Correction: Stimulation of the left dorsolateral prefrontal cortex with slow rTMS enhances verbal memory formation.

[This corrects the article DOI: 10.1371/journal.pbio.3001363.].

Stimulation of the left dorsolateral prefrontal cortex with slow rTMS enhances verbal memory formation.

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. We here present an incidental finding from a simultaneous EEG-TMS experiment as well as a replication of this unexpected effect. Our results reveal that stimulating the left dorsolateral prefrontal cortex (DLPFC) with slow repetitive transcranial magnetic stimulation (rTMS) leads to enhanced word memory performance. A total of 40 healthy human participants engaged in a list learning paradigm. Half of the participants (N = 20) received 1 Hz rTMS to the left DLPFC, while the other half (N = 20) received 1 Hz rTMS to the vertex and served as a control group. Participants receiving left DLPFC stimulation demonstrated enhanced memory performance compared to the control group. This effect was replicated in a within-subjects experiment where 24 participants received 1 Hz rTMS to the left DLPFC and vertex. In this second experiment, DLPFC stimulation also induced better memory performance compared to vertex stimulation. In addition to these behavioural effects, we found that 1 Hz rTMS to DLPFC induced stronger beta power modulation in posterior areas, a state that is known to be beneficial for memory encoding. Further analysis indicated that beta modulations did not have an oscillatory origin. Instead, the observed beta modulations were a result of a spectral tilt, suggesting inhibition of these parietal regions. These results show that applying 1 Hz rTMS to DLPFC, an area involved in episodic memory formation, improves memory performance via modulating neural activity in parietal regions.

The hippocampus as the switchboard between perception and memory.

Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal-cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (55 to 110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8 to 12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue toward mnemonic target representations. In parallel, source-localized EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal-cortical dynamics supporting the recall process.

Entraining neurons via noninvasive electric stimulation improves cognition.

Transcranial Alternating Current Stimulation (tACS) is a method that injects rhythmic currents into the human brain via electrodes attached to the scalp of a participant. This technique allows researchers to control naturally occurring brain rhythms and study their causal relevance for cognition. Recent findings, however, cast doubts on the effectiveness of tACS to stimulate the brain and its mode of action. Two new studies by Vieira and colleagues and Marchesotti and colleagues reported in the current issue report promising new results in showing that tACS can entrain single neuron activity and improve reading abilities in dyslexic individuals.

Spectral fingerprints or spectral tilt? Evidence for distinct oscillatory signatures of memory formation.

Decreases in low-frequency power (2-30 Hz) alongside high-frequency power increases (>40 Hz) have been demonstrated to predict successful memory formation. Parsimoniously, this change in the frequency spectrum can be explained by one factor, a change in the tilt of the power spectrum (from steep to flat) indicating engaged brain regions. A competing view is that the change in the power spectrum contains several distinct brain oscillatory fingerprints, each serving different computations. Here, we contrast these two theories in a parallel magnetoencephalography (MEG)-intracranial electroencephalography (iEEG) study in which healthy participants and epilepsy patients, respectively, studied either familiar verbal material or unfamiliar faces. We investigated whether modulations in specific frequency bands can be dissociated in time and space and by experimental manipulation. Both MEG and iEEG data show that decreases in alpha/beta power specifically predicted the encoding of words but not faces, whereas increases in gamma power and decreases in theta power predicted memory formation irrespective of material. Critically, these different oscillatory signatures of memory encoding were evident in different brain regions. Moreover, high-frequency gamma power increases occurred significantly earlier compared to low-frequency theta power decreases. These results show that simple "spectral tilt" cannot explain common oscillatory changes and demonstrate that brain oscillations in different frequency bands serve different functions for memory encoding.

Directional coupling of slow and fast hippocampal gamma with neocortical alpha/beta oscillations in human episodic memory.

