Anticipating social feedback involves basal forebrain and mesolimbic functional connectivity.

The mesolimbic system and basal forebrain (BF) are implicated in processing rewards and punishment, but their interplay and functional properties of subregions with respect to future social outcomes remain unclear. Therefore, this study investigated regional responses and interregional functional connectivity of the lateral (l), medial (m), and ventral (v) Substantia Nigra (SN), Nucleus Accumbens (NAcc), Nucleus basalis of Meynert (NBM), and Medial Septum/Diagonal Band (MS/DB) during reward and punishment anticipation in a social incentive delay task with neutral, positive, and negative feedback using high-resolution fMRI (1.5mm3). Neuroimaging data (n = 36 healthy humans) of the anticipation phase was analyzed using mass-univariate, functional connectivity, and multivariate-pattern analysis. As expected, participants responded faster when anticipating positive and negative compared to neutral social feedback. At the neural level, anticipating social information engaged valence-related and valence-unrelated functional connectivity patterns involving the BF and mesolimbic areas. Precisely, valence-related connectivity between the lSN and NBM was associated with anticipating neutral social feedback, while connectivity between the vSN and NBM was associated with anticipating positive social feedback. A more complex pattern was observed for anticipating negative social feedback, including connectivity between the lSN and MS/DB, lSN and NAcc, as well as mSN and NAcc. To conclude,  functional connectivity patterns of the BF and mesolimbic areas signal the anticipation of social feedback depending on their emotional valence. As such, our findings give novel insights into the underlying neural processes of social information processing.

Contextual incongruency triggers memory reinstatement and the disruption of neural stability.

Schemas, or internal representation models of the environment, are thought to be central in organising our everyday life behaviour by giving stability and predictiveness to the structure of the world. However, when an element from an unfolding event mismatches the schema-derived expectations, the coherent narrative is interrupted and an update to the current event model representation is required. Here, we asked whether the perceived incongruence of an item from an unfolding event and its impact on memory relied on the disruption of neural stability patterns preceded by the neural reactivation of the memory representations of the just-encoded event. Our study includes data from two different experiments whereby human participants (N = 33, 26 females and N = 18, 16 females, respectively) encoded images of objects preceded by trial-unique sequences of events depicting daily routine. We found that neural stability patterns gradually increased throughout the ongoing exposure to a schema-consistent episode, which was corroborated by the re-analysis of data from two other experiments, and that the brain stability pattern was interrupted when the encoding of an object of the event was incongruent with the ongoing schema. We found that the decrease in neural stability for low-congruence items was seen at ∼1000 ms from object encoding onset and that it was preceded by an enhanced N400 ERP and an increased degree of neural reactivation of the just-encoded episode. Current results offer new insights into the neural mechanisms and their temporal orchestration that are engaged during online encoding of schema-consistent episodic narratives and the detection of incongruencies.

Differential effects of expectancy on memory formation in young and older adults.

Novelty can promote subsequent long-term memory via the mesolimbic system, including the medial temporal lobe and midbrain structures. Importantly, these and other brain regions typically degenerate during healthy aging, which suggests a reduced impact of novelty on learning. However, evidence in favor of such a hypothesis is scarce. Thus, we used functional MRI in combination with an established paradigm in healthy young (19-32 years, n = 30) and older (51-81 years, n = 32) humans. During encoding, colored cues predicted the subsequent presentation of either a novel or previously familiarized image (75% cue validity), and approximately 24 h later, recognition memory for novel images was tested. Behaviorally, expected novel images, as compared to unexpected novel images, were better recognized in young and, to a lesser degree, older subjects. At the neural level, familiar cues activated memory related areas, especially the medial temporal lobe, whereas novelty cues activated the angular gyrus and inferior parietal lobe, which may reflect enhanced attentional processing. During outcome processing, expected novel images activated the medial temporal lobe, angular gyrus and inferior parietal lobe. Importantly, a similar activation pattern was observed for subsequently recognized novel items, which helps to explain the behavioral effect of novelty on long-term memory. Finally, age-effects were pronounced for successfully recognized novel images with relatively stronger activations in attention-related brain regions in older adults; younger adults, on the other hand, showed stronger hippocampal activation. Together, expectancy promotes memory formation for novel items via neural activity in medial temporal lobe structures and this effect appears to be reduced with age.

