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.

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 methylphenidate (MPH) and transcranial direct current stimulation (tDCS) share common underlying mechanisms and cognitive effects, we administered MPH and anodal tDCS (atDCS) over the right inferior frontal gyrus both separately and combined, while healthy adult participants (n = 104) performed a 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 when applied separately, making a common underlying mechanism likely. When both stimulation methods were combined, there was no doubling of effects in the supplementary motor area 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.

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.

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.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

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.

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.

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.

Pretrial Theta Band Activity Affects Context-dependent Modulation of Response Inhibition.

The ability to inhibit a prepotent response is a crucial prerequisite of goal-directed behavior. So far, research on response inhibition has mainly examined these processes when there is little to no cognitive control during the decision to respond. We manipulated the "context" in which response inhibition has to be exerted (i.e., a controlled or an automated context) by combining a Simon task with a go/no-go task and focused on theta band activity. To investigate the role of "context" in response inhibition, we also examined how far theta band activity in the pretrial period modulates context-dependent variations of theta band activity during response inhibition. This was done in an EEG study applying beamforming methods. Here, we examined n = 43 individuals. We show that an automated context, as opposed to a controlled context, compromises response inhibition performance and increases the need for cognitive control. This was also related to context-dependent modulations of theta band activity in superior frontal and middle frontal regions. Of note, results showed that theta band activity in the pretrial period, associated with the right inferior frontal cortex, was substantially correlated with context-dependent modulations of theta band activity during response inhibition. The direction of the obtained correlation provides insights into the functional relevance of a pretrial theta band activity. The data suggest that pretrial theta band activity reflects some form of attentional sampling to inform possible upcoming processes signaling the need for cognitive control.

Auricular transcutaneous vagus nerve stimulation for alcohol use disorder: A chance to improve treatment?

Alcohol use disorder (AUD) is a relapsing-remitting condition characterized by excessive and/or continued alcohol consumption despite harmful consequences. New adjuvant tools, such as noninvasive brain stimulation techniques, might be helpful additions to conventional treatment approaches or even provide an alternative option for patients who fail to respond adequately to other treatment options. Here, we discuss the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON intervention in AUD. Compared with other techniques, atVNS has the advantage of directly stimulating nuclei that synthesize GABA and catecholamines, both of which are functionally altered by alcohol intake in AUD patients. Pharmacological options targeting those neurotransmitters are widely available, but have relatively limited beneficial effects on cognition, even though restoring normal cognitive functioning, especially cognitive control, is key to maintaining abstinence. Against this background, atVNS could be a particularly useful add-on because there is substantial meta-analytic evidence based on studies in healthy individuals that atVNS can enhance cognitive control processes that are crucial to regaining control over drug intake. We discuss essential future research on using atVNS as an ADD-ON intervention in AUD to enhance clinical and cognitive outcomes by providing a translational application. Given that this novel technique can be worn like an earpiece and can be employed without medical supervision/outside the clinical settings, atVNS could be well integratable into the daily life of the patients, where the task of regaining control over drug intake is most challenging.

On the functional role of striatal and anterior cingulate GABA+ in stimulus-response binding.

Successful response selection relies on constantly updating stimulus-response associations. The Theory of Event Coding (TEC) proposes that perception and action are conjointly coded in event files, for which fronto-striatal networks seem to play an important role. However, the exact neurobiochemical mechanism behind event file coding has remained unknown. We investigated the functional relevance of the striatal and anterior cingulate (ACC) GABAergic system using magnetic resonance spectroscopy (MRS). Specifically, the striatal and ACC concentrations of GABA+ referenced against N-acetylaspartate (NAA) were assessed in 35 young healthy males, who subsequently performed a standard event file task. As predicted by the TEC, the participants' responses were modulated by pre-established stimulus response bindings in event files. GABA+/NAA concentrations in the striatum and ACC were not correlated with the overall event binding effect. However, higher GABA+/NAA concentrations in the ACC were correlated with stronger event file binding processes in the early phase of the task. This association disappeared by the end of the task. Taken together, our findings show that striatal GABA+ levels does not seem to modulate event file binding, while ACC GABA+ seem to improve event file binding, but only as long as the participants have not yet gathered sufficient task experience. To the best of our knowledge, this is the first study providing direct evidence for the role of striatal and ACC GABA+ in stimulus-response bindings and thus insights into the brain structure-specific neurobiological aspects of the TEC.