Episodic memories hinge upon our ability to process a wide range of multisensory information and bind this information into a coherent, memorable representation. On a neural level, these 2 processes are thought to be supported by neocortical alpha/beta desynchronization and hippocampal theta/gamma synchronization, respectively. Intuitively, these 2 processes should couple to successfully create and retrieve episodic memories, yet this hypothesis has not been tested empirically. We address this by analyzing human intracranial electroencephalogram data recorded during 2 associative memory tasks. We find that neocortical alpha/beta (8 to 20 Hz) power decreases reliably precede and predict hippocampal "fast" gamma (60 to 80 Hz) power increases during episodic memory formation; during episodic memory retrieval, however, hippocampal "slow" gamma (40 to 50 Hz) power increases reliably precede and predict later neocortical alpha/beta power decreases. We speculate that this coupling reflects the flow of information from the neocortex to the hippocampus during memory formation, and hippocampal pattern completion inducing information reinstatement in the neocortex during memory retrieval.

Disentangling neocortical alpha/beta and hippocampal theta/gamma oscillations in human episodic memory formation.

To form an episodic memory, we must first process a vast amount of sensory information about the to-be-encoded event and then bind these sensory representations together to form a coherent memory trace. While these two cognitive capabilities are thought to have two distinct neural origins, with neocortical alpha/beta oscillations supporting information representation and hippocampal theta-gamma phase-amplitude coupling supporting mnemonic binding, evidence for a dissociation between these two neural markers is conspicuously absent. To address this, seventeen human participants completed an associative memory task that first involved processing information about three sequentially-presented stimuli, and then binding these stimuli together into a coherent memory trace, all the while undergoing MEG recordings. We found that decreases in neocortical alpha/beta power during sequence perception, but not mnemonic binding, correlated with enhanced memory performance. Hippocampal theta/gamma phase-amplitude coupling, however, showed the opposite pattern; increases during mnemonic binding (but not sequence perception) correlated with enhanced memory performance. These results demonstrate that memory-related decreases in neocortical alpha/beta power and memory-related increases in hippocampal theta/gamma phase-amplitude coupling arise at distinct stages of the memory formation process. We speculate that this temporal dissociation reflects a functional dissociation in which neocortical alpha/beta oscillations could support the processing of incoming information relevant to the memory, while hippocampal theta-gamma phase-amplitude coupling could support the binding of this information into a coherent memory trace.

EEG and fMRI evidence for autobiographical memory reactivation in empathy.

Empathy relies on the ability to mirror and to explicitly infer others' inner states. Theoretical accounts suggest that memories play a role in empathy, but direct evidence of reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in two experiments. In Experiment 1, electrophysiological activity (EEG) was recorded from 28 participants. Participants performed an empathy task in which targets for empathy were depicted in contexts for which participants either did or did not have an AM, followed by a task that explicitly required memory retrieval of the AM and non-AM contexts. The retrieval task was implemented to extract the neural fingerprints of AM and non-AM contexts, which were then used to probe data from the empathy task. An EEG pattern classifier was trained and tested across tasks and showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Participants self-reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. A second independent fMRI experiment replicated this behavioural finding and showed increased activation for AM compared to non-AM in the brain networks underlying empathy: precuneus, posterior parietal cortex, superior and inferior parietal lobule, and superior frontal gyrus. Together, our study reports behavioural, electrophysiological, and fMRI evidence that robustly supports AM reactivation in empathy.

Two Spatially Distinct Posterior Alpha Sources Fulfill Different Functional Roles in Attention.

