Effects of catecholaminergic and transcranial direct current stimulation on response inhibition.

BACKGROUND: The principle of gain control determines the efficiency of neuronal processing and can be enhanced with pharmacological or brain stimulation methods. It is a key factor for cognitive control, but the degree of how much gain control may be enhanced underlies a physical limit. METHODS: To investigate whether MPH and tDCS share common underlying mechanisms and cognitive effects, we administered methylphenidate (MPH) and anodal tDCS (atDCS) over the right inferior frontal gyrus both separately and combined, while healthy adult participants (N=104) a performed response selection and inhibition task. The recorded EEG data were analyzed with a focus on theta band activity and source estimation analyses were conducted. RESULTS: The behavioral data show that MPH and atDCS revealed interactive effects on the ability to inhibit responses. Both MPH and atDCS modulated task-related theta oscillations in the supplementary motor area (SMA) when applied separately, making a common underlying mechanism likely. When both stimulation methods were combined, there was no doubling of effects in the SMA, but a shift to inferior frontal areas in the cortical network responsible for theta-driven processing. CONCLUSIONS: The results indicate that both MPH and atDCS likely share a common underlying neuronal mechanism, and interestingly, they demonstrate interactive effects when combined, which are most likely due to the physical limitations of gain control increases. The current study provides critical groundwork for future combined applications of MPH and non-invasive brain stimulation.

Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users - A comparative neurophysiological study.

In stimulant use and addiction, conflict control processes are crucial for regulating substance use and sustaining abstinence, which can be particularly challenging in social-affective situations. Users of methamphetamine (METH, "Ice") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") both experience impulse control deficits, but display different social-affective and addictive profiles. We thus aimed to compare the effects of chronic use of the substituted amphetamines METH and MDMA on conflict control processes in different social-affective contexts (i.e., anger and happiness) and investigate their underlying neurophysiological mechanisms. For this purpose, chronic but recently abstinent users of METH (n = 38) and MDMA (n = 42), as well as amphetamine-naïve healthy controls (n = 83) performed an emotional face-word Stroop paradigm, while event-related potentials (ERPs) were recorded. Instead of substance-specific differences, both MDMA and METH users showed smaller behavioral effects of cognitive-emotional conflict processing (independently of emotional valence) and selective deficits in emotional processing of anger content. Both effects were underpinned by stronger P3 ERP modulations suggesting that users of substituted amphetamines employ altered stimulus-response mapping and decision-making. Given that these processes are modulated by noradrenaline and that both MDMA and METH use may be associated with noradrenergic dysfunctions, the noradrenaline system may underlie the observed substance-related similarities. Better understanding the functional relevance of this currently still under-researched neurotransmitter and its functional changes in chronic users of substituted amphetamines is thus an important avenue for future research.

Gamma-Aminobutyric Acid and Glutamate Concentrations in the Striatum and Anterior Cingulate Cortex Not Found to Be Associated with Cognitive Flexibility.

Behavioral flexibility and goal-directed behavior heavily depend on fronto-striatal networks. Within these circuits, gamma-aminobutyric acid (GABA) and glutamate play an important role in (motor) response inhibition, but it has remained largely unclear whether they are also relevant for cognitive inhibition. We hence investigated the functional role of these transmitters for cognitive inhibition during cognitive flexibility. Healthy young adults performed two paradigms assessing different aspects of cognitive flexibility. Magnetic resonance spectroscopy (MRS) was used to quantify GABA+ and total glutamate/glutamine (Glx) levels in the striatum and anterior cingulate cortex (ACC) referenced to N-acetylaspartate (NAA). We observed typical task switching and backward inhibition effects, but striatal and ACC concentrations of GABA+/NAA and Glx/NAA were not associated with cognitive flexibility in a functionally relevant manner. The assumption of null effects was underpinned by Bayesian testing. These findings suggest that behavioral and cognitive inhibition are functionally distinct faculties, that depend on (at least partly) different brain structures and neurotransmitter systems. While previous studies consistently demonstrated that motor response inhibition is modulated by ACC and striatal GABA levels, our results suggest that the functionally distinct cognitive inhibition required for successful switching is not, or at least to a much lesser degree, modulated by these factors.

The functional connectome of 3,4-methyldioxymethamphetamine-related declarative memory impairments.

