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.

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.

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.

The Role of DRD1 and DRD2 Receptors for Response Selection Under Varying Complexity Levels: Implications for Metacontrol Processes.

BACKGROUND: Highly complex tasks generally benefit from increases in cognitive control, which has been linked to dopamine. Yet, the same amount of control may actually be detrimental in tasks with low complexity so that the task-dependent allocation of cognitive control resources (also known as "metacontrol") is key to expedient and adaptive behavior in various contexts. METHODS: Given that dopamine D1 and D2 receptors have been suggested to exert opposing effects on cognitive control, we investigated the impact of 2 single nucleotide polymorphisms in the DRD1 (rs4532) and DRD2 (rs6277) genes on metacontrol in 195 healthy young adults. Subjects performed 2 consecutive tasks that differed in their demand for control (starting with the less complex task and then performing a more complex task rule). RESULTS: We found carriers of the DRD1 rs4532 G allele to outperform noncarriers in case of high control requirements (i.e., reveal a better response accuracy), but not in case of low control requirements. This was confirmed by Bayesian analyses. No effects of DRD2 rs6277 genotype on either task were evident, again confirmed by Bayesian analyses. CONCLUSIONS: Our findings suggest that higher DRD1 receptor efficiency improves performance during high, but not low, control requirements, probably by promoting a "D1 state," which is characterized by highly stable task set representations. The null findings for DRD2 signaling might be explained by the fact that the "D2 state" is thought to enhance flexible switching between task set representations when our task only featured 1 task set at any given time.

Catecholaminergic Modulation of Conflict Control Depends on the Source of Conflicts.

Background: To display goal-directed behavior, we must be able to resolve response conflicts that arise from processing various distractors. Such conflicts may be triggered by different kinds of distractor stimuli (e.g., priming and flanker stimuli), but it has remained largely unclear whether the functional and neurobiological underpinnings of both conflict types differ. We therefore investigated the functional relevance of the catecholamines dopamine and norepinephrine, which have been shown to increase the signal-to-noise ratio in neuronal processing and should therefore modulate response conflicts. Methods: In a double-blind, randomized, placebo-controlled study design, we examined the effect of methylphenidate (0.5 mg/kg) on both flanker-induced and priming-induced response conflicts in a group of n=25 healthy young adults. We used EEG recordings to examine event-related potentials in combination with source localization analyses to identify the cognitive-neurophysiological subprocesses and functional neuroanatomical structures modulated by methylphenidate. Results: Compared with placebo, methylphenidate decreased flanker conflicts. This was matched by increased congruency effects in the fronto-central N2/P3 event-related potential complex and associated with modulations in the right inferior frontal gyrus. In contrast to this, methylphenidate did not modulate the size of prime-evoked conflicts. Conclusions: Our results suggest that catecholamine-driven increases in signal-to-noise ratio and neural gain control do not equally benefit differently evoked conflicts. This supports the hypothesis of an at least partly different neurobiological basis for flanker- and prime-evoked response conflicts. As the right inferior frontal gyrus plays an important role in inhibition, the catecholaminergic system may reduce flanker conflicts by supporting the inhibition of distracting information.

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.

Evidence for a causal role of superior frontal cortex theta oscillations during the processing of joint subliminal and conscious conflicts.

Consciously and subliminally processed information can both lead to conflicts that hinder goal-directed behaviour. Conflict monitoring processes are required to cope with situations where one or multiple conflicts occur. It has been suggested, that medial-frontal theta oscillations are associated with the implementation of cognitive control and that conflicts increase theta band activity. Still, a causal mechanistic understanding of theta oscillations during the resolution of combined subliminal and conscious conflicts is missing. To investigate this, we combined EEG signal decomposition methods with EEG beamforming approaches and used the obtained information to modulate theta oscillations with tACS in a second experiment. This showed that theta oscillations in the superior frontal cortex (BA6) and the left paracentral lobule encoded stimulus-related processes during the resolution of conflicts arising from both conscious and subliminal information processing. Response selection and motor-related processes encoded by theta oscillations were not similarly modulated. Thus, the joint modulation of conflicts by conscious and subliminal information affects very specific aspects of the information coded in theta oscillations. Results indicate, that entraining theta-oscillations using tACS modulates conflict resolution depending on the already existing theta activity level. In summary, the study provides further evidence that frontal theta oscillations play a crucial role in conflict monitoring and control.

Alcohol Hangover Does Not Alter the Application of Model-Based and Model-Free Learning Strategies.

