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.

Reactivation strength during cued recall is modulated by graph distance within cognitive maps.

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8 min consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms, with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.

An acute bout of high-intensity exercise affects nocturnal sleep and sleep-dependent memory consolidation.

Acute exercise has been shown to affect long-term memory and sleep. However, it is unclear whether exercise-induced changes in sleep architecture are associated with enhanced memory. Recently, it has been shown that exercise followed by a nap improved declarative memory. Whether these effects transfer to night sleep and other memory domains has not yet been studied. Here, we investigate the influence of exercise on nocturnal sleep architecture and associations with sleep-dependent procedural and declarative memory consolidation. Nineteen subjects (23.68 ± 3.97 years) were tested in a balanced cross-over design. In two evening sessions, participants either exercised (high-intensity interval training) or rested immediately after encoding two memory tasks: (1) a finger tapping task and (2) a paired-associate learning task. Subsequent nocturnal sleep was recorded by polysomnography. Retrieval was conducted the following morning. High-intensity interval training lead to an increased declarative memory retention (p = 0.047, d = 0.40) along with a decrease in REM sleep (p = 0.012, d = 0.75). Neither procedural memory nor NREM sleep were significantly affected. Exercise-induced changes in N2 showed a positive correlation with procedural memory retention which did not withstand multiple comparison correction. Exploratory analyses on sleep spindles and slow wave activity did not reveal significant effects. The present findings suggest an exercise-induced enhancement of declarative memory which aligns with changes in nocturnal sleep architecture. This gives additional support for the idea of a potential link between exercise-induced sleep modifications and memory formation which requires further investigation in larger scaled studies.

Enhancing precision in human neuroscience.

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

Automated real-time EEG sleep spindle detection for brain-state-dependent brain stimulation.

Sleep spindles are a hallmark electroencephalographic feature of non-rapid eye movement sleep, and are believed to be instrumental for sleep-dependent memory reactivation and consolidation. However, direct proof of their causal relevance is hard to obtain, and our understanding of their immediate neurophysiological consequences is limited. To investigate their causal role, spindles need to be targeted in real-time with sensory or non-invasive brain-stimulation techniques. While fully automated offline detection algorithms are well established, spindle detection in real-time is highly challenging due to their spontaneous and transient nature. Here, we present the real-time spindle detector, a robust multi-channel electroencephalographic signal-processing algorithm that enables the automated triggering of stimulation during sleep spindles in a phase-specific manner. We validated the real-time spindle detection method by streaming pre-recorded sleep electroencephalographic datasets to a real-time computer system running a Simulink® Real-Time™ implementation of the algorithm. Sleep spindles were detected with high levels of Sensitivity (~83%), Precision (~78%) and a convincing F1-Score (~81%) in reference to state-of-the-art offline algorithms (which reached similar or lower levels when compared with each other), for both naps and full nights, and largely independent of sleep scoring information. Detected spindles were comparable in frequency, duration, amplitude and symmetry, and showed the typical time-frequency characteristics as well as a centroparietal topography. Spindles were detected close to their centre and reliably at the predefined target phase. The real-time spindle detection algorithm therefore empowers researchers to target spindles during human sleep, and apply the stimulation method and experimental paradigm of their choice.

In search of systems consolidation.

Systems consolidation solves the stability-plasticity-dilemma and is a persuasive theory within the neuroscience of memory. The study by Tallman et al. (this issue) adds to the current literature showing that brain activity changes over time follow a power function in some neocortical areas but not in the hippocampus. In our comment, we suggest that a power function may, however, not be the only model that needs to be considered for such an analysis. We also highlight that reasoning by the absence of statistical significance should be replaced by appropriate statistics (e.g., using superiority or equivalence tests).

Brain-wide inferiority and equivalence tests in fMRI group analyses: Selected applications.

Null hypothesis significance testing is the major statistical procedure in fMRI, but provides only a rather limited picture of the effects in a data set. When sample size and power is low relying only on strict significance testing may lead to a host of false negative findings. In contrast, with very large data sets virtually every voxel might become significant. It is thus desirable to complement significance testing with procedures like inferiority and equivalence tests that allow to formally compare effect sizes within and between data sets and offer novel approaches to obtain insight into fMRI data. The major component of these tests are estimates of standardized effect sizes and their confidence intervals. Here, we show how Hedges' g, the bias corrected version of Cohen's d, and its confidence interval can be obtained from SPM t maps. We then demonstrate how these values can be used to evaluate whether nonsignificant effects are really statistically smaller than significant effects to obtain "regions of undecidability" within a data set, and to test for the replicability and lateralization of effects. This method allows the analysis of fMRI data beyond point estimates enabling researchers to take measurement uncertainty into account when interpreting their findings.