Functional coupling between CA3 and laterobasal amygdala supports schema dependent memory formation.

The medial temporal lobe drives semantic congruence dependent memory formation. However, the exact roles of hippocampal subfields and surrounding brain regions remain unclear. Here, we used an established paradigm and high-resolution functional magnetic resonance imaging of the medial temporal lobe together with cytoarchitectonic probability estimates in healthy humans. Behaviorally, robust congruence effects emerged in young and older adults, indicating that schema dependent learning is unimpaired during healthy aging. Within the medial temporal lobe, semantic congruence was associated with hemodynamic activity in the subiculum, CA1, CA3 and dentate gyrus, as well as the entorhinal cortex and laterobasal amygdala. Importantly, a subsequent memory analysis showed increased activity for later remembered vs. later forgotten congruent items specifically within CA3, and this subfield showed enhanced functional connectivity to the laterobasal amygdala. As such, our findings extend current models on schema dependent learning by pinpointing the functional properties of subregions within the medial temporal lobe.

Anticipating social incentives recruits alpha-beta oscillations in the human substantia nigra and invigorates behavior across the life span.

Anticipating social and non-social incentives recruits shared brain structures and promotes behavior. However, little is known about possible age-related behavioral changes, and how the human substantia nigra (SN) signals positive and negative social information. Therefore, we recorded intracranial electroencephalography (iEEG) from the SN of Parkinson's Disease (PD) patients (n = 12, intraoperative, OFF medication) in combination with a social incentive delay task including photos of neutral, positive or negative human gestures and mimics as feedback. We also tested a group of non-operated PD patients (n = 24, ON and OFF medication), and a sample of healthy young (n = 51) and older (n = 52) adults with behavioral readouts only. Behaviorally, the anticipation of both positive and negative social feedback equally accelerated response times in contrast to neutral social feedback in healthy young and older adults. Although this effect was not significant in the group of operated PD patients - most likely due to the small sample size - iEEG recordings in their SN showed a significant increase in alpha-beta power (9-20 Hz) from 300 to 600 ms after cue onset again for both positive and negative cues. Finally, in non-operated PD patients, the behavioral effect was not modulated by medication status (ON vs OFF medication) suggesting that other processes than dopaminergic neuromodulation play a role in driving invigoration by social incentives. Together, our findings provide novel and direct evidence for a role of the SN in processing positive and negative social information via specific oscillatory mechanisms in the alpha-beta range, and they suggest that anticipating social value in simple cue-outcome associations is intact in healthy aging and PD.

Dopamine Enhances Item Novelty Detection via Hippocampal and Associative Recall via Left Lateral Prefrontal Cortex Mechanisms.

The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment.

Age-Related Decreases in the Retrieval Practice Effect Directly Relate to Changes in Alpha-Beta Oscillations.

The retrieval (or testing) of information leads to better memory performance compared with reencoding. This phenomenon is known as "testing effect" or "retrieval practice effect" and has been primarily described in behavioral studies with healthy young subjects. However, possible age-related changes and their associated underlying neural processes, in particular neural oscillations, remain unclear. To address this issue, we used a previously established paradigm in healthy young (N = 27) and elderly (N = 28) male and female human adults while their brain activity was being recorded using EEG. Subjects viewed prefamiliarized scene images intermixed with new scenes and classified them as indoor versus outdoor (encoding task) or old versus new (retrieval task). Subsequently, subjects performed a recognition memory task 10 min and 24 h after encoding. Behaviorally, both age groups showed the testing effect at both time points but, importantly, it was less pronounced in the elderly. At the neural level, the retrieval compared with the encoding task was accompanied by power decreases in the alpha (9-12 Hz) and beta bands (13-30 Hz), possibly reflecting task demands, and this difference was more pronounced in the elderly. Finally, a correlation analysis revealed that those elderly who displayed a more pronounced testing effect exhibited a neural pattern that was more similar to the younger subjects. These findings provide evidence that the testing effect decreases across the life span, and they suggest that changes in alpha-beta oscillations play a direct role.SIGNIFICANCE STATEMENT Learning new and retrieving old information is part of everyday human life. Understanding how learning processes can be optimized therefore has direct applications in the realm of educational and rehabilitative contexts. Here, we show that retrieval practice is a strategy to optimize encoding into long-term memory in both young and elderly humans. Importantly, retrieval practice was significantly reduced in the elderly and closely related to changes in alpha (9-13 Hz) and beta band (13-30 Hz) oscillations. Our findings suggest that decreased retrieval practice effects across the life span contribute to, and may reflect, age-related declines in memory performance. They further provide new insights into the underlying neural mechanisms and point toward future avenues for neuro-modulatory interventions.