Frequent alcohol binges shift behavior from goal-directed to habitual processing modes. This shift in reward-associated learning strategies plays a key role in the development and maintenance of alcohol use disorders and seems to persist during (early stages of) sobriety in at-risk drinkers. Yet still, it has remained unclear whether this phenomenon might be associated with alcohol hangover and thus also be found in social drinkers. In an experimental crossover design, n = 25 healthy young male participants performed a two-step decision-making task once sober and once hungover (i.e., when reaching sobriety after consuming 2.6 g of alcohol per estimated liter of total body water). This task allows the separation of effortful model-based and computationally less demanding model-free learning strategies. The experimental induction of alcohol hangover was successful, but we found no significant hangover effects on model-based and model-free learning scores, the balance between model-free and model-based valuation (ω), or perseveration tendencies (π). Bayesian analyses provided positive evidence for the null hypothesis for all measures except π (anecdotal evidence for the null hypothesis). Taken together, alcohol hangover, which results from a single binge drinking episode, does not impair the application of effortful and computationally costly model-based learning strategies and/or increase model-free learning strategies. This supports the notion that the behavioral deficits observed in at-risk drinkers are most likely not caused by the immediate aftereffects of individual binge drinking events.

Acute Alcohol Effects on Response Inhibition Depend on Response Automatization, but not on GABA or Glutamate Levels in the ACC and Striatum.

Alcohol increases GABAergic signaling and decreases glutamatergic signaling in the brain. Variations in these neurotransmitter levels may modulate/predict executive functioning. Matching this, strong impairments of response inhibition are one of the most consistently reported cognitive/behavioral effects of acute alcohol intoxication. However, it has never been investigated whether baseline differences in these neurotransmitters allow to predict how much alcohol intoxication impairs response inhibition, and whether this is reflected in neurophysiological measures of cognitive control. We used MR spectroscopy to assess baseline (i.e., sober) GABA and glutamate levels in the anterior cingulate cortex (ACC) and striatum in n = 30 healthy young males, who were subsequently tested once sober and once intoxicated (1.01 permille). Inhibition was assessed with the sustained attention to response task (SART). This paradigm also allows to examine the effect of different degrees of response automatization, which is a known modulator for response inhibition, but does not seem to be substantially impaired during acute intoxication. As a neurophysiological correlate of response inhibition and control, we quantified EEG-derived theta band power and located its source using beamforming analyses. We found that alcohol-induced response inhibition deficits only occurred in the case of response automatization. This was reflected by decreased theta band activity in the left supplementary motor area (SMA), which may reflect modulations in the encoding of a surprise signal in response to inhibition cues. However, we did not find that differences in baseline (i.e., sober) GABA or glutamate levels significantly modulated differences in the size of alcohol-induced inhibition deficits.

The Intensity of Early Attentional Processing, but Not Conflict Monitoring, Determines the Size of Subliminal Response Conflicts.

Response conflicts hamper goal-directed behavior and may be evoked by both consciously and subliminally (unconsciously) processed information. Yet, not much is known about the mechanisms and brain regions driving the size of subliminally induced conflicts. We hence combined a response conflict paradigm featuring subliminal primes and conscious flankers with in-depth neurophysiological (EEG) analyses, including source localization in a sample of N = 243 healthy subjects. Intra-individual differences in the size of subliminal conflicts were reflected both during early attentional stimulus processing (prime-associated N1 and target-associated P1 and N1 amplitudes) and conflict monitoring (N2 amplitudes). On the neuroanatomical level, this was reflected by activity modulations in the TPJ (BA39, BA40) and V2 (BA18), which are known to be involved in attentional stimulus processing and task set maintenance. In addition to a "standard" analysis of event-related potentials, we also conducted a purely data-driven machine learning approach using support vector machines (SVM) in order to identify neurophysiological features which do not only reflect the size of subliminal conflict, but actually allow to classify/predict it. This showed that only extremely early information processing (about 65 ms after the onset of the prime) was predictive of subliminal conflict size. Importantly, this predictive feature occurred before target information could even be processed and was reflected by activity in the left middle frontal gyrus (BA6) and insula (BA13). We conclude that differences in task set maintenance and potentially also in subliminal attentional processing of task-relevant features, but not conflict monitoring, determine the size of subliminally induced response conflicts.

Young frequent binge drinkers show no behavioral deficits in inhibitory control and cognitive flexibility.

Alcohol intoxication and abuse are well-known to cause impairments in executive functioning and control. Still, we know surprisingly little about individuals engaging in frequent binge drinking, even though they have an increased risk to develop an alcohol use disorder (AUD) later in life. As this risk has been suggested to be linked to (premorbid) executive deficits, we assessed changes in cognitive flexibility and inhibition with the help of a switching task and a stop-change task. Both paradigms had previously been shown to be modulated by alcohol, as well as by functional variations in dopaminergic and GABAergic neurotransmission. We employed an extreme group approach, where we compared pre-selected samples of frequent binge drinkers and non-frequent binge drinkers, all of which had stably pursued their respective consumption pattern for at least 3 years. In combination with Bayes analyses, our results showed that individuals engaging in frequent binge drinking showed no impairments of cognitive flexibility or inhibition, as compared to non-frequent binge drinkers. These observations suggest that frequent binge drinking alone is not associated with the cognitive control deficits commonly observed in AUD. Importantly, the investigated executive functions are known to be altered both during binge drinking and in individuals with AUD. It could hence be speculated that their intermittent consumption pattern prevents non-AUD frequent binge drinkers from the homeostatic counter-regulations of alcohol- and control-associated neurotransmitter systems that may be observed in AUD patients. Yet, this hypothesis still needs to be tested in future research, including studies that combine MR and molecular imaging.

