EEG decoders track memory dynamics.

Encoding- and retrieval-related neural activity jointly determine mnemonic success. We ask whether electroencephalographic activity can reliably predict encoding and retrieval success on individual trials. Each of 98 participants performed a delayed recall task on 576 lists across 24 experimental sessions. Logistic regression classifiers trained on spectral features measured immediately preceding spoken recall of individual words successfully predict whether or not those words belonged to the target list. Classifiers trained on features measured during word encoding also reliably predict whether those words will be subsequently recalled and further predict the temporal and semantic organization of the recalled items. These findings link neural variability predictive of successful memory with item-to-context binding, a key cognitive process thought to underlie episodic memory function.

MTL neurons phase-lock to human hippocampal theta.

Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here, we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2-4 Hz) or fast (6-10 Hz) theta bands, with a significant subset exhibiting nested slow theta × beta frequency (13-20 Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.

Human Hippocampal Ripples Signal Encoding of Episodic Memories.

Direct human brain recordings have confirmed the presence of high-frequency oscillatory events, termed ripples, during awake behavior. While many prior studies have focused on medial temporal lobe (MTL) ripples during memory retrieval, here we investigate ripples during memory encoding. Specifically, we ask whether ripples during encoding predict whether and how memories are subsequently recalled. Detecting ripples from MTL electrodes implanted in 116 neurosurgical participants (n = 61 male) performing a verbal episodic memory task, we find that encoding ripples do not distinguish recalled from not recalled items in any MTL region, even as high-frequency activity during encoding predicts recall in these same regions. Instead, hippocampal ripples increase during encoding of items that subsequently lead to recall of temporally and semantically associated items during retrieval, a phenomenon known as clustering. This subsequent clustering effect arises specifically when hippocampal ripples co-occur during encoding and retrieval, suggesting that ripples mediate both encoding and reinstatement of episodic memories.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Benefits of sharing neurophysiology data from the BRAIN Initiative Research Opportunities in Humans Consortium.

Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.

A neural code for time and space in the human brain.

Time and space are primary dimensions of human experience. Separate lines of investigation have identified neural correlates of time and space, yet little is known about how these representations converge during self-guided experience. Here, 10 subjects with intracranially implanted microelectrodes play a timed, virtual navigation game featuring object search and retrieval tasks separated by fixed delays. Time cells and place cells activate in parallel during timed navigation intervals, whereas a separate time cell sequence spans inter-task delays. The prevalence, firing rates, and behavioral coding strengths of time cells and place cells are indistinguishable-yet time cells selectively remap between search and retrieval tasks, while place cell responses remain stable. Thus, the brain can represent time and space as overlapping but dissociable dimensions. Time cells and place cells may constitute a biological basis for the cognitive map of spatiotemporal context onto which memories are written.

Hippocampal activity predicts contextual misattribution of false memories.

Failure of contextual retrieval can lead to false recall, wherein people retrieve an item or experience that occurred in a different context or did not occur at all. Whereas the hippocampus is thought to play a crucial role in memory retrieval, we lack understanding of how the hippocampus supports retrieval of items related to a target context while disregarding related but irrelevant information. Using direct electrical recordings from the human hippocampus, we investigate the neural process underlying contextual misattribution of false memories. In two large datasets, we characterize key physiological differences between correct and false recalls that emerge immediately prior to vocalization. By differentiating between false recalls that share high or low contextual similarity with the target context, we show that low-frequency activity (6 to 18 Hz) in the hippocampus tracks similarity between the current and retrieved context. Applying multivariate decoding methods, we were able to reliably predict the contextual source of the to-be-recalled item. Our findings elucidate one of the hallmark features of episodic memory: our ability to distinguish between memories that were formed on different occasions.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Biomarker-guided neuromodulation aids memory in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

Forward and backward recall dynamics.

Although possible to recall in both forward and backward order, recall proceeds most naturally in the order of encoding. Prior studies ask whether and how forward and backward recall differ. We reexamine this classic question by studying recall dynamics while varying the predictability and timing of forward and backward cues. Although overall accuracy did not differ by recall direction, recall dynamics highlight key distinctions. Forward recall exhibits a modest advantage for correct transitions following errors, independent of cueing predictability and list length. Without consistent directional cueing, participants initiate backward recall more accurately, but this effect reverses with predictable directional cues. Following omissions, participants commit more fill-in errors in backward recall. Our findings implicate an asymmetric, cue-dependent retrieval process underlying forward and backward recall, with relative contributions of primacy and recency depending on directional predictability. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.