The chronic intake of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") bears a strong risk for sustained declarative memory impairments. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. To uncover alterations in the whole brain connectome between groups, we employed a data-driven multi-voxel pattern analysis (MVPA) approach on participants' resting-state functional magnetic resonance imaging data. Recent MDMA use was confirmed by hair analyses. MDMA users showed lower performance in delayed recall across tasks compared to well-matched controls with moderate-to-strong effect sizes. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. Post hoc seed-based connectivity analyses with this cluster unraveled hypoconnectivity to temporal areas belonging to the auditory network and hyperconnectivity to dorsal parietal regions belonging to the dorsal attention network in MDMA users. Seed-based connectivity strength was associated with verbal memory performance in the whole sample as well as with MDMA intake patterns in the user group. Our findings suggest that functional underpinnings of MDMA-related memory impairments encompass altered patterns of multimodal sensory integration within auditory processing regions to a functional heteromodal connector hub, the left postcentral gyrus. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing.

Pilot study on the influence of acute alcohol exposure on biophysical parameters of leukocytes.

Objective: This pilot study explores the influence of acute alcohol exposure on cell mechanical properties of steady-state and activated leukocytes conducted with real-time deformability cytometry. Methods: Nineteen healthy male volunteers were enrolled to investigate the effect of binge drinking on biophysical properties and cell counts of peripheral blood leukocytes. Each participant consumed an individualized amount of alcohol to achieve a blood alcohol concentration of 1.2 ‰ as a mean peak. In addition, we also incubated whole blood samples from healthy donors with various ethanol concentrations and performed stimulation experiments using lipopolysaccharide and CytoStim™ in the presence of ethanol. Results: Our findings indicate that the biophysical properties of steady-state leukocytes are not significantly affected by a single episode of binge drinking within the first two hours. However, we observed significant alterations in relative cell counts and a shift toward a memory T cell phenotype. Moreover, exposure to ethanol during stimulation appears to inhibit the cytoskeleton reorganization of monocytes, as evidenced by a hindered increase in cell deformability. Conclusion: Our observations indicate the promising potential of cell mechanical analysis in understanding the influence of ethanol on immune cell functions. Nevertheless, additional investigations in this field are warranted to validate biophysical properties as biomarkers or prognostic indicators for alcohol-related changes in the immune system.

Neurophysiological mechanisms underlying the differential effect of reward prospect on response selection and inhibition.

Reward and cognitive control play crucial roles in shaping goal-directed behavior. Yet, the behavioral and neural underpinnings of interactive effects of both processes in driving our actions towards a particular goal have remained rather unclear. Given the importance of inhibitory control, we investigated the effect of reward prospect on the modulatory influence of automatic versus controlled processes during response inhibition. For this, a performance-contingent monetary reward for both correct response selection and response inhibition was added to a Simon NoGo task, which manipulates the relationship of automatic and controlled processes in Go and NoGo trials. A neurophysiological approach was used by combining EEG temporal signal decomposition and source localization methods. Compared to a non-rewarded control group, rewarded participants showed faster response execution, as well as overall lower response selection and inhibition accuracy (shifted speed-accuracy tradeoff). Interestingly, the reward group displayed a larger interference of the interactive effects of automatic versus controlled processes during response inhibition (i.e., a larger Simon NoGo effect), but not during response selection. The reward-specific behavioral effect was mirrored by the P3 amplitude, underlining the importance of stimulus-response association processes in explaining variability in response inhibition performance. The selective reward-induced neurophysiological modulation was associated with lower activation differences in relevant structures spanning the inferior frontal and parietal cortex, as well as higher activation differences in the somatosensory cortex. Taken together, this study highlights relevant neuroanatomical structures underlying selective reward effects on response inhibition and extends previous reports on the possible detrimental effect of reward-triggered performance trade-offs on cognitive control processes.

The Impact of COVID-19 Lockdowns in Germany on Mood, Attention Control, Immune Fitness, and Quality of Life of Young Adults with Self-Reported Impaired Wound Healing.

