N-back task at 90 min after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p < 0.001), and the plasma response was higher than for young adults with the same dose (p < 0.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p = 0.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p = 0.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults

Dose-dependent effects of oral tyrosine administration on plasma tyrosine levels and cognition in aging

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60–75 years) received a single administration of 100, 150, or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18–35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210, and 240 min after tyrosine intake. Working memory was assessed using the N-back task at 90 min after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p < 0.001), and the plasma response was higher than for young adults with the same dose (p < 0.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p = 0.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p = 0.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults

Catecholaminergic modulation of the cost of cognitive control in healthy older adults

Catecholamines have long been associated with cognitive control and value-based decision-making. More recently, we have shown that catecholamines also modulate value-based decision-making about whether or not to engage in cognitive control. Yet it is unclear whether catecholamines influence these decisions by altering the subjective value of control. Thus, we tested whether tyrosine, a catecholamine precursor altered the subjective value of performing a demanding working memory task among healthy older adults (60-75 years). Contrary to our prediction, tyrosine administration did not significantly increase the subjective value of conducting an N-back task for reward, as a main effect. Instead, in line with our previous study, drug effects varied as a function of participants’ trait impulsivity scores. Specifically, tyrosine increased the subjective value of conducting an N-back task in low impulsive participants, while reducing its value in more impulsive participants. One implication of these findings is that the over-the-counter tyrosine supplements may be accompanied by an undermining effect on the motivation to perform demanding cognitive tasks, at least in certain older adults. Taken together, these findings indicate that catecholamines can alter cognitive control by modulating motivation (rather than just the ability) to exert cognitive control

Neuro-cognitive effects of acute tyrosine administration on reactive and proactive response inhibition in healthy older adults

The aging brain is characterized by altered dopamine signaling. The amino acid tyrosine, a catecholamine precursor, is known to improve cognitive performance in young adults, especially during high environmental demands. Tyrosine administration might also affect catecholamine transmission in the aging brain, thereby improving cognitive functioning. In healthy older adults, impairments have been demonstrated in two forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing) under high information load. However, no study has directly compared the effects of a catecholamine precursor on reactive and load-dependent proactive inhibition. In this study we explored the effects of tyrosine on reactive and proactive response inhibition and signal in dopaminergically innervated fronto-striatal regions. Depending on age, tyrosine might lead to beneficial or detrimental neurocognitive effects. We aimed to address these hypotheses in 24 healthy older human adults (aged 61-72 years) using fMRI in a double blind, counterbalanced, placebo-controlled, within-subject design. Across the group, tyrosine did not alter reactive or proactive inhibition behaviorally but did increase fronto-parietal proactive inhibition-related activation. When taking age into account, tyrosine affected proactive inhibition both behaviorally and neurally. Specifically, increasing age was associated with a greater detrimental effect of tyrosine compared with placebo on proactive slowing. Moreover, with increasing age, tyrosine decreased fronto-striatal and parietal proactive signal, which correlated positively with tyrosine’s effects on proactive slowing. Concluding, tyrosine negatively affected proactive response slowing and associated fronto-striatal activation in an age-dependent manner, highlighting the importance of catecholamines, perhaps particularly dopamine, for proactive response inhibition in older adults.</p

Correction: Investigating the gut microbiota composition of individuals with attention-deficit/hyperactivity disorder and association with symptoms (Microorganisms

The authors wish to make the following correction to this paper [1]: After the publication of the manuscript, the authors recognized a mismatch in the link between the microbiota sequencing data (from ADHD cases and controls) and their descriptive and behavioral data. Thus, the manuscript had to be reanalyzed and rewritten, resulting in different results and conclusion. The main difference is that the case-control comparison resulted in different bacteria differences. Moreover, we did not find an association (only at trend level) between the microbiome relative abundance and inattention score. The corrected results, discussion, and conclusion, can be found below. Due to the changes the abstract, and material and methods section had to be adjusted as well. The changes are provided below. The authors would like to apologize for any inconvenience caused to the readers by these changes. Changes in Abstract The results and conclusion in the abstract changed to: Alpha and Beta-diversity were not different between participants with ADHD and healthy controls. Three genera showed nominal differences (puncorrected < 0.05) between both groups (Prevotella_9, Coprococcus_2 and Intestinibacter) and were further tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, a time delay between feces collection and symptoms assessment, medication use and family relatedness). Our results show that the variation of a genus from the Lachnospiraceae family (Coprococcus_2) showed a trend of being negatively associated with inattention symptoms. Furthermore, we showed that the relative abundance of four genera was reduced by ADHD medication (puncorrected < 0.05). Overall, our results may support the role of the gut microbiota in the pathophysiology of ADHD. Given the scarcity of studies on the gut microbiota in individuals with ADHD, the current results are an important contribution to this field. More studies are needed into the gut microbiota as part of the pathology of ADHD, especially with a bigger sample size across the lifespan and more detailed information about lifestyle. Changes in Materials and Methods Certain changes had to be applied in the material and methods section. First, for easier maintenance and reproducibility, we used R software instead of SPSS to reanalyze microbiome data. This means that we calculated the alpha-diversity metrics using the R function microbiome::alpha (version 1.6.0) and the composition analysis using “phyloseq” R package version 1.28.0. Second, we used the nonparametric Mann-Whitney U test method in order to identify differences in genera between cases and controls. This was visualized by using a boxplot with a summary table representing the number of zeros using “ggpubr” R package version 0.4.0.999. Third, in the regression analyses, we had to adjust the number of total tests used in FDR to 6 and not 14 tests. Fourth, the new results of the “2.2.9. Correlation Analysis and Multiple Regression with All Selected Genera” are shown in the Supplementary Materials. Changes in Results The data had to be reanalyzed; thus, all the results changed includes all the tables and figures. For easier readability, the whole (corrected) results section is provided below: 3. Results 3.1. Subjects Characteristics The general characteristics of the studied sample are presented in Table 1. Mean age, median BMI, percentage of males, and differences in days between fecal collection and ADHD symptoms assessment (diff_days) were similar among the two groups. As expected, mean inattention and hyperactivity/impulsivity scores were statistically different between the ADHD and control groups. Out of the 41 participants with ADHD, 19 were using medication for ADHD. (Figure and Table Presented)

Investigating the gut microbiota composition of individuals with attention-deficit/hyperactivity disorder and association with symptoms

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (NADHD = 42; Ncontrols = 50; NsubthreholdADHD = 15; range age: 13–29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences (p < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use, and family relatedness). Our results show that variation of a genus from the Ruminococcaceae family (Ruminococcaceae_UCG_004) is associated (after multiple testing correction) with inattention symptoms and support the potential role of gut microbiota in ADHD pathophysiology.</p