Directing attention helps to extract relevant information and suppress distracters. Alpha brain oscillations (8-12 Hz) are crucial for this process, with power decreases facilitating processing of important information and power increases inhibiting brain regions processing irrelevant information. Evidence for this phenomenon arises from visual attention studies (Worden et al., 2000); however, the effect also exists in other modalities, including the somatosensory system (Haegens et al., 2011) and intersensory attention tasks (Foxe and Snyder, 2011). We investigated in human participants (10 females, 10 males) the role of alpha oscillations in focused (0/100%) versus divided (40/60%) attention, both across modalities (visual/somatosensory; Experiment 1) and within the same modality (visual domain: across hemifields; Experiment 2) while recording EEG over 128 scalp electrodes. In Experiment 1, participants divided their attention between visual and somatosensory modality to determine the temporal/spatial frequency of a target stimulus (vibrotactile stimulus/Gabor grating). In Experiment 2, participants divided attention between two visual hemifields to identify the orientation of a Gabor grating. In both experiments, prestimulus alpha power in visual areas decreased linearly with increasing attention to visual stimuli. In contrast, prestimulus alpha power in parietal areas was lower when attention was divided between modalities/hemifields compared with focused attention. These results suggest there are two alpha sources, one of which reflects the "visual spotlight of attention" and the other reflects attentional effort. To our knowledge, this is the first study to show that attention recruits two spatially distinct alpha sources in occipital and parietal brain regions, acting simultaneously but serving different functions in attention.SIGNIFICANCE STATEMENT Attention to one spatial location/sensory modality leads to power changes of alpha oscillations (∼10 Hz) with decreased power over regions processing relevant information and power increases to actively inhibit areas processing "to-be-ignored" information. Here, we used detailed source modeling to investigate EEG data recorded during separate unimodal (visual) and multimodal (visual and somatosensory) attention tasks. Participants either focused their attention on one modality/spatial location or directed it to both. We show for the first time two distinct alpha sources are active simultaneously but play different roles. A sensory (visual) alpha source was linearly modulated by attention representing the "visual spotlight of attention." By contrast, a parietal alpha source was modulated by attentional effort, showing lowest alpha power when attention was divided.

Low-Frequency Oscillations Code Speech during Verbal Working Memory.

The way the human brain represents speech in memory is still unknown. An obvious characteristic of speech is its evolvement over time. During speech processing, neural oscillations are modulated by the temporal properties of the acoustic speech signal, but also acquired knowledge on the temporal structure of language influences speech perception-related brain activity. This suggests that speech could be represented in the temporal domain, a form of representation that the brain also uses to encode autobiographic memories. Empirical evidence for such a memory code is lacking. We investigated the nature of speech memory representations using direct cortical recordings in the left perisylvian cortex during delayed sentence reproduction in female and male patients undergoing awake tumor surgery. Our results reveal that the brain endogenously represents speech in the temporal domain. Temporal pattern similarity analyses revealed that the phase of frontotemporal low-frequency oscillations, primarily in the beta range, represents sentence identity in working memory. The positive relationship between beta power during working memory and task performance suggests that working memory representations benefit from increased phase separation.SIGNIFICANCE STATEMENT Memory is an endogenous source of information based on experience. While neural oscillations encode autobiographic memories in the temporal domain, little is known on their contribution to memory representations of human speech. Our electrocortical recordings in participants who maintain sentences in memory identify the phase of left frontotemporal beta oscillations as the most prominent information carrier of sentence identity. These observations provide evidence for a theoretical model on speech memory representations and explain why interfering with beta oscillations in the left inferior frontal cortex diminishes verbal working memory capacity. The lack of sentence identity coding at the syllabic rate suggests that sentences are represented in memory in a more abstract form compared with speech coding during speech perception and production.

The Sync/deSync Model: How a Synchronized Hippocampus and a Desynchronized Neocortex Code Memories.