CHRM2 Genotype Affects Inhibitory Control Mechanisms During Cognitive Flexibility.

The cholinergic system is one of the most important neurotransmitter systems, but knowledge about the relevance of the cholinergic muscarinergic receptor system for cognitive functions is still scarce. Evidence suggests that the cholinergic muscarinic 2 receptor (CHRM2) plays an important role in the processing of cueing/prior information that help to increase the efficacy of lower-level attentional processes. In the current study, we investigated whether this is also the case for higher-level cognitive flexibility mechanisms. To this end, we tested N = 210 healthy adults with a backward inhibition task, in which prior information needs to be used to guide cognitive flexibility mechanisms. Testing different polymorphisms of the CHRM2 gene, we found that variation in this gene play a role in cognitive flexibility. It could be demonstrated that rs8191992 TT genotype carriers are better able to suppress no longer relevant information and to use prior information for cognitive flexibility, compared to A allele carriers. We further found that rs2350780 GG genotype carriers performed worse than A allele carriers. The results broaden the relevance of the CHRM2 system for cognitive functions beyond attentional selection processes. Corroborating recent theories on the relevance of the cholinergic system for cognitive processes, these results suggest that CHRM2 is important to process of "prior information" needed to inform subsequent cognitive operations. Considering the importance of prior information for adaptive behavioral control, it is possible that CHRM2 also modulates other instances of higher-level cognitive processes as long as these require the processing of "prior information."

Catecholaminergic effects on inhibitory control depend on the interplay of prior task experience and working memory demands.

BACKGROUND: Catecholamines affect response inhibition, but the effects of methylphenidate on inhibitory control in healthy subjects are heterogenous. Theoretical considerations suggest that working memory demands and learning/familiarization processes are important factors to consider regarding catecholaminergic effects on response inhibition. AIMS: The purpose of this study was to examine the role of working memory demands and familiarization for methylphenidate effects on response inhibition. METHODS: Twenty-eight healthy adults received a single dose of methylphenidate (0.5 mg/kg) or placebo in a randomised, double-blind, crossover study design. The subjects were tested using a working memory-modulated response inhibition paradigm that combined a Go/Nogo task with a mental rotation task. RESULTS: Methylphenidate effects were largest in the most challenging mental rotation condition. The direction of effects depended on the extent of the participants' task experience. When performing the task for the first time, methylphenidate impaired response inhibition performance in the most challenging mental rotation condition, as reflected by an increased false alarm rate. In sharp contrast to this, methylphenidate seemed to improve response execution performance in the most challenging condition when performing the task for the second time as reflected by reaction times on Go trials. CONCLUSION: Effects of catecholamines on inhibitory control processes depend on the interplay of two factors: (a) working memory demands, and (b) learning or familiarization with a task. It seems that the net effect of increases in gain control and decreases in working memory processes determines the methylphenidate effect on response inhibition. Hence, crossover study designs likely underestimate methylphenidate effects on cognitive functions.

Neuronal networks underlying the conjoint modulation of response selection by subliminal and consciously induced cognitive conflicts.

Goal-directed behavior has been shown to be affected by consciously and subliminally induced conflicts. Both types of conflict conjointly modulate behavioral performance, but the underlying neuronal mechanisms have remained unclear. While cognitive control is linked to oscillations in the theta frequency band, there are several mechanisms via which theta oscillations may enable cognitive control: via the coordination and synchronization of a large and complex neuronal network and/or via local processes within the medial frontal cortex. We, therefore, investigated this issue with a focus on theta oscillations and the underlying neuronal networks. For this purpose, n = 40 healthy young participants performed a conflict paradigm that combines conscious and subliminal distractors while an EEG was recorded. The data show that separate processes modulate the theta-based activation and organization of cognitive control networks: EEG beamforming analyses showed that variations in theta band power generated in the supplementary motor area reflected the need for control and task-relevant goal shielding, as both conflicts as well as their conjoint effect on behavior increased theta power. Yet, large networks were not modulated by this and graph theoretical analyses of the efficiency (i.e. small worldness) of theta-driven networks did not reflect the need for control. Instead, theta network efficiency was decreased by subliminal conflicts only. This dissociation suggests that while both kinds of conflict require control and goal shielding, which are induced by an increase in theta band power and modulate processes in the medial frontal cortex, only non-conscious conflicts diminish the efficiency of theta-driven large-scale networks.

