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Genetic and environmental factors play a role in the cause and development of attention-deficit/hyperactivity disorder (ADHD). Recent studies have suggested an important role of the gut-brain axis (GBA) and intestinal microbiota in modulating the risk of ADHD. Here, the authors provide a brief overview of the clinical and biological picture of ADHD and how the GBA could be involved in its cause. They discuss key biological mechanisms involved in the GBA and how these may increase the risk of developing ADHD. Understanding these mechanisms may help to characterize novel treatment options via identification of disease biomarkers.

The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 hours, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischaemic stroke, autism spectrum disorder and mood- and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Also, variations in fasting patterns, total caloric intake and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and Randomized Clinical Trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.

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&ndash, 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 &lt, 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.

Contains fulltext : 215914.pdf (Publisher’s version ) (Closed access) Stressors induce physiological changes in the brain and periphery that support adaptive defensive responses. The consequences of psychological stress on cognitive functioning are often measured in laboratory settings using experimentally induced stress that leads to mainly negative subjective feelings. There is a need for verification of these studies using real-life stressors that may potentially induce both positive and negative subjective feelings. In an observational study, we investigated real-life stress induced by voluntary stage performance at a large-scale music festival, including 126 participants (60 female, age range = 16-57 years). Our primary measurements involved salivary cortisol, heart rate, blood pressure, and positive and negative affect. In addition, participants completed a 2-back working memory task and a speeded decision-making task. We found that stage performance significantly increased salivary cortisol - with a particularly low number of cortisol non-responders - and heart rate, even when controlling for potential confounding factors, such as sleep, movement, and alcohol use. Interestingly, stage performance significantly decreased negative affect while increasing positive affect. This positively experienced stressor ("eustressor") was related to impaired working memory performance: the stronger the increases in cortisol, the slower participants responded to targets. Decision-making, however, was not affected. In conclusion, we show how stressful experiences in real-life can lead to positive affect, but still have a similar negative impact on cognitive functioning. We suggest that future research should focus more on the consequences of real-life stressors, and the consequences of eustress, in order to extend our understanding of the concept of psychological stress. 11 p.

Contains fulltext : 219278.pdf (Publisher’s version ) (Open Access) 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, exploratory analyses indicated that 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.

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

The great majority of studies on repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool for auditory verbal hallucinations (AVH) have used 1-Hz stimulation with inconsistent results. Recently, it has been suggested that 20-Hz rTMS has strong therapeutic effects. It is conceivable that this 20-Hz stimulation is more effective than 1-Hz stimulation. The aim of this preliminary study is to investigate the efficacy of 20-Hz rTMS compared with 1-Hz rTMS as a treatment for AVH. Eighteen schizophrenia patients with medication-resistant AVH were randomized over two treatment groups. Each group received either 20 min of 1-Hz rTMS or 13 trains of 20-Hz rTMS daily over 1 week. After week 1, patients received a follow-up treatment once a week for 3 weeks. Stimulation location was based on individual AVH-related activation patterns identified with functional magnetic resonance imaging. Severity of AVH was monitored with the Auditory Hallucination Rating Scale (AHRS). Both groups showed a decrease in AVH after week 1 of rTMS. This decrease was significant for the 20-Hz group and the 1-Hz group. When the two treatment types were compared, no treatment type was superior. Based on these results we cannot conclude whether high frequency rTMS is more effective against AVH than is traditional 1-Hz rTMS. More research is needed to optimize stimulation parameters and to investigate potential target locations for stimulation.

Contains fulltext : 182736.pdf (Publisher’s version ) (Open Access) 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

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, we previously demonstrated impairments 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 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. To conclude, 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.

Contains fulltext : 166343.pdf (Publisher’s version ) (Closed access) Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition (anticipatory response slowing), which might be particularly evident with high information load. We used functional magnetic resonance imaging in young (n = 25, age range 18-32) and older adults (n = 23, 61-74) with a stop-signal task. Relative to young adults, older adults exhibited impaired reactive inhibition (i.e., longer stop-signal reaction time) and increased blood oxygen level-dependent (BOLD) signal for successful versus unsuccessful inhibition in the left frontal cortex and cerebellum. Furthermore, older adults also exhibited impaired proactive slowing, but only as a function of information load. This load-dependent behavioral deficit was accompanied by a failure to increase blood oxygen level-dependent (BOLD) signal under high information load in lateral frontal cortex, presupplementary motor area and striatum. Our findings suggest that inhibitory deficits in older adults are caused both by reduced stopping abilities and by diminished preparation capacity during information overload.

Item does not contain fulltext SUMMARY: Stimulating brain areas with transcranial magnetic stimulation (TMS) while concurrently and noninvasively recording brain activity changes through functional MRI enables a new range of investigations about causal interregional interactions in the human brain. However, standard head-coil arrangements for current methods for concurrent TMS-functional MRI somewhat restrict the cortical brain regions that can be targeted with TMS because space in typical MR head coils is limited. Another limitation for concurrent TMS-functional MRI approaches concerns the estimation of the precise stimulation site, which can limit the interpretation of the activity changes induced by TMS and increase the variability of the stimulation effects. Here, we present a novel approach using flexible MR receiver coils, allowing for stimulation of a large part of the cortex including more lateral areas. Furthermore, we present a fast and economical method to determine the precise location of the stimulation coil during scanning. This point-based registration method can accurately compute, during scanning, where TMS pulses are delivered. We validated this approach by stimulating medial (M1) and more lateral (dorsal part of the supramarginal gyrus) brain areas concurrently with functional MRI. Activation close to but not directly at the stimulated location and in distal areas connected to the targeted site was observed. This study provides a proof of concept that TMS of medial and lateral brain areas is feasible without significantly compromising brain coverage and that one can precisely determine the exact coil location inside the bore to verify targeting of brain areas.

Item does not contain fulltext Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

Stopping an action requires suppression of the primary motor cortex (M1). Inhibitory control over M1 relies on a network including the right inferior frontal cortex (rIFC) and the supplementary motor complex (SMC), but how these regions interact to exert inhibitory control over M1 is unknown. Specifically, the hierarchical position of the rIFC and SMC with respect to each other, the routes by which these regions control M1, and the causal involvement of these regions in proactive and reactive inhibition remain unclear. We used off-line repetitive TMS to perturb neural activity in the rIFC and SMC followed by fMRI to examine effects on activation in the networks involved in proactive and reactive inhibition, as assessed with a modified stop-signal task. We found repetitive TMS effects on reactive inhibition only. rIFC and SMC stimulation shortened the stop-signal RT (SSRT) and a shorter SSRT was associated with increased M1 deactivation. Furthermore, rIFC and SMC stimulation increased right striatal activation, implicating frontostriatal pathways in reactive inhibition. Finally, rIFC stimulation altered SMC activation, but SMC stimulation did not alter rIFC activation, indicating that rIFC lies upstream from SMC. These findings extend our knowledge about the functional organization of inhibitory control, an important component of executive functioning, showing that rIFC exerts reactive control over M1 via SMC and right striatum.