Neural oscillations are important for memory formation in the brain. The desynchronization of alpha (10 Hz) oscillations in the neocortex has been shown to predict successful memory encoding and retrieval. However, when engaging in learning, it has been found that the hippocampus synchronizes in theta (4 Hz) oscillations, and that learning is dependent on the phase of theta. This inconsistency as to whether synchronization is "good" for memory formation leads to confusion over which oscillations we should expect to see and where during learning paradigm experiments. This paper seeks to respond to this inconsistency by presenting a neural network model of how a well functioning learning system could exhibit both of these phenomena, i.e., desynchronization of alpha and synchronization of theta during successful memory encoding.We present a spiking neural network (the Sync/deSync model) of the neocortical and hippocampal system. The simulated hippocampus learns through an adapted spike-time dependent plasticity rule, in which weight change is modulated by the phase of an extrinsically generated theta oscillation. Additionally, a global passive weight decay is incorporated, which is also modulated by theta phase. In this way, the Sync/deSync model exhibits theta phase-dependent long-term potentiation and long-term depression. We simulated a learning paradigm experiment and compared the oscillatory dynamics of our model with those observed in single-cell and scalp-EEG studies of the medial temporal lobe. Our Sync/deSync model suggests that both the desynchronization of neocortical alpha and the synchronization of hippocampal theta are necessary for successful memory encoding and retrieval.SIGNIFICANCE STATEMENT A fundamental question is the role of rhythmic activation of neurons, i.e., how and why their firing oscillates between high and low rates. A particularly important question is how oscillatory dynamics between the neocortex and hippocampus support memory formation. We present a spiking neural-network model of such memory formation, with the central ideas that (1) in neocortex, neurons need to break out of an alpha oscillation to represent a stimulus (i.e., alpha desynchronizes), whereas (2) in hippocampus, the firing of neurons at theta facilitates formation of memories (i.e., theta synchronizes). Accordingly, successful memory formation is marked by reduced neocortical alpha and increased hippocampal theta. This pattern has been observed experimentally and gives our model its name-the Sync/deSync model.

Single-Trial Phase Entrainment of Theta Oscillations in Sensory Regions Predicts Human Associative Memory Performance.

Episodic memories are rich in sensory information and often contain integrated information from different sensory modalities. For instance, we can store memories of a recent concert with visual and auditory impressions being integrated in one episode. Theta oscillations have recently been implicated in playing a causal role synchronizing and effectively binding the different modalities together in memory. However, an open question is whether momentary fluctuations in theta synchronization predict the likelihood of associative memory formation for multisensory events. To address this question we entrained the visual and auditory cortex at theta frequency (4 Hz) and in a synchronous or asynchronous manner by modulating the luminance and volume of movies and sounds at 4 Hz, with a phase offset at 0° or 180°. EEG activity from human subjects (both sexes) was recorded while they memorized the association between a movie and a sound. Associative memory performance was significantly enhanced in the 0° compared with the 180° condition. Source-level analysis demonstrated that the physical stimuli effectively entrained their respective cortical areas with a corresponding phase offset. The findings suggested a successful replication of a previous study (Clouter et al., 2017). Importantly, the strength of entrainment during encoding correlated with the efficacy of associative memory such that small phase differences between visual and auditory cortex predicted a high likelihood of correct retrieval in a later recall test. These findings suggest that theta oscillations serve a specific function in the episodic memory system: binding the contents of different modalities into coherent memory episodes.SIGNIFICANCE STATEMENT How multisensory experiences are bound to form a coherent episodic memory representation is one of the fundamental questions in human episodic memory research. Evidence from animal literature suggests that the relative timing between an input and theta oscillations in the hippocampus is crucial for memory formation. We precisely controlled the timing between visual and auditory stimuli and the neural oscillations at 4 Hz using a multisensory entrainment paradigm. Human associative memory formation depends on coincident timing between sensory streams processed by the corresponding brain regions. We provide evidence for a significant role of relative timing of neural theta activity in human episodic memory on a single-trial level, which reveals a crucial mechanism underlying human episodic memory.

Addressing challenges of high spatial resolution UHF fMRI for group analysis of higher-order cognitive tasks: An inter-sensory task directing attention between visual and somatosensory domains.

Functional MRI at ultra-high field (UHF, ≥7 T) provides significant increases in BOLD contrast-to-noise ratio (CNR) compared with conventional field strength (3 T), and has been exploited for reduced field-of-view, high spatial resolution mapping of primary sensory areas. Applying these high spatial resolution methods to investigate whole brain functional responses to higher-order cognitive tasks leads to a number of challenges, in particular how to perform robust group-level statistical analyses. This study addresses these challenges using an inter-sensory cognitive task which modulates top-down attention at graded levels between the visual and somatosensory domains. At the individual level, highly focal functional activation to the task and task difficulty (modulated by attention levels) were detectable due to the high CNR at UHF. However, to assess group level effects, both anatomical and functional variability must be considered during analysis. We demonstrate the importance of surface over volume normalisation and the requirement of no spatial smoothing when assessing highly focal activity. Using novel group analysis on anatomically parcellated brain regions, we show that in higher cognitive areas (parietal and dorsal-lateral-prefrontal cortex) fMRI responses to graded attention levels were modulated quadratically, whilst in visual cortex and VIP, responses were modulated linearly. These group fMRI responses were not seen clearly using conventional second-level GLM analyses, illustrating the limitations of a conventional approach when investigating such focal responses in higher cognitive regions which are more anatomically variable. The approaches demonstrated here complement other advanced analysis methods such as multivariate pattern analysis, allowing UHF to be fully exploited in cognitive neuroscience.