Hippocampal Theta and Episodic Memory.

Computational models of rodent physiology implicate hippocampal theta as a key modulator of learning and memory (Buzsáki and Moser, 2013; Lisman and Jensen, 2013), yet human hippocampal recordings have shown divergent theta correlates of memory formation. Herweg et al. (2020) suggest that decreases in memory-related broadband power mask narrowband theta increases. Their survey also notes that the theta oscillations appear most prominently in contrasts that isolate memory retrieval processes and when aggregating signals across large brain regions. We evaluate these hypotheses by analyzing human hippocampal recordings captured as 162 neurosurgical patients (n = 86 female) performed a free recall task. Using the Irregular-Resampling Auto-Spectral Analysis (IRASA) to separate broad and narrowband components of the field potential, we show that (1) broadband and narrowband components of theta exhibit opposite effects, with broadband signals decreasing and narrowband theta increasing during successful encoding; (2) whereas low-frequency theta oscillations increase before successful recall, higher-frequency theta and alpha oscillations decrease, masking the positive effect of theta when aggregating across the full band; and (3) the effects of theta on memory encoding and retrieval do not differ between reference schemes that accentuate local signals (bipolar) and those that aggregate signals globally (whole-brain average). In line with computational models that ascribe a fundamental role for hippocampal theta in memory, our large-scale study of human hippocampal recordings shows that 3-4 Hz theta oscillations reliably increase during successful memory encoding and before spontaneous recall of previously studied items.SIGNIFICANCE STATEMENT Analyzing recordings from 162 participants, we resolve a long-standing question regarding the role of hippocampal theta oscillations in the formation and retrieval of episodic memories. We show that broadband spectral changes confound estimates of narrowband theta activity, thereby accounting for inconsistent results in the literature. After accounting for broadband effects, we find that increased theta activity marks successful encoding and retrieval of episodic memories, supporting rodent models that ascribe a key role for hippocampal theta in memory function.

Direct brain recordings suggest a causal subsequent-memory effect.

Endogenous variation in brain state and stimulus-specific evoked activity can both contribute to successful encoding. Previous studies, however, have not clearly distinguished among these components. We address this question by analysing intracranial EEG recorded from epilepsy patients as they studied and subsequently recalled lists of words. We first trained classifiers to predict recall of either single items or entire lists and found that both classifiers exhibited similar performance. We found that list-level classifier output-a biomarker of successful encoding-tracked item presentation and recall events, despite having no information about the trial structure. Across widespread brain regions, decreased low- and increased high-frequency activity (HFA) marked successful encoding of both items and lists. We found regional differences in the hippocampus and prefrontal cortex, where in the hippocampus HFA correlated more strongly with item recall, whereas, in the prefrontal cortex, HFA correlated more strongly with list performance. Despite subtle differences in item- and list-level features, the similarity in overall classification performance, spectral signatures of successful recall and fluctuations of spectral activity across the encoding period argue for a shared endogenous process that causally impacts the brain's ability to learn new information.

Modality effects in free recall: A retrieved-context account.

The modality effect refers to the robust finding that memory performance differs for items presented aurally, as compared with visually. Whereas auditory presentation leads to stronger recency performance in immediate recall, visual presentation often produces better primacy performance (the inverse modality effect). To investigate and model these differences, we conducted two large-scale web-based immediate free recall experiments. In both experiments, participants studied visual and auditory word lists of varying lengths and rates of presentation. We observed typical modality and inverse modality effects, while also discovering that participants were more likely to initiate recall from recent items on auditory trials than on visual trials. However, modality effects persisted regardless of the first item recalled. Meanwhile, an analysis of intrusion errors revealed that participants were more likely on visual trials than on auditory trials to erroneously recall words from one list prior. Furthermore, words presented in the same modality as the present list intruded more often than those presented in a different modality. We next developed a retrieved-context account of the modality effect by fitting the Context Maintenance and Retrieval model to data across multiple list lengths. Through our simulations, we demonstrate that the modality effect can be explained by faster contextual drift and stronger context-to-item association formation during auditory presentation, relative to visual. Our modeling shows that modality effects can arise without hypothesizing distinct memory stores for recent and remote information. Finally, we propose that modality effects may derive primarily from the temporal dynamics of stimuli, rather than their modality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Hippocampal ripples signal contextually mediated episodic recall.

