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Background. The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the SLC6A4 gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decreased function of this transporter, altered serotonergic regulation, an increased risk of psychiatric pathology and type-2 diabetes and obesity, especially in older women. Aged female mice with the complete (Sert−/−: KO) or partial (Sert+/−: HET) loss of SERT exhibit more pronounced negative effects following their exposure to a Western diet in comparison to wild-type (Sert+/+: WT) animals. Aims. We hypothesized that these effects might be mediated by an altered gut microbiota, which has been shown to influence serotonin metabolism. We performed V4 16S rRNA sequencing of the gut microbiota in 12-month-old WT, KO and HET female mice that were housed on a control or Western diet for three weeks. Results. The relative abundance of 11 genera was increased, and the abundance of 6 genera was decreased in the Western-diet-housed mice compared to the controls. There were correlations between the abundance of Streptococcus and Ruminococcaceae_UCG-014 and the expression of the pro-inflammatory marker Toll-like-Receptor 4 (Tlr4) in the dorsal raphe, as well as the expression of the mitochondrial activity marker perixome-proliferator-activated-receptor-cofactor-1b (Ppargc1b) in the prefrontal cortex. Although there was no significant impact of genotype on the microbiota in animals fed with the Control diet, there were significant interactions between diet and genotype. Following FDR correction, the Western diet increased the relative abundance of Intestinimonas and Atopostipes in the KO animals, which was not observed in the other groups. Erysipelatoclostridium abundance was increased by the Western diet in the WT group but not in HET or KO animals. Conclusions. The enhanced effects of a challenge with a Western diet in SERT-deficient mice include the altered representation of several gut genera, such as Intestinimonas, Atopostipes and Erysipelatoclostridium, which are also implicated in serotonergic and lipid metabolism. The manipulation of these genera may prove useful in individuals with the short SERT allele.

Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the EHMT1 gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota may constitute a, yet unexplored, mechanism underlying clinical variation, as they are an important modifier of the gut-brain-axis. To test whether variation in the gut microbiota is part of KS, we investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members. Both alpha and beta diversity of patients were different from their family members. Genus Coprococcus 3 was lower in abundance in patients compared to family members. Moreover, abundance of genus Merdibacter was lower in patients versus family members, but only in the participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% variance in the beta diversity. Also, within this group, we detected higher levels of Coprococcus 3 and Atopobiaceae – uncultured associated with higher symptoms severity. Our results show significant differences in the gut microbiota composition of patients with KS compared to their family members, suggesting that these differences are part of the KS phenotype.

1AbstractA body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. A growing number of studies have investigated the association between the gut microbiota and brain connectivity in humans. Linking brain connectivity measures to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, includingPrevotella,Bacteroides,RuminococcusandBlautiawere most consistently reported in association with brain connectivity. Additionally, the salience (specifically the insula and anterior cingulate cortex), default mode and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, the specificity of the signal is yet unclear as most findings were poorly replicated across studies. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employ data-driven multivariate analysis strategy.

Benefits of exploring the effect of the gut microbiota on the brain Danique Mulder, Mirjam Bloemendaal & Alejandro Arias Vásquez from the departments of Psychiatry & Human Genetics, Radboud University Medical Center, look at gut microbiota and our understanding of its effects on the human brain. Dr. Christof Koch, Chief Scientist and President of the Allen Institute for Brain Science once said: “We don’t even understand the brain of a worm,” when asked how close we were to understanding how the human brain works (1). One thing we have been able to discover is that our brain does not function fractionated or in isolation. A wealth of brain studies tells us, in fact, that multiple and sometimes large areas of the brain are involved in even the most mundane memory tasks and when strong emotions are involved, millions of neurons can become more active and help us modify behaviors. Moreover, the brain is intrinsically linked with other bodily functions, including those taking place in the gastro-intestinal tract (GIt).

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.

Background. Dietary habits may influence chronic low-grade inflammation in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. Methods. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of the 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation (NPEM) was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. Results. We identified 3 dietary patterns, characterized as “high-meat” (meat and sweetened drink), “prudent diet” (fish, fruit, legumes and vegetables) and “high alcohol” (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. Conclusion. A meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. Our study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.

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.

Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci and Bifidobacteria in healthy, female subjects (probiotics group n=27, placebo group n=29). In an identical pre- and post-session, subjects performed a working memory task before and after an acute stress intervention. One-month supplementation of probiotics changed the gut microbial community (within probiotics group Pweighted unifrac=0.008). This change was driven by a nominal increase in eight genera in the probiotics group relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005 and Ruminococcaceae_UCG-010. Of these, the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics’ effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fibre intake). That is, subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fibre degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g. maintaining intestinal- and blood-brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.

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.

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 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.

The ability to stop a prepared response (reactive inhibition) appears to depend on the degree to which stopping is expected (proactive inhibition). Functional MRI studies have shown that activation during proactive and reactive inhibition overlaps, suggesting that the whole neural network for reactive inhibition becomes already activated in anticipation of stopping. However, these studies measured proactive inhibition as the effect of stop-signal probability on activation during go trials. Therefore, activation could reflect expectation of a stop-signal (evoked by the stop-signal probability cue), but also violation of this expectation because stop-signals do not occur on go trials. We addressed this problem, using a stop-signal task in which the stop-signal probability cue and the go-signal were separated in time. Hence, we could separate activation during the cue, reflecting expectation of the stop-signal, from activation during the go-signal, reflecting expectation of the stop-signal or violation of that expectation. During the cue, the striatum, the supplementary motor complex (SMC), and the midbrain activated. During the go-signal, the right inferior parietal cortex (IPC) and the right inferior frontal cortex (IFC) activated. These findings suggest that the neural network previously associated with proactive inhibition can be subdivided into two components. One component, including the striatum, the SMC, and the midbrain, activated during the cue, implicating this network in proactive inhibition. Another component, consisting of the right IPC and the right IFC, activated during the go-signal. Rather than being involved in proactive inhibition, this network appears to be involved in processes associated with violation of expectations. Hum Brain Mapp 34:2015–2024, 2013. © 2011 Wiley Periodicals, Inc.

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.