BACKGROUND: Previous studies in Dutch young adults revealed that individuals with self-reported impaired wound healing reported poorer mood, increased inattention and impulsivity, poorer quality of life, and poorer immune fitness compared to healthy controls. Another study revealed that the negative impact of lockdowns during the 2019 coronavirus disease (COVID-19) pandemic was significantly more profound among the impaired wound healing group than the control group. The purpose of the current study was to replicate and extend these findings among young adults living in Germany. METHODS: A retrospective, cross-sectional survey was conducted among N = 317 young adults living in Germany, 18-35 years old. They were allocated to the IWH group (N = 66) or the control group (N-251). Participants completed the Attention Control Scale, and mood, quality of life, and immune fitness were assessed with single-item ratings. All assessments were made for (1) the period before the COVID-19 pandemic, (2) the first lockdown period, March-May 2020, (3) the first no-lockdown period, summer 2020, (4) the second lockdown, November 2020 to May 2021, and (5) the second no-lockdown period, summer 2021. RESULTS: The impaired wound healing group reported significantly poorer mood, quality of life, and immune fitness. The effects were evident before the pandemic. The impaired wound healing group scored significantly poorer on attention focusing, but no significant differences between the groups were found for attention shifting. During the pandemic, negative lockdown effects (i.e., further aggravation of mood and immune fitness and lower quality of life) were evident in both groups but significantly more profound in the impaired wound healing group. No differences between the groups were found for the no-lockdown periods. CONCLUSION: Individuals with self-reported impaired wound healing have significantly poorer mood, attention focusing, and immune fitness and report a poorer quality of life than healthy controls. The impact of COVID-19 lockdowns was significantly more profound in the impaired wound-healing group.

Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. METHODS: We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. RESULTS: Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. CONCLUSION: Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

Aperiodic neural activity reflects metacontrol.

Higher-level cognitive functions are mediated via complex oscillatory activity patterns and its analysis is dominating cognitive neuroscience research. However, besides oscillatory (period) activity, also aperiodic activity constitutes neural dynamics, but its relevance for higher-level cognitive functions is only beginning to be understood. The present study examined whether the broadband EEG aperiodic activity reflects principles of metacontrol. Metacontrol conceptualizes whether it is more useful to engage in more flexible processing of incoming information or to shield cognitive processes from incoming information (persistence-heavy processing). We examined EEG and behavioral data from a sample of n = 191 healthy participants performing a Simon Go/NoGo task that can be assumed to induce different metacontrol states (persistence-biased vs. flexibility-biased). Aperiodic activity was estimated using the FOOOF toolbox in the EEG power spectrum. There was a higher aperiodic exponent and offset in NoGo trials compared with Go trials, in incongruent (Go) trials compared with congruent (Go) trials. Thus, aperiodic activity increases during persistence-heavy processing, but decreases during flexibility-heavy processing. These findings link aperiodic features of the EEG signal and concepts describing the dynamics of how cognitive control modes are applied. Therefore, the study substantially extends the importance of aperiodic activity in understanding cognitive functions.

Striatal Iron Deposition in Recreational MDMA (Ecstasy) Users.

BACKGROUND: The common club drug MDMA (also known as ecstasy) enhances mood, sensory perception, energy, sociability, and euphoria. While MDMA has been shown to produce neurotoxicity in animal models, research on its potential neurotoxic effects in humans is inconclusive and has focused primarily on the serotonin system. METHODS: We investigated 34 regular, largely pure MDMA users for signs of premature neurodegenerative processes in the form of increased iron load in comparison to a group of 36 age-, sex-, and education-matched MDMA-naïve control subjects. We used quantitative susceptibility mapping, a novel tool able to detect even small tissue (nonheme) iron accumulations. Cortical and relevant subcortical gray matter structures were grouped into 8 regions of interest and analyzed. RESULTS: Significantly increased iron deposition in the striatum was evident in the MDMA user group. The effect survived correction for multiple comparisons and remained after controlling for relevant confounding factors, including age, smoking, and stimulant co-use. Although no significant linear relationship between measurements of the amounts of MDMA intake (hair analysis and self-reports) and quantitative susceptibility mapping values was observed, increased striatal iron deposition might nevertheless point to MDMA-induced neurotoxic processes. Additional factors (hyperthermia and simultaneous co-use of other substances) that possibly amplify neurotoxic effects of MDMA during the state of acute intoxication are discussed. CONCLUSIONS: The demonstrated increased striatal iron accumulation may indicate that regular MDMA users have an increased risk potential for neurodegenerative diseases with progressing age.

Alcohol-induced deficits in reactive control of response selection and inhibition are counteracted by a seemingly paradox increase in proactive control.

High-dose alcohol intoxication reduces cognitive control, including inhibition. Although inhibition deficits may contribute to the behavioral deficits commonly observed in alcohol use disorder (AUD), many questions about potentially modulating factors have remained unanswered. We examined the effects of experimentally induced high-dose alcohol intoxication (~ 1.1 ‰) on the interplay between controlled vs. automatic response selection and inhibition in healthy young men. A holistic EEG-based theta activity analysis that considered both reactive control during task performance and preceding proactive control processes was run. It revealed a previously unknown seesaw relationship, with decreased reactive control, but paradoxically increased proactive control. Most importantly, alcohol-induced increases in proactive occipital theta band power were associated with reductions in negative alcohol effects on reactive control processes associated with decreased activity in the SMA and medial frontal cortex. Our findings demonstrate that research should not solely focus on immediate effects during task performance. Aside from differential neurobiochemical and neuroanatomical effects of alcohol, it is also conceivable that proactive control may have been recruited in a (secondary) response to compensate for alcohol-induced impairments in reactive control. Against this background, it could be promising to investigate changes in such compensatory mechanisms in pronounced alcohol-associated inhibition deficits, like in AUD patients.