The Presynaptic Regulation of Dopamine and Norepinephrine Synthesis Has Dissociable Effects on Different Kinds of Cognitive Conflicts.

Goal-directed behavior requires the ability to resolve subliminally or consciously induced response conflicts, both of which may benefit from catecholamine-induced increases in gain control. We investigated the effects of presynaptic differences in dopamine and norepinephrine synthesis with the help of the tyrosine hydroxylase (TH) rs10770141 and the dopamine-ß-hydroxylase (DBH) rs1611115, rs6271, and rs1611122 polymorphisms. Conscious and subliminal response conflicts were induced with flanker and prime distractors in (n = 207) healthy young participants while neurophysiological data (EEG) was recorded. The results demonstrated that the increased presynaptic catecholamine synthesis associated with the TH rs10770141 TT genotype improves cognitive control in case of consciously perceived (flanker) conflicts, but not in case of subliminally processed (prime) conflicts. Only norepinephrine seemed to also modulate subliminal conflict processing, as evidenced by better performance of the DBH rs1611122 CC genotype in case of high subliminal conflict load. Better performance was linked to larger conflict-induced modulations in post-response alpha band power arising from parietal and inferior frontal regions, which likely helps to suppress the processing of distracting information. In summary, presynaptic catecholamine synthesis benefits consciously perceived conflicts by improving the suppression of distracting information following a conflict. Subliminal conflicts were modulated via the same mechanism, but only by norepinephrine.

Methamphetamine Users Show No Behavioral Deficits in Response Selection After Protracted Abstinence.

Introduction: Chronic recreational methamphetamine use causes dopaminergic neurotoxicity, which has been linked to impairments in executive functioning. Within this functional domain, response selection and the resolution of associated conflicts have repeatedly been demonstrated to be strongly modulated by dopamine. Yet, it has never been investigated whether chronic methamphetamine use leads to general impairments in response selection (i.e., irrespective of consumption-associated behavior) after substance use is discontinued. Materials and Methods: We tested n = 24 abstinent methamphetamine users (on average 2.7 years of abstinence) and n = 24 individually matched controls in a cross-sectional design with a flanker task. Results: Compared to healthy controls, former methamphetamine consumers had significantly slower reaction times, but did not show differences in the size of the flanker or Gratton effect, or post-error slowing. Complementary Bayesian analyses further substantiated this lack of effects despite prior consumption for an average of 7.2 years. Discussion: The ability to select a correct response from a subset of conflicting alternatives, as well as the selective attention required for this seem to be largely preserved in case of prolonged abstinence. Likewise, the ability to take previous contextual information into account during response selection and to process errors seem to be largely preserved as well. Complementing previously published finding of worse inhibition/interference control in abstinent consumers, our results suggest that not all executive domains are (equally) impaired by methamphetamine, possibly because different cognitive processes require different levels of dopamine activity.

Alcohol Hangover Increases Conflict Load via Faster Processing of Subliminal Information.

The detrimental effects of acute alcohol intoxication and long-term alcohol (ab)use on cognition are well-known. Yet, only little is known about the cognitive effects of an acute alcohol hangover, even though it might affect executive functions associated with workplace performance or driving skills. Given that alcohol hangover may increase the speed of information accumulation, we assessed the behavioral effects of conflict load (induced by a subliminal prime) on cognitive control, as assessed via the Flanker effect. We employed a counter-balanced within-subject design, where n = 25 healthy young males were tested once after a sober night and once after a night of experimentally induced heavy drinking of cheap brandy/red wine (2.6375 g alcohol per estimated liter of body water within 2-3 h). Alcohol hangover neither increased the cognitive conflicts induced by consciously processed distractors alone (i.e., the Flanker effect), nor modulated conflict adaptation (i.e., the Gratton effect). Instead, hangover potentiated the detrimental effects of conflicting subliminal primes on top-down cognitive conflicts. This effect was likely due to an increase in the speed of information accumulation from visual stimuli and the resulting increase in subliminal conflict load induced by incompatible primes. We further found the size of this effect to be positively correlated with age and subjective sleepiness during the hangover state, but the hangover effect remained significant even after correcting for those covariates. We further found no correlation of the behavioral effect with the subjective overall rating of hangover symptoms or the maximal breath alcohol concentration reached during prior intoxication. Taken together, our findings suggest that alcohol hangover may affect cognitive performance due to an increase in non-conscious processing of visual distractors. While the size of this effect might increase with age and sleepiness, it is not entirely dependent on those covariates and not necessarily related to subjective ratings of general hangover symptoms/impairment.