The gains of a 4-week cognitive training are not modulated by novelty.

Cognitive training should not only improve performance of the trained task, but also untrained abilities. Exposure to novelty can improve subsequent memory performance, suggesting that novelty exposure might be a critical factor to promote the effects of cognitive training. Therefore, we combined a 4-week working memory training with novelty exposure. Neuropsychological tests and MRI data were acquired before and after training to analyze behavior and changes in gray matter volume, myelination, and iron levels. In total, 83 healthy older humans participated in one of three groups: Two groups completed a 4-week computerized cognitive training of a two-back working memory task, either in combination with novel or with familiarized nature movies. A third group did not receive any training. As expected, both training groups showed improvements in task specific working memory performance and reaction times. However, there were no transfer or novelty effects on fluid intelligence, verbal memory, digit-span, and executive functions. At the neural level, no significant micro- or macrostructural changes emerged in either group. Our findings suggest that working memory training in healthy older adults is associated with task-specific improvements, but these gains do not transfer to other cognitive domains, and it does not lead to structural brain changes.

Retrieval Demands Adaptively Change Striatal Old/New Signals and Boost Subsequent Long-Term Memory.

The striatum is a central part of the dopaminergic mesolimbic system and contributes both to the encoding and retrieval of long-term memories. In this regard, the co-occurrence of striatal novelty and retrieval success effects in independent studies underlines the structure's double duty and suggests dynamic contextual adaptation. To test this hypothesis and further investigate the underlying mechanisms of encoding and retrieval dynamics, human subjects viewed pre-familiarized scene images intermixed with new scenes and classified them as indoor versus outdoor (encoding task) or old versus new (retrieval task), while fMRI and eye tracking data were recorded. Subsequently, subjects performed a final recognition task. As hypothesized, striatal activity and pupil size reflected task-conditional salience of old and new stimuli, but, unexpectedly, this effect was not reflected in the substantia nigra and ventral tegmental area (SN/VTA), medial temporal lobe, or subsequent memory performance. Instead, subsequent memory generally benefitted from retrieval, an effect possibly driven by task difficulty and activity in a network including different parts of the striatum and SN/VTA. Our findings extend memory models of encoding and retrieval dynamics by pinpointing a specific contextual factor that differentially modulates the functional properties of the mesolimbic system.SIGNIFICANCE STATEMENT The mesolimbic system is involved in the encoding and retrieval of information but it is unclear how these two processes are achieved within the same network of brain regions. In particular, memory retrieval and novelty encoding were considered in independent studies, implying that novelty (new > old) and retrieval success (old > new) effects may co-occur in the striatum. Here, we used a common framework implicating the striatum, but not other parts of the mesolimbic system, in tracking context-dependent salience of old and new information. The current study, therefore, paves the way for a more comprehensive understanding of the functional properties of the mesolimbic system during memory encoding and retrieval.

Semantic Congruence Accelerates the Onset of the Neural Signals of Successful Memory Encoding.