The Temporal Signature of Memories: Identification of a General Mechanism for Dynamic Memory Replay in Humans.

Reinstatement of dynamic memories requires the replay of neural patterns that unfold over time in a similar manner as during perception. However, little is known about the mechanisms that guide such a temporally structured replay in humans, because previous studies used either unsuitable methods or paradigms to address this question. Here, we overcome these limitations by developing a new analysis method to detect the replay of temporal patterns in a paradigm that requires participants to mentally replay short sound or video clips. We show that memory reinstatement is accompanied by a decrease of low-frequency (8 Hz) power, which carries a temporal phase signature of the replayed stimulus. These replay effects were evident in the visual as well as in the auditory domain and were localized to sensory-specific regions. These results suggest low-frequency phase to be a domain-general mechanism that orchestrates dynamic memory replay in humans.

Across-subjects classification of stimulus modality from human MEG high frequency activity.

Single-trial analyses have the potential to uncover meaningful brain dynamics that are obscured when averaging across trials. However, low signal-to-noise ratio (SNR) can impede the use of single-trial analyses and decoding methods. In this study, we investigate the applicability of a single-trial approach to decode stimulus modality from magnetoencephalographic (MEG) high frequency activity. In order to classify the auditory versus visual presentation of words, we combine beamformer source reconstruction with the random forest classification method. To enable group level inference, the classification is embedded in an across-subjects framework. We show that single-trial gamma SNR allows for good classification performance (accuracy across subjects: 66.44%). This implies that the characteristics of high frequency activity have a high consistency across trials and subjects. The random forest classifier assigned informational value to activity in both auditory and visual cortex with high spatial specificity. Across time, gamma power was most informative during stimulus presentation. Among all frequency bands, the 75 Hz to 95 Hz band was the most informative frequency band in visual as well as in auditory areas. Especially in visual areas, a broad range of gamma frequencies (55 Hz to 125 Hz) contributed to the successful classification. Thus, we demonstrate the feasibility of single-trial approaches for decoding the stimulus modality across subjects from high frequency activity and describe the discriminative gamma activity in time, frequency, and space.

Replay of Stimulus-specific Temporal Patterns during Associative Memory Formation.

Forming a memory often entails the association of recent experience with present events. This recent experience is usually an information-rich and dynamic representation of the world around us. We here show that associating a static cue with a previously shown dynamic stimulus yields a detectable, dynamic representation of this stimulus. We further implicate this representation in the decrease of low-frequency power (∼4-30 Hz) in the ongoing EEG, which is a well-known correlate of successful memory formation. The reappearance of content-specific patterns in desynchronizing brain oscillations was observed in two sensory domains, that is, in a visual condition and in an auditory condition. Together with previous results, these data suggest a mechanism that generalizes across domains and processes, in which the decrease in oscillatory power allows for the dynamic representation of information in ongoing brain oscillations.

Episodic Memory Retrieval Functionally Relies on Very Rapid Reactivation of Sensory Information.

