Neurobiological mechanisms of control in alcohol use disorder – Moving towards mechanism-based non-invasive brain stimulation treatments

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour

On the effects of multimodal information integration in multitasking

There have recently been considerable advances in our understanding of the neuronal mechanisms underlying multitasking, but the role of multimodal integration for this faculty has remained rather unclear. We examined this issue by comparing different modality combinations in a multitasking (stop-change) paradigm. In-depth neurophysiological analyses of event-related potentials (ERPs) were conducted to complement the obtained behavioral data. Specifically, we applied signal decomposition using second order blind identification (SOBI) to the multi-subject ERP data and source localization. We found that both general multimodal information integration and modality-specific aspects (potentially related to task difficulty) modulate behavioral performance and associated neurophysiological correlates. Simultaneous multimodal input generally increased early attentional processing of visual stimuli (i.e. P1 and N1 amplitudes) as well as measures of cognitive effort and conflict (i.e. central P3 amplitudes). Yet, tactile-visual input caused larger impairments in multitasking than audio-visual input. General aspects of multimodal information integration modulated the activity in the premotor cortex (BA 6) as well as different visual association areas concerned with the integration of visual information with input from other modalities (BA 19, BA 21, BA 37). On top of this, differences in the specific combination of modalities also affected performance and measures of conflict/effort originating in prefrontal regions (BA 6)

Relationship between alcohol hangover and physical endurance performance: Walking the Samaria Gorge

Alcohol hangover is a potentially debilitating state. Several studies have demonstrated that it does not seem to impair strength or short-term endurance, but its effects on continuous exercise performance/long-term endurance have never been investigated. Therefore, the aim of the current study was to assess hiking performance of participants who walked the 15.8 km Samaria Gorge in Crete, Greece. Participants completed a survey in the morning before walking the Gorge, and in the afternoon after completion of the walk. Demographics, data on previous evening alcohol consumption, sleep, hangover symptoms, and walking performance were assessed. Data from N=299 participants with a mean (SD) age of 38.9 (11.0) years were analyzed. N=223 participants (74.6%) consumed alcohol the evening before walking the Samaria Gorge, and N= 176 (78.9%) of those reported a hangover. They consumed a mean (SD) of 3.0 (1.8) alcoholic drinks (10 g alcohol each) with a corresponding next-morning hangover severity of 4.6 (2.4) on a 0–10 scale. Participants with a hangover reported feeling significantly more exhausted after the walk compared to participants with no hangover. The groups did not significantly differ in duration of the walk, and the number and duration of breaks. Overall hangover severity, assessed either before, during, or after walking the Samaria Gorge was not significantly correlated with any walking outcome. In conclusion, hungover participants experienced significantly more exhaustion when performing physical activity at the same level as non-hungover participants

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

On the Neurophysiological Mechanisms Underlying the Adaptability to Varying Cognitive Control Demands

Cognitive control processes are advantageous when routines would not lead to the desired outcome, but this can be ill-advised when automated behavior is advantageous. The aim of this study was to identify neural dynamics related to the ability to adapt to different cognitive control demands – a process that has been referred to as ‘metacontrol.’ A sample of N = 227 healthy subjects that was split in a ‘high’ and ‘low adaptability’ group based on the behavioral performance in a task with varying control demands. To examine the neurophysiological mechanisms, we combined event-related potential (ERP) recordings with source localization and machine learning approaches. The results show that individuals who are better at strategically adapting to different cognitive control demands benefit from automatizing their response processes in situations where little cognitive control is needed. On a neurophysiological level, neither perceptual/attentional selection processes nor conflict monitoring processes paralleled the behavioral data, although the latter showed a descriptive trend. Behavioral differences in metacontrol abilities were only significantly mirrored by the modulation of response-locked P3 amplitudes, which were accompanied by activation differences in insula (BA13) and middle frontal gyrus (BA9). The machine learning result corroborated this by identifying a predictive/classification feature near the peak of the response-locked P3, which arose from the anterior cingulate cortex (BA24; BA33). In short, we found that metacontrol is associated to the ability to manage response selection processes, especially the ability to effectively downregulate cognitive control under low cognitive control requirements, rather than the ability to upregulate cognitive control