As the stream of experience unfolds, our memory system rapidly transforms current inputs into long-lasting meaningful memories. A putative neural mechanism that strongly influences how input elements are transformed into meaningful memory codes relies on the ability to integrate them with existing structures of knowledge or schemas. However, it is not yet clear whether schema-related integration neural mechanisms occur during online encoding. In the current investigation, we examined the encoding-dependent nature of this phenomenon in humans. We showed that actively integrating words with congruent semantic information provided by a category cue enhances memory for words and increases false recall. The memory effect of such active integration with congruent information was robust, even with an interference task occurring right after each encoding word list. In addition, via electroencephalography, we show in 2 separate studies that the onset of the neural signals of successful encoding appeared early (∼400 ms) during the encoding of congruent words. That the neural signals of successful encoding of congruent and incongruent information followed similarly ∼200 ms later suggests that this earlier neural response contributed to memory formation. We propose that the encoding of events that are congruent with readily available contextual semantics can trigger an accelerated onset of the neural mechanisms, supporting the integration of semantic information with the event input. This faster onset would result in a long-lasting and meaningful memory trace for the event but, at the same time, make it difficult to distinguish it from plausible but never encoded events (i.e., related false memories). SIGNIFICANCE STATEMENT: Conceptual or schema congruence has a strong influence on long-term memory. However, the question of whether schema-related integration neural mechanisms occur during online encoding has yet to be clarified. We investigated the neural mechanisms reflecting how the active integration of words with congruent semantic categories enhances memory for words and increases false recall of semantically related words. We analyzed event-related potentials during encoding and showed that the onset of the neural signals of successful encoding appeared early (∼400 ms) during the encoding of congruent words. Our findings indicate that congruent events can trigger an accelerated onset of neural encoding mechanisms supporting the integration of semantic information with the event input.

Theta oscillations underlie retrieval success effects in the nucleus accumbens and anterior thalamus: Evidence from human intracranial recordings.

Previous imaging studies independently highlighted the role of the anterior thalamus (ANT) and nucleus accumbens (NAcc) in successful memory retrieval. While these findings accord with theoretical models, the precise temporal, oscillatory and network dynamics as well as the interplay between the NAcc and ANT in successfully retrieving information from long-term memory are largely unknown. We addressed this issue by recording intracranial electroencephalography in human epilepsy patients from the NAcc (n = 5) and ANT (n = 4) during an old/new recognition test. Our findings demonstrate that differences in event-related potentials between correctly classified old (i.e., studied) and new (i.e., unstudied) images emerged in the NAcc and ANT already between 200 and 600 ms after stimulus onset. Moreover, time-frequency analyses revealed theta (4-8 Hz) power decreases for old compared to new items in the NAcc and the opposite effect in the ANT. Importantly, Granger causality analyses revealed a directional communication from ANT to NAcc suggesting that entrainment from ANT drives successful memory retrieval. Together, our findings show evidence for the notion that the NAcc and ANT receive memory signals, and that theta oscillations may serve as a mechanism to bind these distributed neural assemblies.

Iron Level and Myelin Content in the Ventral Striatum Predict Memory Performance in the Aging Brain.

Age-related memory impairments have been associated with structural changes in the dopaminergic system, but the underlying mechanisms remain unclear. Recent work indicates that iron accumulation might be of particular relevance. As iron accumulates, a degeneration of myelin sheaths has been observed in the elderly, but the relationship between both and their impact on memory performance in healthy elderly humans remain important open questions. To address this issue, we combined an established behavioral paradigm to test memory performance [verbal learning memory test (VLMT)] with state of the art quantitative magnetic resonance imaging techniques allowing us to quantify the degree of myelination and iron accumulation via markers of tissue microstructure in a group of young (18-32 years) and healthy elderly humans (55-79 years). As expected, we observed a decrease in gray matter volume and myelin, and an increase of iron in the elderly relative to the young subjects within widespread brain regions, including the basal ganglia. Furthermore, higher levels of iron within the ventral striatum were accompanied by a negative correlation between myelin and iron specific for the elderly participants. Importantly, both markers of iron and myelin (and their ratio) predicted the performance of the elderly in the VLMT. This suggests that ventral striatum iron accumulation is linked to demyelination and impairments in declarative memory. Together, our data provide novel insights into underlying microstructural mechanisms of memory decline in the elderly. SIGNIFICANCE STATEMENT: Memory decline in healthy elderly is a common phenomenon, but the underlying neural mechanisms remain unclear. We used a novel approach that allowed us to combine behavior and whole-brain measures of iron, myelin, and gray matter in the participant's individual subspace to analyze structure-structure and structure-behavior interactions. We were able to show, that age-related high levels of iron are accompanied by a negative correlation of iron and myelin in the ventral striatum, which predicted individual memory performance. As such, our findings provide unprecedented insights into the basic mechanisms of memory decline in the elderly.