High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples support memory retrieval. However, it is unclear if ripples signal the reinstatement of episodic memories. Analyzing electrophysiological MTL recordings from 245 neurosurgical participants performing episodic recall tasks, we find that the rate of hippocampal ripples rises just prior to the free recall of recently formed memories. This prerecall ripple effect (PRE) is stronger in the CA1 and CA3/dentate gyrus (CA3/DG) subfields of the hippocampus than the neighboring MTL regions entorhinal and parahippocampal cortex. PRE is also stronger prior to the retrieval of temporally and semantically clustered, as compared with unclustered, recalls, indicating the involvement of ripples in contextual reinstatement, which is a hallmark of episodic memory.

Advances in human intracranial electroencephalography research, guidelines and good practices.

Since the second-half of the twentieth century, intracranial electroencephalography (iEEG), including both electrocorticography (ECoG) and stereo-electroencephalography (sEEG), has provided an intimate view into the human brain. At the interface between fundamental research and the clinic, iEEG provides both high temporal resolution and high spatial specificity but comes with constraints, such as the individual's tailored sparsity of electrode sampling. Over the years, researchers in neuroscience developed their practices to make the most of the iEEG approach. Here we offer a critical review of iEEG research practices in a didactic framework for newcomers, as well addressing issues encountered by proficient researchers. The scope is threefold: (i) review common practices in iEEG research, (ii) suggest potential guidelines for working with iEEG data and answer frequently asked questions based on the most widespread practices, and (iii) based on current neurophysiological knowledge and methodologies, pave the way to good practice standards in iEEG research. The organization of this paper follows the steps of iEEG data processing. The first section contextualizes iEEG data collection. The second section focuses on localization of intracranial electrodes. The third section highlights the main pre-processing steps. The fourth section presents iEEG signal analysis methods. The fifth section discusses statistical approaches. The sixth section draws some unique perspectives on iEEG research. Finally, to ensure a consistent nomenclature throughout the manuscript and to align with other guidelines, e.g., Brain Imaging Data Structure (BIDS) and the OHBM Committee on Best Practices in Data Analysis and Sharing (COBIDAS), we provide a glossary to disambiguate terms related to iEEG research.

Temporal lobe interictal spikes disrupt encoding and retrieval of verbal memory: A subregion analysis.

OBJECTIVE: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall. METHODS: Seventy-eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre-encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed-effects logistic regression. RESULTS: IS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63-.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27-.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66-.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62-.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08-.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07-.8, p < .05) reduced the probability of recalling a word. SIGNIFICANCE: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory.

Features of intracranial interictal epileptiform discharges associated with memory encoding.

OBJECTIVE: Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding. METHODS: Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance. RESULTS: We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance. SIGNIFICANCE: Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity.

Theta-burst stimulation entrains frequency-specific oscillatory responses.

BACKGROUND: Brain stimulation has emerged as a powerful tool in human neuroscience, becoming integral to next-generation psychiatric and neurologic therapeutics. Theta-burst stimulation (TBS), in which electrical pulses are delivered in rhythmic bouts of 3-8 Hz, seeks to recapitulate neural activity seen endogenously during cognitive tasks. A growing literature suggests that TBS can be used to alter or enhance cognitive processes, but little is known about how these stimulation events influence underlying neural activity. OBJECTIVE: Our study sought to investigate the effect of direct electrical TBS on mesoscale neural activity in humans by asking (1) whether TBS evokes persistent theta oscillations in cortical areas, (2) whether these oscillations occur at the stimulated frequency, and (3) whether stimulation events propagate in a manner consistent with underlying functional and structural brain architecture. METHODS: We recruited 20 neurosurgical epilepsy patients with indwelling electrodes and delivered direct cortical TBS at varying locations and frequencies. Simultaneous iEEG was recorded from non-stimulated electrodes and analyzed to understand how TBS influences mesoscale neural activity. RESULTS: We found that TBS rapidly evoked theta rhythms in widespread brain regions, preferentially at the stimulation frequency, and that these oscillations persisted for hundreds of milliseconds post stimulation offset. Furthermore, the functional connectivity between recording and stimulation sites predicted the strength of theta response, suggesting that underlying brain architecture guides the flow of stimulation through the brain. CONCLUSIONS: By demonstrating that cortical TBS induces frequency-specific oscillatory responses, our results suggest this technology can be used to directly and predictably influence the activity of cognitively-relevant brain networks.