Neurophysiological principles of inhibitory control processes during cognitive flexibility.

Inhibitory control plays an indispensable role in cognitive flexibility. Nevertheless, the neurophysiological principles underlying this are incompletely understood. This owes to the fact that the representational dynamics, as coded in oscillatory neural activity of different frequency bands has not been considered until now-despite being of conceptual relevance. Moreover, it is unclear in how far distinct functional neuroanatomical regions are concomitantly involved in the processing of representational dynamics. We examine these questions using a combination of EEG methods. We show that theta-band activity plays an essential role for inhibitory control processes during cognitive flexibility across informational aspects coded in distinct fractions of the neurophysiological signal. It is shown that posterior parietal structures and the inferior parietal cortex seem to be the most important cortical region for inhibitory control processes during cognitive flexibility. Theta-band activity plays an essential role in processes of retrieving the previously inhibited representations related to the current task during cognitive flexibility. The representational content relevant for inhibitory processes during cognitive flexibility is coded in the theta frequency band. We outline how the observed neural mechanisms inform recent overarching cognitive frameworks on how flexible action control is accomplished.

The role of visual association cortices during response selection processes in interference-modulated response stopping.

Response inhibition and the ability to navigate distracting information are both integral parts of cognitive control and are imperative to adaptive behavior in everyday life. Thus far, research has only inconclusively been able to draw inferences regarding the association between response stopping and the effects of interfering information. Using a novel combination of the Simon task and a stop signal task, the current study set out to investigate the behavioral as well as the neurophysiological underpinnings of the relationship between response stopping and interference processing. We tested n = 27 healthy individuals and combined temporal EEG signal decomposition with source localization methods to delineate the precise neurophysiological dynamics and functional neuroanatomical structures associated with conflict effects on response stopping. The results showed that stopping performance was compromised by conflicts. Importantly, these behavioral effects were reflected by specific aspects of information coded in the neurophysiological signal, indicating that conflict effects during response stopping are not mediated via purely perceptual processes. Rather, it is the processing of specific, stop-relevant stimulus features in the sensory regions during response selection, which underlies the emergence of conflict effects in response stopping. The findings connect research regarding response stopping with overarching theoretical frameworks of perception-action integration.

Does chronic use of amphetamine-type stimulants impair interference control? - A meta-analysis.

In substance use and addiction, inhibitory control is key to ignoring triggers, withstanding craving and maintaining abstinence. In amphetamine-type stimulant (ATS) users, most research focused on behavioral inhibition, but largely neglected the equally important subdomain of cognitive interference control. Given its crucial role in managing consumption, we investigated the relationship between interference control and chronic ATS use in adults. A database search (Pubmed & Web of Science) and relevant reviews were used to identify eligible studies. Effect sizes were estimated with random effects models. Subgroup, meta-regression, and sensitivity analyses explored heterogeneity in effect sizes. We identified 61 studies (53 datasets) assessing interference control in 1873 ATS users and 1905 controls. Findings revealed robust small effect sizes for ATS-related deficits in interference control, which were mainly seen in methamphetamine, as compared to MDMA users. The differential effects are likely due to tolerance-induced dopaminergic deficiencies (presumably most pronounced in methamphetamine users). Similarities between different ATS could be due to noradrenergic deficiencies; but elucidating their functional role in ATS users requires further/more research.

Evidence for independent representational contents in inhibitory control subprocesses associated with frontoparietal cortices.

Inhibitory control processes have intensively been studied in cognitive science for the past decades. Even though the neural dynamics underlying these processes are increasingly better understood, a critical open question is how the representational dynamics of the inhibitory control processes are modulated when engaging in response inhibition in a relatively automatic or a controlled mode. Against the background of an overarching theory of perception-action integration, we combine temporal and spatial EEG signal decomposition methods with multivariate pattern analysis and source localization to obtain fine-grained insights into the neural dynamics of the representational content of response inhibition. For this purpose, we used a sample of N = 40 healthy adult participants. The behavioural data suggest that response inhibition was better in a more controlled than a more automated response execution mode. Regarding neural dynamics, effects of response inhibition modes relied on a concomitant coding of stimulus-related information and rules of how stimulus information is related to the appropriate motor programme. Crucially, these fractions of information, which are encoded at the same time in the neurophysiological signal, are based on two independent spatial neurophysiological activity patterns, also showing differences in the temporal stability of the representational content. Source localizations revealed that the precuneus and inferior parietal cortex regions are more relevant than prefrontal areas for the representation of stimulus-response selection codes. We provide a blueprint how a concatenation of EEG signal analysis methods, capturing distinct aspects of neural dynamics, can be connected to cognitive science theory on the importance of representations in action control.

On the Role of Stimulus-Response Context in Inhibitory Control in Alcohol Use Disorder.

The behavioral and neural dynamics of response inhibition deficits in alcohol use disorder (AUD) are still largely unclear, despite them possibly being key to the mechanistic understanding of the disorder. Our study investigated the effect of automatic vs. controlled processing during response inhibition in participants with mild-to-moderate AUD and matched healthy controls. For this, a Simon Nogo task was combined with EEG signal decomposition, multivariate pattern analysis (MVPA), and source localization methods. The final sample comprised n = 59 (32♂) AUD participants and n = 64 (28♂) control participants. Compared with the control group, AUD participants showed overall better response inhibition performance. Furthermore, the AUD group was less influenced by the modulatory effect of automatic vs. controlled processes during response inhibition (i.e., had a smaller Simon Nogo effect). The neurophysiological data revealed that the reduced Simon Nogo effect in the AUD group was associated with reduced activation differences between congruent and incongruent Nogo trials in the inferior and middle frontal gyrus. Notably, the drinking frequency (but not the number of AUD criteria we had used to distinguish groups) predicted the extent of the Simon Nogo effect. We suggest that the counterintuitive advantage of participants with mild-to-moderate AUD over those in the control group could be explained by the allostatic model of drinking effects.

White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a serotonin- and noradrenaline-releasing substance, currently among the most widely used illicit substances worldwide. In animal studies, repeated exposure to MDMA has been associated with dendritic but also axonal degeneration in the brain. However, translation of the axonal findings, specifically, to humans has been repeatedly questioned and the few existing studies investigating white matter alterations in human chronic MDMA users have yielded conflicting findings. In this study, we combined whole-brain diffusion tensor imaging and neurofilament light chain (NfL) analysis in blood to reveal potential MDMA-induced axonal neuropathology. To this end, we assessed 39 chronic MDMA users and 39 matched MDMA-naïve healthy controls. MDMA users showed increased fractional anisotropy in several white matter tracts, most prominently in the corpus callosum as well as corticospinal tracts, with these findings partly related to MDMA use intensity. However, the NfL levels of MDMA users were not significantly different from those of controls. We conclude that MDMA use is not associated with significant white matter lesions due to the absence of reduced fractional anisotropy and increased NfL levels commonly observed in conditions associated with white matter lesions, including stimulant and ketamine use disorders. Hence, the MDMA-induced axonal degradation demonstrated in animal models was not observed in this human study of chronic MDMA users.

The importance of resource allocation for the interplay between automatic and cognitive control in response inhibition - An EEG source localization study.

Goal-directed behavior often requires the inhibition of prepotent automatic responses. Response inhibition encompasses several top-down cognitive operations embedded in a neural network extending from fronto-cortical regions to subcortical nuclei. Yet, it has remained unclear whether the early allocation of cognitive resources also modulates response inhibition performance and neural structures involved in this process. To investigate this question, we used a Simon Nogo task, which was designed to manipulate the relationship between automaticity and cognitive control during response inhibition, and combined it with an electroencephalogram (EEG) and source localization approach. We showed that the early allocation of cognitive resources, as reflected by the P2 amplitude, might be a critical determinant in the interplay between automaticity and cognitive control in response inhibition. Specifically, the obtained results demonstrated that individual variations in cognitive resource allocation modulated the need for conflict monitoring and engagement in cognitive control processes, as reflected by N2 and P3b amplitudes, respectively. Importantly, larger P2 amplitudes were associated with higher activation in cortical regions encompassing the temporo-parietal junction (TPJ). This stresses the importance of this cortical region for the encoding of relevant stimulus information to resolve conflicting contexts in response inhibition. The increased cognitive control in more automatic contexts was also reflected by higher activation of the superior and medial frontal cortices. These findings provide a new perspective on response inhibition, suggesting that early resource allocation is a central modulator of the interaction between automaticity and cognitive control.