Bayesian model selection favors parametric over categorical fMRI subsequent memory models in young and older adults.

Subsequent memory paradigms allow to identify neural correlates of successful encoding by separating brain responses as a function of memory performance during later retrieval. In functional magnetic resonance imaging (fMRI), the paradigm typically elicits activations of medial temporal lobe, prefrontal and parietal cortical structures in young, healthy participants. This categorical approach is, however, limited by insufficient memory performance in older and particularly memory-impaired individuals. A parametric modulation of encoding-related activations with memory confidence could overcome this limitation. Here, we applied cross-validated Bayesian model selection (cvBMS) for first-level fMRI models to a visual subsequent memory paradigm in young (18-35 years) and older (51-80 years) adults. Nested cvBMS revealed that parametric models, especially with non-linear transformations of memory confidence ratings, outperformed categorical models in explaining the fMRI signal variance during encoding. We thereby provide a framework for improving the modeling of encoding-related activations and for applying subsequent memory paradigms to memory-impaired individuals.

Learning of novel semantic relationships via sudden comprehension is associated with a hippocampus-independent network.

Sudden comprehension-or insight-during problem-solving can enhance learning, but the underlying neural processes are largely unknown. We investigated neural correlates of learning from sudden comprehension using functional magnetic resonance imaging and a verbal problem-solving task. Solutions and "solutions" to solvable and unsolvable verbal problems, respectively, were presented to induce sudden comprehension or continued incomprehension. We found activations of the hippocampus, medial prefrontal cortex (mPFC), amygdala, and striatum during sudden comprehension. Notably, however, mPFC and temporo-parietal neocortical structures rather than the hippocampus were associated with later learning of suddenly comprehended solutions. Moreover, difficult compared to easy sudden comprehension elicited midbrain activations and was associated with successful learning, pointing to learning via intrinsic reward. Sudden comprehension of novel semantic associations may constitute a special case of long-term memory formation primarily mediated by the mPFC, expanding our knowledge of its role in prior-knowledge-dependent memory.

Gradual acquisition of visuospatial associative memory representations via the dorsal precuneus.

Activation of parietal cortex structures like the precuneus is commonly observed during explicit memory retrieval, but the role of parietal cortices in encoding has only recently been appreciated and is still poorly understood. Considering the importance of the precuneus in human visual attention and imagery, we aimed to assess a potential role for the precuneus in the encoding of visuospatial representations into long-term memory. We therefore investigated the acquisition of constant versus repeatedly shuffled configurations of icons on background images over five subsequent days in 32 young, healthy volunteers. Functional magnetic resonance imaging was conducted on Days 1, 2, and 5, and persistent memory traces were assessed by a delayed memory test after another 5 days. Constant compared to shuffled configurations were associated with significant improvement of position recognition from Day 1 to 5 and better delayed memory performance. Bilateral dorsal precuneus activations separated constant from shuffled configurations from Day 2 onward, and coactivation of the precuneus and hippocampus dissociated recognized and forgotten configurations, irrespective of condition. Furthermore, learning of constant configurations elicited increased functional coupling of the precuneus with dorsal and ventral visual stream structures. Our results identify the precuneus as a key brain structure in the acquisition of detailed visuospatial information by orchestrating a parieto-occipito-temporal network.

Feelings-of-Warmth Increase More Abruptly for Verbal Riddles Solved With in Contrast to Without Aha! Experience.

When we are confronted with a new problem, we typically try to apply strategies that have worked in the past and which usually lead closer to the solution incrementally. However, sometimes, either during a problem-solving attempt that does not seem to lead closer to the solution, or when we have given up on problem-solving for the moment, the solution seems to appear out of nowhere. This is often called a moment of insight. Whereas the cognitive processes of getting closer to the solution are still unknown for insight problem-solving, there are two diverging theories on the subjective feeling of getting closer to the solution: (1) One that states that an intuitive feeling of closeness to the solution increases slowly, but incrementally, before it surpasses the threshold to consciousness and becomes verbalizable (=insight) (continuous approach), and (2) another that proposes that the feeling of closeness to the solution does not increase before it exceeds the threshold to consciousness (discontinuous approach). Here, we investigated the subjective feeling of closeness to the solution, assessed as feeling-of-warmth (FoW), its relationship to solving the problem versus being presented with it and whether a feeling of Aha! was experienced. Additionally, we tested whether Aha! experiences are more likely when the problem is solved actively by the participant or presented to the participant after an unsuccessful problem-solving attempt, and whether the frequency of Aha! experiences correlates with problem difficulty. To our knowledge, this is the first study combining the CRAT with FoW assessments for the named conditions (solved/unsolved, three difficulty levels, Aha!/no Aha!). We used a verbal problem-solving task, the Compound Remote Associates Task (CRAT). Our data revealed that Aha! experiences were more often reported for solutions generated by the participant compared to solutions presented after unsuccessful problem-solving. Moreover, FoW curves showed a steeper increase for the last two FoW ratings when problems were solved with Aha! in contrast to without Aha!. Based on this observation, we provide a preliminary explanation for the underlying cognitive process of solving CRA problems via insight.