Episodic memory retrieval is assumed to rely on the rapid reactivation of sensory information that was present during encoding, a process termed "ecphory." We investigated the functional relevance of this scarcely understood process in two experiments in human participants. We presented stimuli to the left or right of fixation at encoding, followed by an episodic memory test with centrally presented retrieval cues. This allowed us to track the reactivation of lateralized sensory memory traces during retrieval. Successful episodic retrieval led to a very early (∼100-200 ms) reactivation of lateralized alpha/beta (10-25 Hz) electroencephalographic (EEG) power decreases in the visual cortex contralateral to the visual field at encoding. Applying rhythmic transcranial magnetic stimulation to interfere with early retrieval processing in the visual cortex led to decreased episodic memory performance specifically for items encoded in the visual field contralateral to the site of stimulation. These results demonstrate, for the first time, that episodic memory functionally relies on very rapid reactivation of sensory information. SIGNIFICANCE STATEMENT: Remembering personal experiences requires a "mental time travel" to revisit sensory information perceived in the past. This process is typically described as a controlled, relatively slow process. However, by using electroencephalography to measure neural activity with a high time resolution, we show that such episodic retrieval entails a very rapid reactivation of sensory brain areas. Using transcranial magnetic stimulation to alter brain function during retrieval revealed that this early sensory reactivation is causally relevant for conscious remembering. These results give first neural evidence for a functional, preconscious component of episodic remembering. This provides new insight into the nature of human memory and may help in the understanding of psychiatric conditions that involve the automatic intrusion of unwanted memories.

Temporal-pattern similarity analysis reveals the beneficial and detrimental effects of context reinstatement on human memory.

A powerful force in human memory is the context in which memories are encoded (Tulving and Thomson, 1973). Several studies suggest that the reinstatement of neural encoding patterns is beneficial for memory retrieval (Manning et al., 2011; Staresina et al., 2012; Jafarpour et al., 2014). However, reinstatement of the original encoding context is not always helpful, for instance, when retrieving a memory in a different contextual situation (Smith and Vela, 2001). It is an open question whether such context-dependent memory effects can be captured by the reinstatement of neural patterns. We investigated this question by applying temporal and spatial pattern similarity analysis in MEG and intracranial EEG in a context-match paradigm. Items (words) were tagged by individual dynamic context stimuli (movies). The results show that beta oscillatory phase in visual regions and the parahippocampal cortex tracks the incidental reinstatement of individual context trajectories on a single-trial level. Crucially, memory benefitted from reinstatement when the encoding and retrieval contexts matched but suffered from reinstatement when the contexts did not match.

Brain oscillations track the formation of episodic memories in the real world.

Despite the well-known influence of environmental context on episodic memory, little has been done to increase contextual richness within the lab. This leaves a blind spot lingering over the neuronal correlates of episodic memory formation in day-to-day life. To address this, we presented participants with a series of words to memorise along a pre-designated route across campus while a mobile EEG system acquired ongoing neural activity. Replicating lab-based subsequent memory effects (SMEs), we identified significant low to mid frequency power decreases (<30Hz), including beta power decreases over the left inferior frontal gyrus. When investigating the oscillatory correlates of temporal and spatial context binding, we found that items strongly bound to spatial context exhibited significantly greater theta power decreases than items strongly bound to temporal context. These findings expand upon lab-based studies by demonstrating the influence of real world contextual factors that underpin memory formation.

Brain Oscillations Mediate Successful Suppression of Unwanted Memories.

To avoid thinking of unwanted memories can be a successful strategy to forget. Studying brain oscillations as measures of local and inter-regional processing, we shed light on the neural dynamics underlying memory suppression. Employing the think/no-think paradigm, 24 healthy human subjects repeatedly retrieved (think condition) or avoided thinking of (no-think condition) a previously learned target memory upon being presented with a reminder stimulus. Think and no-think instructions were delivered by means of a precue that preceded the reminder by 1 s. This allowed us to segregate neural control mechanisms that were triggered by the precue from the effect of suppression on target memory networks after presentation of the reminder. Control effects were reflected in increased power in the theta (5-9 Hz) frequency band in the medial and dorsolateral prefrontal cortex and higher long-range alpha (10-14 Hz) phase synchronization. Successful suppression of target memories was reflected in a decrease of theta oscillatory power in the medial temporal lobes and reduced long-range theta phase synchronization emerged after presentation of the reminder. Our results suggest that intentional memory suppression correlates with increased neural communication in cognitive control networks that act in down-regulating local and inter-regional processing related to memory retrieval.