[Arousal and regulatory systems in the system of research domain criteria]. / Erregungs- und Regulationssysteme im System der Research Domain Criteria.

BACKGROUND: The RDoC (research domain criteria) domain arousal and regulatory systems plays an important role for psychiatric disorders. OBJECTIVE: What is the association between physiology and function of arousal, sleep and circadian rhythms and psychiatric disorders? What are the therapeutic consequences? MATERIAL AND METHOD: In this narrative review the most important findings related to the topic are presented briefly and concisely. First, the physiology and function of the systems are described. Then the association with various psychiatric disorders is elucidated and therapeutic approaches are discussed. RESULTS: The treatment of disorders of the arousal system plays a role in a broad group of psychiatric disorders. It is especially important to incorporate the disturbance of the arousal system into therapeutic concepts of affective disorders, schizophrenia, attention deficit hyperactivity disorder (ADHD) and substance abuse. CONCLUSION: The dimensional concept of RDoC is reflected in DSM­5 in the simultaneous registration of sleep disturbances and psychiatric disorders, which has important therapeutic consequences. The relationship between sleep function and the development of psychiatric disorders needs continued intensive research.

Specific changes in sleep oscillations after blocking human metabotropic glutamate receptor 5 in the absence of altered memory function.

BACKGROUND: Sleep consolidates declarative memory by repeated replay linked to the cardinal oscillations of non-rapid eye movement (NonREM) sleep. However, there is so far little evidence of classical glutamatergic plasticity induced by this replay. Rather, we have previously reported that blocking N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors does not affect sleep-dependent consolidation of declarative memory. AIMS: The aim of this study was to investigate the role of metabotropic glutamate receptor 5 (mGluR5) in memory processing during sleep. METHODS: In two placebo-controlled within-subject crossover experiments with 20 healthy humans each, we used fenobam to block mGluR5 during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) in the evening, then received the drug and recall was tested the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II participants learned new word-pairs in the morning after sleep. RESULTS/OUTCOMES: Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12-15 Hz spindles but augmented 2-4 Hz delta waves, whereas in rapid eye movement (REM) sleep it suppressed 4-8 Hz theta and 16-22 Hz beta waves. Notably, under fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. CONCLUSIONS/INTERPRETATIONS: Our findings indicate that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations.

Consolidation of Reward Memory during Sleep Does Not Require Dopaminergic Activation.

Sleep enhances memories, especially if they are related to future rewards. Although dopamine has been shown to be a key determinant during reward learning, the role of dopaminergic neurotransmission for amplifying reward-related memories during sleep remains unclear. In this study, we scrutinize the idea that dopamine is needed for the preferential consolidation of rewarded information. We impaired dopaminergic neurotransmission, thereby aiming to wipe out preferential sleep-dependent consolidation of high- over low-rewarded memories during sleep. Following a double-blind, balanced, crossover design, 17 young healthy men received the dopamine d2-like receptor blocker sulpiride (800 mg) or placebo, after learning a motivated learning task. The task required participants to memorize 80 highly and 80 lowly rewarded pictures. Half of them were presented for a short (750 msec) and a long (1500 msec) duration, respectively, which permitted dissociation of the effects of reward on sleep-associated consolidation from those of mere encoding depth. Retrieval was tested after a retention interval of approximately 22 hr that included 8 hr of nocturnal sleep. As expected, at retrieval, highly rewarded memories were remembered better than lowly rewarded memories, under placebo. However, there was no evidence for an effect of reducing dopaminergic neurotransmission with sulpiride during sleep on this differential retention of rewarded information. This result indicates that dopaminergic activation likely is not required for the preferential consolidation of reward-associated memory. Rather, it appears that dopaminergic activation only tags such memories at encoding for intensified reprocessing during sleep.

Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications.

Sleep is essential for memory formation. Active systems consolidation maintains that memory traces that are initially stored in a transient store such as the hippocampus are gradually redistributed towards more permanent storage sites such as the cortex during sleep replay. The complementary synaptic homeostasis theory posits that weak memory traces are erased during sleep through a competitive down-selection mechanism, ensuring the brain's capability to learn new information. We discuss evidence from neuropharmacological experiments in humans to show how major neurotransmitters and neuromodulators are implicated in these memory processes. As to the major excitatory neurotransmitter glutamate that plays a prominent role in inducing synaptic consolidation, we show that these processes, while strengthening cortical memory traces during sleep, are insufficient to explain the consolidation of hippocampus-dependent declarative memories. In the inhibitory GABAergic system, we will offer insights how drugs may alter the intricate interplay of sleep oscillations that have been identified to be crucial for strengthening memories during sleep. Regarding the dopaminergic reward system, we will show how it is engaged during sleep replay, but that dopaminergic neuromodulation likely plays a side role for enhancing relevant memories during sleep. Also, we briefly go into basic evidence on acetylcholine and cortisol whose low tone during slow wave sleep (SWS) is crucial in supporting hippocampal-to-neocortical memory transmission. Finally, we will outline how these insights can be used to improve treatment of neuropsychiatric disorders focusing mainly on anxiety disorders, depression, and addiction that are strongly related to memory processing.

Vast Amounts of Encoded Items Nullify but Do Not Reverse the Effect of Sleep on Declarative Memory.

Sleep strengthens memories by repeatedly reactivating associated neuron ensembles. Our studies show that although long-term memory for a medium number of word-pairs (160) benefits from sleep, a large number (320) does not. This suggests an upper limit to the amount of information that has access to sleep-dependent declarative memory consolidation, which is possibly linked to the availability of reactivation opportunities. Due to competing processes of global forgetting that are active during sleep, we hypothesized that even larger amounts of information would enhance the proportion of information that is actively forgotten during sleep. In the present study, we aimed to induce such forgetting by challenging the sleeping brain with vast amounts of to be remembered information. For this, 78 participants learned a very large number of 640 word-pairs interspersed with periods of quiet awake rest over the course of an entire day and then either slept or stayed awake during the night. Recall was tested after another night of regular sleep. Results revealed comparable retention rates between the sleep and wake groups. Although this null-effect can be reconciled with the concept of limited capacities available for sleep-dependent consolidation, it contradicts our hypothesis that sleep would increase forgetting compared to the wake group. Additional exploratory analyses relying on equivalence testing and Bayesian statistics reveal that there is evidence against sleep having a detrimental effect on the retention of declarative memory at high information loads. We argue that forgetting occurs in both wake and sleep states through different mechanisms, i.e., through increased interference and through global synaptic downscaling, respectively. Both of these processes might scale similarly with information load.

Oxytocin curbs calorie intake via food-specific increases in the activity of brain areas that process reward and establish cognitive control.

The hypothalamic neurohormone oxytocin decreases food intake via largely unexplored mechanisms. We investigated the central nervous mediation of oxytocin's hypophagic effect in comparison to its impact on the processing of generalized rewards. Fifteen fasted normal-weight, young men received intranasal oxytocin (24 IU) or placebo before functional magnetic resonance imaging (fMRI) measurements of brain activity during exposure to food stimuli and a monetary incentive delay task (MID). Subsequently, ad-libitum breakfast intake was assessed. Oxytocin compared to placebo increased activity in the ventromedial prefrontal cortex, supplementary motor area, anterior cingulate, and ventrolateral prefrontal cortices in response to high- vs. low-calorie food images in the fasted state, and reduced calorie intake by 12%. During anticipation of monetary rewards, oxytocin compared to placebo augmented striatal, orbitofrontal and insular activity without altering MID performance. We conclude that during the anticipation of generalized rewards, oxytocin stimulates dopaminergic reward-processing circuits. In contrast, oxytocin restrains food intake by enhancing the activity of brain regions that exert cognitive control, while concomitantly increasing the activity of structures that process food reward value. This pattern points towards a specific role of oxytocin in the regulation of eating behaviour in humans that might be of relevance for potential clinical applications.

Sculpting memory during sleep: concurrent consolidation and forgetting.

There is compelling evidence that sleep actively supports the formation of long-lasting memory representations. Experimental cuing of memories proved that neural replay of representations during sleep plays a causal role for this consolidation, which has also been shown to promote neocortical synaptic plasticity and spine formation. Concurrently, sleep has been proposed to facilitate forgetting through processes of synaptic renormalisation. This view received indirect support by findings in humans of sleep enhancing TMS-evoked plasticity and capabilities for encoding new information. First direct behavioural evidence of sleep inducing forgetting has only recently emerged after encoding large amounts of stimuli in adults. We propose forgetting complements sleep-dependent consolidation and facilitates gist abstraction especially at high memory loads, when reactivation-based consolidation reaches capacity limits.

The Limited Capacity of Sleep-Dependent Memory Consolidation.

Sleep supports memory consolidation. However, the conceptually important influence of the amount of items encoded in a memory test on this effect has not been investigated. In two experiments, participants (n = 101) learned lists of word-pairs varying in length (40, 160, 320 word-pairs) in the evening before a night of sleep (sleep group) or of sleep deprivation (wake group). After 36 h (including a night allowing recovery sleep) retrieval was tested. Compared with wakefulness, post-learning sleep enhanced retention for the 160 word-pair condition (p < 0.01), importantly, this effect completely vanished for the 320 word-pair condition. This result indicates a limited capacity for sleep-dependent memory consolidation, which is consistent with an active system consolidation view on sleep's role for memory, if it is complemented by processes of active forgetting and/or gist abstraction. Whereas the absolute benefit from sleep should have increased with increasing amounts of successfully encoded items, if sleep only passively protected memory from interference. Moreover, the finding that retention performance was significantly diminished for the 320 word-pair condition compared to the 160 word-pair condition in the sleep group, makes it tempting to speculate that with increasing loads of information encoded during wakefulness, sleep might favor processes of forgetting over consolidation.

Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation.

The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information.

Sleep smart-optimizing sleep for declarative learning and memory.

The last decade has witnessed a spurt of new publications documenting sleep's essential contribution to the brains ability to form lasting memories. For the declarative memory domain, slow wave sleep (the deepest sleep stage) has the greatest beneficial effect on the consolidation of memories acquired during preceding wakefulness. The finding that newly encoded memories become reactivated during subsequent sleep fostered the idea that reactivation leads to the strengthening and transformation of the memory trace. According to the active system consolidation account, trace reactivation leads to the redistribution of the transient memory representations from the hippocampus to the long-lasting knowledge networks of the cortex. Apart from consolidating previously learned information, sleep also facilitates the encoding of new memories after sleep, which probably relies on the renormalization of synaptic weights during sleep as suggested by the synaptic homeostasis theory. During wakefulness overshooting potentiation causes an imbalance in synaptic weights that is countered by synaptic downscaling during subsequent sleep. This review briefly introduces the basic concepts and central findings of the research on sleep and memory, and discusses implications of this lab-based work for everyday applications to make the best possible use of sleep's beneficial effect on learning and memory.

Dopamine D2-like receptor activation wipes out preferential consolidation of high over low reward memories during human sleep.

Memory formation is a selective process in which reward contingencies determine which memory is maintained and which is forgotten. Sleep plays a pivotal role in maintaining information for the long term and has been shown to specifically benefit memories that are associated with reward. Key to memory consolidation during sleep is a neuronal reactivation of newly encoded representations. However, it is unclear whether preferential consolidation of memories associated with reward requires the reactivation of dopaminergic circuitry known to mediate reward effects at encoding. In a placebo-controlled, double-blind, balanced crossover experiment, we show that the dopamine D2-like receptor agonist pramipexole given during sleep wipes out reward contingencies. Before sleep, 16 men learned 160 pictures of landscapes and interiors that were associated with high or low rewards, if they were identified between new stimuli at retrieval 24 hr later. In the placebo condition, the participants retained significantly more pictures that promised a high reward. In the pramipexole condition, this difference was wiped out, and performance for the low reward pictures was as high as that for high reward pictures. Pramipexole did not generally enhance memory consolidation probably because of the fact that the dopaminergic agonist concurrently suppressed both SWS and REM sleep. These results are consistent with the concept that preferential consolidation of reward-associated memories relies on hippocampus-driven reactivation within the dopaminergic reward system during sleep, whereby during sleep reward contingencies are fed back to the hippocampus to strengthen specific memories, possibly, through dopaminergic facilitation of long-term potentiation.