Inhibition of Information Flow to the Default Mode Network During Self-Reference Versus Reference to Others.

The default mode network (DMN), a network centered around the cortical midline, shows deactivation during most cognitive tasks and pronounced resting-state connectivity, but is actively engaged in self-reference and social cognition. It is, however, yet unclear how information reaches the DMN during social cognitive processing. Here, we addressed this question using dynamic causal modeling (DCM) of functional magnetic resonance imaging (fMRI) data acquired during self-reference (SR) and reference to others (OR). Both conditions engaged the left inferior frontal gyrus (LIFG), most likely reflecting semantic processing. Within the DMN, self-reference preferentially elicited rostral anterior cingulate and ventromedial prefrontal cortex (rACC/vmPFC) activity, whereas OR engaged posterior cingulate and precuneus (PCC/PreCun). DCM revealed that the regulation of information flow to the DMN was primarily inhibitory. Most prominently, SR elicited inhibited information flow from the LIFG to the PCC/PreCun, while OR was associated with suppression of the connectivity from the LIFG to the rACC/vmPFC. These results suggest that task-related DMN activation is enabled by inhibitory down-regulation of task-irrelevant information flow when switching from rest to stimulus-specific processing.

Neural Correlates of Learning from Induced Insight: A Case for Reward-Based Episodic Encoding.

Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items-which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning.

Event-Related Potential Effects of Object Repetition Depend on Attention and Part-Whole Configuration.

The effects of spatial attention and part-whole configuration on recognition of repeated objects were investigated with behavioral and event-related potential (ERP) measures. Short-term repetition effects were measured for probe objects as a function of whether a preceding prime object was shown as an intact image or coarsely scrambled (split into two halves) and whether or not it had been attended during the prime display. In line with previous behavioral experiments, priming effects were observed from both intact and split primes for attended objects, but only from intact (repeated same-view) objects when they were unattended. These behavioral results were reflected in ERP waveforms at occipital-temporal locations as more negative-going deflections for repeated items in the time window between 220 and 300 ms after probe onset (N250r). Attended intact images showed generally more enhanced repetition effects than split ones. Unattended images showed repetition effects only when presented in an intact configuration, and this finding was limited to the right-hemisphere electrodes. Repetition effects in earlier (before 200 ms) time windows were limited to attended conditions at occipito-temporal sites during the N1, a component linked to the encoding of object structure, while repetition effects at central locations during the same time window (P150) were found for attended and unattended probes but only when repeated in the same intact configuration. The data indicate that view-generalization is mediated by a combination of analytic (part-based) representations and automatic view-dependent representations.

Clinical, neuropsychological, and pre-stimulus dorsomedial thalamic nucleus electrophysiological data in deep brain stimulation patients.

The data presented here comprise clinical, neuropsychological, and intrathalamic electrophysiological data from 7 patients with pharmacoresistant focal epilepsy and are related to the article "Pre-stimulus thalamic theta power predicts human memory formation" C.M. Sweeney-Reed, T. Zaehle, J. Voges, F.C. Schmitt, L. Buentjen, K. Kopitzki, et al. (2016) [1]. The patients participated in a memory paradigm after receiving electrodes implanted in the DMTN due to the surgical approach taken in electrode insertion for deep brain stimulation of the anterior thalamic nucleus. Epilepsy duration and pre-operative neuropsychological tests provide an indication of the profile of patients receiving intrathalamic electrode implantation and the memory capabilities in such a patient group. The electrophysiological data were recorded from the right DMTN preceding stimulus presentation during intentional memory encoding. The patients viewed a series of photographic scenes, which they judged as indoors or outdoors. The 900 ms epochs prior to stimulus presentation were labeled as preceding successful or unsuccessful subsequent memory formation according to a subsequent memory test for the items. The difference between theta power preceding successful versus unsuccessful subsequent memory formation is shown against time for each patient individually.

Pre-stimulus thalamic theta power predicts human memory formation.