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

The selection of appropriate responses is a complex endeavor requiring the integration of many different sources of information in fronto-striatal-thalamic circuits. An often neglected but relevant piece of information is provided by proprioceptive inputs about the current position of our limbs. This study examines the importance of striatal and thalamic GABA levels in these processes using GABA-edited magnetic resonance spectroscopy (GABAMRS) and a Simon task featuring proprioception-induced interference in healthy subjects. As a possible model of deficits in the processing of proprioceptive information, we also included Parkinson's disease (PD) patients in this study.The results show that proprioceptive information about unusual postures complicates response selection processes in controls, but not in PD patients. The well-known deficits of PD patients in processing proprioceptive information can turn into a benefit when altered proprioceptive information would normally complicate response selection processes. Striatal and thalamic GABA levels play dissociable roles in the modulation of response selection processes by proprioceptive information: Striatal GABA levels seem to be important for the general speed of responding, most likely because striatal GABA promotes response selection. In contrast, the modulation of response conflict by proprioceptive information is closely related to thalamic GABA concentrations with higher concentration being related to a smaller response conflict effect. The most likely explanation for this finding is that the thalamus is involved in the integration of sensorimotor, attentional, and cognitive information for the purpose of response formation. Yet, this effect in the thalamus vanishes when controls and PD patients were analyzed separately

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

Advantages and limitations of naturalistic study designs and their implementation in alcohol hangover research

In alcohol hangover research, both naturalistic designs and randomized controlled trials (RCTs) are successfully employed to study the causes, consequences, and treatments of hangovers. Although increasingly applied in both social sciences and medical research, the suitability of naturalistic study designs remains a topic of debate. In both types of study design, screening participants and conducting assessments on-site (e.g., psychometric tests, questionnaires, and biomarker assessments) are usually equally rigorous and follow the same standard operating procedures. However, they differ in the levels of monitoring and restrictions imposed on behaviors of participants before the assessments are conducted (e.g., drinking behaviors resulting in the next day hangover). These behaviors are highly controlled in RCTs and uncontrolled in naturalistic studies. As a result, the largest difference between naturalistic studies and RCTs is their ecological validity, which is usually significantly lower for RCTs and (related to that) the degree of standardization of experimental intervention, which is usually significantly higher for RCTs. In this paper, we specifically discuss the application of naturalistic study designs and RCTs in hangover research. It is debated whether it is necessary to control certain behaviors that precede the hangover state when the aim of a study is to examine the effects of the hangover state itself. If the preceding factors and behaviors are not in the focus of the research question, a naturalistic study design should be preferred whenever one aims to better mimic or understand real-life situations in experimental/intervention studies. Furthermore, to improve the level of control in naturalistic studies, mobile technology can be applied to provide more continuous and objective real-time data, without investigators interfering with participant behaviors or the lab environment impacting on the subjective state. However, for other studies, it may be essential that certain behaviors are strictly controlled. It is, for example, vital that both test days are comparable in terms of consumed alcohol and achieved hangover severity levels when comparing the efficacy and safety of a hangover treatment with a placebo treatment day. This is best accomplished with the help of a highly controlled RCT design

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

COVID-19 Lockdown Effects on Mood, Alcohol Consumption, Academic Functioning, and Perceived Immune Fitness: Data from Young Adults in Germany

Recently, a study was conducted in the Netherlands to evaluate the impact of the coronavirus disease (COVID-19) pandemic and its associated lockdown periods on academic functioning, mood, and health correlates, such as alcohol consumption. The Dutch study revealed that lockdowns were associated with significantly poorer mood and reductions in perceived immune fitness. Overall, a reduction in alcohol consumption during lockdown periods was shown. Academic functioning in terms of self-reported performance was unaffected. However, a significant reduction in interactions with other students and teachers was reported. However, there was considerable variability among students; both increases and reductions in alcohol consumption were reported, as well as both improvements and poorer academic functioning during periods of lockdown. The aim of the current online study was to replicate these findings in Germany. To achieve this, a slightly modified version of the survey was administered among young adults (aged 18 to 35 years old) in Germany. The survey assessed possible changes in self-reported academic functioning, mood, and health correlates, such as smoking and alcohol consumption, perceived immune functioning, and sleep quality during periods of lockdown as compared to periods with no lockdowns. Retrospective assessments were made for five periods, including (1) ‘BP’ (the period before the COVID-19 pandemic), (2) ‘L1’ (the first lockdown period, March–May 2020), (3) ‘NL1’ (the first no-lockdown period, summer 2020), (4) ‘L2’ (the second lockdown, November 2020 to May 2021), and (5) ‘NL2’ (the second no-lockdown period, summer 2021). This article describes the content of the survey and the corresponding dataset. The survey was completed by 371 participants. Dataset: The dataset is submitted as a Supplementary File. Dataset License: CC0