Theta-Alpha Oscillations Bind the Hippocampus, Prefrontal Cortex, and Striatum during Recollection: Evidence from Simultaneous EEG-fMRI.

Recollection of contextual information represents the core of human recognition memory. It has been associated with theta (4-8 Hz) power in electrophysiological recordings and, independently, with BOLD effects in a network including the hippocampus and frontal cortex. Although the notion of the hippocampus coordinating neocortical activity by synchronization in the theta range is common among theoretical models of recollection, direct evidence supporting this hypothesis is scarce. To address this apparent gap in our understanding of memory processes, we combined EEG and fMRI during a remember/know recognition task. We can show that recollection-specific theta-alpha (4-13 Hz) effects are correlated with increases in hippocampal connectivity with the PFC and, importantly, the striatum, areas that have been linked repeatedly to retrieval success. Together, our results provide compelling evidence that low-frequency oscillations in the theta and alpha range provide a mechanism to functionally bind the hippocampus, PFC, and striatum during successful recollection. SIGNIFICANCE STATEMENT: Low-frequency oscillations are supposed to drive the binding of information across a large-scale network centered on the hippocampus, which supports mnemonic functions. The electrophysiological means to investigate this phenomenon in humans (EEG/MEG), however, are inherently limited by their spatial resolution and therefore do not allow a precise localization of the brain regions involved. By combining EEG with BOLD-derived estimates of hippocampal connectivity during recognition, we can identify the striatum and specific areas in the medial and lateral PFC as part of a circuit linked to low-frequency oscillations (4-13 Hz) that promotes hippocampus-dependent context retrieval. Therefore, the current study closes an apparent gap in our understanding of the network dynamics of memory retrieval.

Acetylcholine modulates human working memory and subsequent familiarity based recognition via alpha oscillations.

Working memory (WM) can be defined as the ability to maintain and process physically absent information for a short period of time. This vital cognitive function has been related to cholinergic neuromodulation and, in independent work, to theta (4-8Hz) and alpha (9-14Hz) band oscillations. However, the relationship between both aspects remains unclear. To fill this apparent gap, we used electroencephalography (EEG) and a within-subject design in healthy humans who either received the acetylcholinesterase inhibitor galantamine (8mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images were memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested according to a remember/know paradigm. As a main finding, we can show that both theta and alpha oscillations scale during WM maintenance as a function of WM load; this resembles the typical performance decrease. Importantly, cholinergic stimulation via galantamine administration slowed down retrieval speed during WM and reduced associated alpha but not theta power, suggesting a functional relationship between alpha oscillations and WM performance. At LTM, this pattern was accompanied by impaired familiarity based recognition. These findings show that stimulating the healthy cholinergic system impairs WM and subsequent recognition, which is in line with the notion of a quadratic relationship between acetylcholine levels and cognitive functions. Moreover, our data provide empirical evidence for a specific role of alpha oscillations in acetylcholine dependent WM and associated LTM formation.

Altered salience processing in attention deficit hyperactivity disorder.

Attentional problems in patients with attention deficit hyperactivity disorder (ADHD) have often been linked with deficits in cognitive control. Whether these deficits are associated with increased sensitivity to external salient stimuli remains unclear. To address this issue, we acquired functional brain images (fMRI) in 38 boys with and without ADHD (age: 11-16 years). To differentiate the effects of item novelty, contextual rareness and task relevance, participants performed a visual oddball task including four stimulus categories: a frequent standard picture (62.5%), unique novel pictures (12.5%), one repeated rare picture (12.5%), and a target picture (12.5%) that required a specific motor response. As a main finding, we can show considerable overlap in novelty-related BOLD responses between both groups, but only healthy participants showed neural deactivation in temporal as well as frontal regions in response to novel pictures. Furthermore, only ADHD patients, but not healthy controls, engaged wide parts of the novelty network when processing the rare but familiar picture. Our results provide first evidence that ADHD patients show enhanced neural activity in response to novel but behaviorally irrelevant stimuli as well as reduced habituation to familiar items. These findings suggest an inefficient use of neuronal resources in children with ADHD that could be closely linked to increased distractibility.