Pre-stimulus theta (4-8Hz) power in the hippocampus and neocortex predicts whether a memory for a subsequent event will be formed. Anatomical studies reveal thalamus-hippocampal connectivity, and lesion, neuroimaging, and electrophysiological studies show that memory processing involves the dorsomedial (DMTN) and anterior thalamic nuclei (ATN). The small size and deep location of these nuclei have limited real-time study of their activity, however, and it is unknown whether pre-stimulus theta power predictive of successful memory formation is also found in these subcortical structures. We recorded human electrophysiological data from the DMTN and ATN of 7 patients receiving deep brain stimulation for refractory epilepsy. We found that greater pre-stimulus theta power in the right DMTN was associated with successful memory encoding, predicting both behavioral outcome and post-stimulus correlates of successful memory formation. In particular, significant correlations were observed between right DMTN theta power and both frontal theta and right ATN gamma (32-50Hz) phase alignment, and frontal-ATN theta-gamma cross-frequency coupling. We draw the following primary conclusions. Our results provide direct electrophysiological evidence in humans of a role for the DMTN as well as the ATN in memory formation. Furthermore, prediction of subsequent memory performance by pre-stimulus thalamic oscillations provides evidence that post-stimulus differences in thalamic activity that index successful and unsuccessful encoding reflect brain processes specifically underpinning memory formation. Finally, the findings broaden the understanding of brain states that facilitate memory encoding to include subcortical as well as cortical structures.

Generation and the subjective feeling of "aha!" are independently related to learning from insight.

It has been proposed that sudden insight into the solutions of problems can enhance long-term memory for those solutions. However, the nature of insight has been operationalized differently across studies. Here, we examined two main aspects of insight problem-solving-the generation of a solution and the subjective "aha!" experience-and experimentally evaluated their respective relationships to long-term memory formation (encoding). Our results suggest that generation (generated solution vs. presented solution) and the "aha!" experience ("aha!" vs. no "aha!") are independently related to learning from insight, as well as to the emotional response towards understanding the solution during encoding. Moreover, we analyzed the relationship between generation and the "aha!" experience and two different kinds of later memory tests, direct (intentional) and indirect (incidental). Here, we found that the generation effect was larger for indirect testing, reflecting more automatic retrieval processes, while the relationship with the occurrence of an "aha!" experience was somewhat larger for direct testing. Our results suggest that both the generation of a solution and the subjective experience of "aha!" indicate processes that benefit long-term memory formation, though differently. This beneficial effect is possibly due to the intrinsic reward associated with sudden comprehension and the detection of schema-consistency, i.e., that novel information can be easily integrated into existing knowledge.

Thalamic theta phase alignment predicts human memory formation and anterior thalamic cross-frequency coupling.

Previously we reported electrophysiological evidence for a role for the anterior thalamic nucleus (ATN) in human memory formation (Sweeney-Reed et al., 2014). Theta-gamma cross-frequency coupling (CFC) predicted successful memory formation, with the involvement of gamma oscillations suggesting memory-relevant local processing in the ATN. The importance of the theta frequency range in memory processing is well-established, and phase alignment of oscillations is considered to be necessary for synaptic plasticity. We hypothesized that theta phase alignment in the ATN would be necessary for memory encoding. Further analysis of the electrophysiological data reveal that phase alignment in the theta rhythm was greater during successful compared with unsuccessful encoding, and that this alignment was correlated with the CFC. These findings support an active processing role for the ATN during memory formation.

Spatial attention enhances object coding in local and distributed representations of the lateral occipital complex.

The modulation of neural activity in visual cortex is thought to be a key mechanism of visual attention. The investigation of attentional modulation in high-level visual areas, however, is hampered by the lack of clear tuning or contrast response functions. In the present functional magnetic resonance imaging study we therefore systematically assessed how small voxel-wise biases in object preference across hundreds of voxels in the lateral occipital complex were affected when attention was directed to objects. We found that the strength of attentional modulation depended on a voxel's object preference in the absence of attention, a pattern indicative of an amplificatory mechanism. Our results show that such attentional modulation effectively increased the mutual information between voxel responses and object identity. Further, these local modulatory effects led to improved information-based object readout at the level of multi-voxel activation patterns and to an increased reproducibility of these patterns across repeated presentations. We conclude that attentional modulation enhances object coding in local and distributed object representations of the lateral occipital complex.

Non-holistic coding of objects in lateral occipital complex with and without attention.

A fundamental issue in visual cognition is whether high-level visual areas code objects in a part-based or a view-based (holistic) format. Previous behavioral and neuroimaging studies that examined the viewpoint invariance of object recognition have yielded ambiguous results, providing evidence for either type of representational format. A critical factor distinguishing the two formats could be the availability of attentional resources, as a number of priming studies have found greater viewpoint invariance for attended compared to unattended objects. It has therefore been suggested that the activation of part-based representations requires attention, whereas the activation of holistic representations occurs automatically irrespective of attention. Using functional magnetic resonance imaging in combination with a novel multivariate pattern analysis approach, the present study probed the format of object representations in human lateral occipital complex and its dependence on attention. We presented human participants with intact and half-split versions of objects that were either attended or unattended. Cross-classifying between intact and split objects, we found that the object-related information coded in activation patterns of intact objects is fully preserved in the patterns of split objects and vice versa. Importantly, the generalization between intact and split objects did not depend on attention. We conclude that lateral occipital complex codes objects in a non-holistic format, both in the presence and absence of attention.

Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation.

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.

Intentional retrieval suppression can conceal guilty knowledge in ERP memory detection tests.

Brain-activity markers of guilty knowledge have been promoted as accurate and reliable measures for establishing criminal culpability. Tests based on these markers interpret the presence or absence of memory-related neural activity as diagnostic of whether or not incriminating information is stored in a suspect's brain. This conclusion critically relies on the untested assumption that reminders of a crime uncontrollably elicit memory-related brain activity. However, recent research indicates that, in some circumstances, humans can control whether they remember a previous experience by intentionally suppressing retrieval. We examined whether people could use retrieval suppression to conceal neural evidence of incriminating memories as indexed by Event-Related Potentials (ERPs). When people were motivated to suppress crime retrieval, their memory-related ERP effects were significantly decreased, allowing guilty individuals to evade detection. Our findings indicate that brain measures of guilty knowledge may be under criminals' intentional control and place limits on their use in legal settings.

The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans.

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing-independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal-cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long-term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory.

Memory signals from the thalamus: early thalamocortical phase synchronization entrains gamma oscillations during long-term memory retrieval.

The thalamus is believed to be a key node in human memory networks, however, very little is known about its real-time functional role. Here we examined the dynamics of thalamocortical communication during long-term episodic memory retrieval in two experiments. In experiment 1, intrathalamic and surface EEG was recorded in an epileptic patient implanted with depth electrodes for brain stimulation therapy. In a recognition memory test, early (300-500 ms) stimulus-linked oscillatory synchrony between mediodorsal thalamic and frontal surface electrodes at beta frequency (20 Hz) was enhanced for correctly remembered old compared to correctly rejected new items. Directionality measures (Granger causality) indicated that the thalamus was the sender, and the neocortex the receiver, of this beta signal, which also modulated the power of neocortical gamma (55-80 Hz) oscillations (cross-frequency coupling). Experiment 2 validated the cross-frequency coupling effects in a healthy participant sample. Confirming the findings from experiment 1, significantly increased cross-frequency coupling was found over frontal scalp electrodes during successful recognition. Extending anatomical knowledge on thalamic connectivity with frontal neocortex, these results suggest that the thalamus sends an early memory signal to frontal regions, triggering further memory search processes.

Rapid memory reactivation revealed by oscillatory entrainment.

Episodic memory refers to humans' unique ability to mentally reconstruct past events. Neurocomputational models predict that remembering entails the reinstatement of brain activity that was present when an event was initially experienced [1-5], a claim that has recently gained support from functional imaging work in humans [6-14]. The nature of this reactivation, however, is still unclear. Cognitive models claim that retrieval is set off by an early reactivation of stored memory representations ("ecphory") [15-17]. However, reinstatement as found in imaging studies might also reflect postretrieval processes that operate on the products of retrieval and are thus a consequence rather than a precondition of remembering. Here, we used frequency entrainment as a novel method of tagging memories in the human electroencephalogram (EEG). Participants studied words presented on flickering backgrounds, entraining a steady-state brain response at either 6 or 10 Hz. We found that these frequency signatures rapidly reemerged during a later memory test when participants successfully recognized a word. An additional behavioral experiment suggested that this reactivation occurs in the absence of conscious memory for the frequencies entrained during study. The findings provide empirical evidence for the role of rapid, likely unconscious memory reactivation during retrieval.

Motivational salience modulates hippocampal repetition suppression and functional connectivity in humans.

Repetition suppression (RS) is a rapid decrease of stimulus-related neuronal responses upon repeated presentation of a stimulus. Previous studies have demonstrated that negative emotional salience of stimuli enhances RS. It is, however, unclear how motivational salience of stimuli, such as reward-predicting value, influences RS for complex visual stimuli, and which brain regions might show differences in RS for reward-predicting and neutral stimuli. Here we investigated the influence of motivational salience on RS of complex scenes using event-related functional magnetic resonance imaging. Thirty young healthy volunteers performed a monetary incentive delay task with complex scenes (indoor vs. outdoor) serving as neutral or reward-predicting cue pictures. Each cue picture was presented three times. In line with previous findings, reward anticipation was associated with activations in the ventral striatum, midbrain, and orbitofrontal cortex (OFC). Stimulus repetition was associated with pronounced RS in ventral visual stream areas like the parahippocampal place area (PPA). An interaction of reward anticipation and RS was specifically observed in the anterior hippocampus, where a response decrease across repetitions was observed for the reward-predicting scenes only. Functional connectivity analysis further revealed specific activity-dependent connectivity increases of the hippocampus and the PPA and OFC. Our results suggest that hippocampal RS is sensitive to reward-predicting properties of stimuli and might therefore reflect a rapid, adaptive neural response mechanism for motivationally salient information.

Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.