An Oppositional Tolerance Account for Potential Cognitive Deficits Caused by the Discontinuation of Antidepressant Drugs.

Depression is the leading cause of disability worldwide, making antidepressant drugs the most used psychiatric drugs in the USA. Withdrawal effects and rebound symptoms frequently occur after the reduction and/or discontinuation of these drugs. Although these phenomena have been investigated with respect to the clinical symptomatology, no studies have systematically investigated the effects of withdrawal/rebound on general cognition. We present a novel framework based on the idea of allostatic adaptation, which allows to predict how different antidepressants likely impair different cognitive processes as a result of withdrawal and rebound effects. This framework relies on the assumptions that the type of cognitive impairments evoked by an antidepressant is determined by the targeted neurotransmitter systems, while the severity of deficits depends on its half-life. Our model predicts that the severity of detrimental cognitive withdrawal and rebound effects increases with a shorter half-life of the discontinued antidepressant drug. It further proposes drug-specific effects: antidepressants mainly targeting serotonin should primarily impair aversive and emotional processing, those targeting norepinephrine should impair the processing of alerting signals, those targeting dopamine should impair motivational processes and reward processing, and those targeting acetylcholine should impair spatial learning and memory. We hope that this framework will motivate further research to better understand and explain cognitive changes as a consequence of antidepressant discontinuation.

Automatic aspects of response selection remain unchanged during high-dose alcohol intoxication.

Regular binge-drinking increases the risk of developing alcohol use disorder (AUD) and induces similar acute effects on behavioral control, particularly in case of response selection conflicts. No such effects have been reported for automatic/bottom-up response selection, even though AUD alters automaticity. However, it has never been reliably tested whether this domain is truly unchanged during high-dose alcohol intoxication. To investigate this question with the help of Bayesian analyses, we subjected n=31 young healthy male participants to a within-subject design, where each participant was tested twice in a counter-balanced order (ie, once sober and once intoxicated at 1.1‰). On each appointment, the participants performed the S-R paradigm, which assesses automatic stimulus-response (S-R) binding within the framework of the theory of event coding (TEC). In short, the TEC states that stimulus features and responses become encoded in an event file when they occur simultaneously. These event files will be reactivated by any matching stimulus feature, thus facilitating the encoded response (and hampering different responses). Alcohol led to a general decrease in behavioral performance, as demonstrated by significant main effects of intoxication status on accuracy and response times (all P ≤ .009). We also reproduced typical task effects, but did not find any significant interactions with the intoxication factor (all P ≥ .099). The latter was further substantiated by Bayesian analyses providing positive to strong evidence for the null hypothesis. Taken together, our results demonstrate that even high-dose alcohol intoxication does not impair automatic response selection/S-R associations.

Acute alcohol intoxication modulates the temporal dynamics of resting electroencephalography networks.

This study aimed to provide a currently missing link between general intoxication-induced changes in overall brain activity and the multiple cognitive control deficits typically observed during acute alcohol intoxication. For that purpose, we analyzed the effects of acute alcohol intoxication (1.1‰) on the four archetypal electroencephalography (EEG) resting networks (i.e., microstates A-D) and their temporal dynamics (e.g., coverage and transitions from one microstate to another), as well as on self-reported resting-state cognition in n = 22 healthy young males using a counterbalanced within-subject design. Our microstate analyses indicated that alcohol increased the coverage of the visual processing-related microstate B at the expense of the autonomic processing-related microstate C. Add-on exploratory analyses revealed that alcohol increased transitions from microstate C to microstate B and decreased bidirectional transitions between microstate C and the attention-related microstate D. In line with the observed alcohol-induced decrease of the autonomic processing-related microstate C, participants reported decreases of their somatic awareness during intoxication, which were positively associated with more transitions from microstate C to microstate B. In sum, the observed effects provide mechanistic insights into how alcohol might hamper cognitive processing by generally prioritizing the bottom-up processing of visual stimuli over top-down internal information processing. The fact that this was found during the resting state further proves that alcohol-induced changes in brain activity are continuously present and do not only emerge during demanding situations or tasks.

Using temporal EEG signal decomposition to identify specific neurophysiological correlates of distractor-response bindings proposed by the theory of event coding.

The ability to cope with distracting information is a major requirement for goal-directed behavior. It is particularly challenged when distracting information is either potentially relevant or temporally close to goal-directed responses, resulting in so-called distractor-response bindings. According to the theory of event coding (TEC), distractor-response bindings should be reflected by processes in the event file, but not in object file (which stores stimulus features) or the action file (which stores response features). But even though the predictions of this theory are quite elaborated, their electrophysiological underpinnings and the associated functional neuroanatomical structures have remained largely elusive. To examine this, we used a distractor-response binding paradigm in combination with temporal EEG signal decomposition (RIDE) and source localization techniques. We showed that distractor-response binding effects are exclusively evident in the N450 time window of the central C-cluster. Source reconstructions revealed that distractor-response binding effects were associated with brain regions involved in updating internal representations by using task-relevant information to decide on response execution (temporo-parietal junction, BA40), alongside with brain regions involved in conflict resolution processes (right middle frontal gyrus, BA8). Our results suggest that RIDE can be used to dissociate binding processes from stimulus- and response-related processes. On top of this, the results of EEG decomposition match the key assumption of the TEC, that distractor-response bindings occur in event files, but not in object files or action files. The results show how cognitive-theoretical frameworks, such as the TEC, can directly be mapped onto the underlying neurophysiological processes using EEG signal decomposition.

Dopamine D1, but not D2, signaling protects mental representations from distracting bottom-up influences.

Goal-directed behavior is affected by subliminally and consciously induced conflicts. Both seem to be modulated by catecholamines, especially dopamine. On the basis of cognitive theoretical and neurobiological considerations, we investigated the effects of dopamine D1 and D2 signaling with the help of unweighted polygenic scores in n = 207 healthy young human subjects. We used a task that combines subliminal primes with conscious flankers to induce conflicts. Dopamine D1 scores were formed based on DRD1 rs4532, CALY rs2298122 and TH rs10770141 single nucleotide polymorphisms (SNPs), while dopamine D2 scores were formed based on DRD2 rs6277 and NPY2R rs2234759 SNPs. We used EEG recordings and source localization analyses to identify differentially modulated neurophysiological sub-processes and functional neuroanatomical structures. Increased dopamine D1 signaling was associated with decreases in consciously induced conflicts. This decrease was due to enhanced stimulus-response mapping in the premotor cortex (BA6), as reflected by an increased P3 amplitude in incongruent trials. Attentional processes remained unaffected by dopamine D1 signaling. The effect of dopamine D2 signaling on conscious conflicts did not reach significance. Subliminally induced conflicts were neither modulated by dopamine D1, nor by dopamine D2 signaling. Our findings suggest that dopamine D1 signaling benefits consciously induced conflicts, presumably by improving the suppression of distracting information via gain control-initiated increases in top-down control processes associated with pre-motor regions. Dopamine D2 signaling does not seem to mediate behavioral differences. Probably, this is because the D2 state facilitates switching between (conflicting) top-down-selected mental representations, but not necessarily between top-down processes and bottom-up distractor information.

High-dose ethanol intoxication decreases 1/f neural noise or scale-free neural activity in the resting state.

Binge drinking is a frequent phenomenon in many western societies and has been associated with an increased risk of developing alcohol use disorder later in life. Yet, the effects of high-dose alcohol intoxication on neurophysiological processes are still quite poorly understood. This is particularly the case given that neurophysiological brain activity not only contains recurring (oscillatory) patterns of activity, but also a significant fraction of "scale-free" or arrhythmic dynamics referred to as 1/f type activity, pink noise, or 1/f neural noise. Neurobiological considerations suggest that it should be modulated by alcohol intoxication. To investigate this assumption, we collected resting state EEG data from n = 23 healthy young male subjects in a crossover design, where each subject was once tested sober and once tested while intoxicated (mean breath alcohol concentration of 1.1 permille ±0.2). Analyses of the 1/f neural dynamics showed that ethanol intoxication decreased resting state 1/f neural noise, as compared with a sober state. The effects were strongest when the eyes were closed and particularly reliable in the beta frequency band. Given that the dynamics of the beta band have been shown to strongly depend on GABAA receptor neural transmission, this finding nicely aligns with the fact that ethanol increases GABAergic signaling. The study reveals a currently unreported effect of binge drinking on neurophysiological dynamics, which likely revealed a higher sensitivity for ethanol effects than most commonly considered measures of power in neural oscillations. Implications and applicability of these findings are discussed.

How high-dose alcohol intoxication affects the interplay of automatic and controlled processes.

Binge drinking is an increasingly prevalent pattern of alcohol consumption that impairs top-down cognitive control to a much stronger degree than automatic response generation. Even though an imbalance of those two antagonistic processes fosters the development and maintenance of alcohol use disorders (AUDs), it has never been directly investigated how binge drinking affects the interaction of those two processes. We therefore assessed a sample of n = 35 healthy young men who were asked to perform a newly developed Simon Nogo paradigm once sober and once intoxicated (~1.2‰) in a balanced within-subject design. Additionally, an EEG was recorded to dissociate controlled and automatic cognitive subprocesses. The results demonstrate that alcohol seems to reduce top-down cognitive control. This control impairment was associated with changes in S-R mapping (reflected by a reduced parietal P3 amplitude), top-down response selection (reflected by modulations of lateralized readiness potentials), and (the evaluation of) response inhibition (reflected by modulations of the Nogo P3). In sharp contrast to this, automatic processing does not seem to be equally altered, as we found neither increases nor decreases in this domain. Most importantly, we also found that the interaction between control and automatisms might be less impaired by alcohol than control alone, which may help to overcome alcohol-induced response inhibition deficits. These "carryover" effects of control from one domain to the other could potentially prove beneficial in AUDs.

Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

Apolipoprotein ε4 is associated with better cognitive control allocation in healthy young adults.

Many gene variants may impair our health and cognitive abilities at old age, but some of them paradoxically improve the same or similar functions at much younger age (antagonistic pleiotropy hypothesis). Such a diametric pattern may also hold true for the ancestral Apolipoprotein E (APOE) ε4 allele, which increases the risk for Alzheimer's disease and cognitive decline in old age, but may benefit (pre)frontal (executive) functions in young carriers. We therefore investigated potential cognitive benefits of the risk allele on cognitive control capacities and top-down control allocation ("metacontrol") in n = 190 healthy young adults. On a behavioral level, we found young APOE ε4 carriers to better adapt to different degrees of cognitive control requirements, with superior performance in case of high control demands. On a neurophysiological level, these group differences were reflected by modulations of the N450 component, which were rooted in activation differences of the superior frontal gyrus (SFG, BA8). Taken together, our results suggest that young ε4 carriers are more efficient than non-carriers at allocating cognitive control resources based on the actual task requirements (i.e. metacontrol), as they seem to experience less conflict/exert less effort and recruit fewer additional prefrontal areas when task set complexity increases. We further found that ε2 carriers processed implicit spatial stimulus features to a stronger degree than ε3 and ε4 carriers, but failed to benefit from this, as the additional information likely increased response selection conflicts. This finding should however be treated with ample caution as the group of ε2 carriers was comparatively small.