Anticipation of electric shocks modulates low beta power and event-related fields during memory encoding.

In humans, the temporal and oscillatory dynamics of pain anticipation and its effects on long-term memory are largely unknown. Here, we investigated this open question by using a previously established behavioral paradigm in combination with magnetoencephalography (MEG). Healthy human subjects encoded a series of scene images, which was combined with cues predicting an aversive electric shock with different probabilities (0.2, 0.5 or 0.8). After encoding, memory for the studied images was tested using a remember/know recognition task. Behaviorally, pain anticipation did not modulate recollection-based recognition memory per se, but interacted with the perceived unpleasantness of the electric shock [visual analogue scale rating from 1 (not unpleasant) to 10 (highly unpleasant)]. More precisely, the relationship between pain anticipation and recollection followed an inverted u-shaped function the more unpleasant the shocks were rated by a subject. At the physiological level, this quadratic effect was mimicked in the event-related magnetic fields associated with successful memory formation ('DM-effect') ∼450ms after image onset at left frontal sensors. Importantly, across all subjects, shock anticipation modulated oscillatory power in the low beta frequency range (13-20Hz) in a linear fashion at left temporal sensors. Taken together, our findings indicate that beta oscillations provide a generic mechanism underlying pain anticipation; the effect on subsequent long-term memory, on the other hand, is much more variable and depends on the level of individual pain perception. As such, our findings give new and important insights into how aversive motivational states can drive memory formation.

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases.

BACKGROUND: Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. METHODS: We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. RESULTS: We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. LIMITATIONS: Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. CONCLUSION: The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine.

Pharmacological dissociation of novelty responses in the human brain.

Repeated processing of the same information is associated with decreased neuronal responses, termed repetition suppression (RS). Although RS effects (i.e., the difference in activity between novel and repeated stimuli) have been demonstrated within several brain regions, such as the medial temporal lobe, their precise neural mechanisms still remain unclear. Here, we used functional magnetic resonance imaging together with psychopharmacology in 48 healthy human subjects, demonstrating that RS effects within the mesolimbic system are differentially modulated by cholinergic and dopaminergic stimulation. The dopamine precursor levodopa (100 mg) attenuated RS within the hippocampus, parahippocampal cortex, and substantia nigra/ventral tegmental area, and the degree of this reduction correlated with recognition memory performance 24 h later. The acetylcholinesterase inhibitor galantamine (8 mg), in contrast, reversed RS into repetition enhancement, showing no relationship to subsequent recognition memory. This suggests that novelty sensitive neural populations of the mesolimbic system can dynamically shift their responses depending on the balance of cholinergic and dopaminergic neurotransmission, and these shifts can influence memory retention.

Nucleus accumbens activity dissociates different forms of salience: evidence from human intracranial recordings.

Theoretical models and empirical work indicate a critical role of the NAcc in salience processing. For instance, the NAcc not only responds to appetitive and aversive information, but it also signals novelty, contextual deviance, and action monitoring. However, because most studies have investigated only one specific type of salience independently, it remains unclear how the NAcc concurrently differentiates between different forms of salience. To investigate this issue, we used intracranial electroencephalography in human epilepsy patients together with a previously established visual oddball paradigm. Here, three different oddball categories (novel, neutral, and target images) were infrequently presented among a standard scene image, and subjects responded to the target via button press. This task allowed us to differentiate "item novelty" (new vs neutral oddballs) from "contextual deviance" (neutral oddballs vs standard images) and "targetness" (target vs neutral oddballs). Time-frequency analysis revealed a dissociation between item novelty and contextual deviance on the basis of decreases in either θ (4-8 Hz) or ß power (20-30 Hz). Targetness, on the other hand, was signaled by positive deflections in the stimulus-locked local field potentials, which, importantly, correlated with subjects' reaction times. These findings indicate that, in an ongoing stream of information, the NAcc differentiates between types of salience by distinct neural mechanisms to guide goal-directed behavior.

White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging.