Neural activity differentiates novel and learned event boundaries.

People parse continuous experiences at natural breakpoints called event boundaries, which is important for understanding an environment's causal structure and for responding to uncertainty within it. However, it remains unclear how different forms of uncertainty affect the parsing of continuous experiences and how such uncertainty influences the brain's processing of ongoing events. We exposed human participants of both sexes (N = 34) to a continuous sequence of semantically meaningless images. We generated sequences from random walks through a graph that grouped images into temporal communities. After learning, we asked participants to segment another sequence at natural breakpoints (event boundaries). Participants segmented the sequence at learned transitions between communities, as well as at novel transitions, suggesting that people can segment temporally extended experiences into events based on learned structure as well as prediction error. Greater segmentation at Novel boundaries was associated with enhanced parietal scalp EEG activity between 250-450 ms after stimulus onset. Multivariate classification of EEG activity showed that Novel and Learned boundaries evoked distinct patterns of neural activity, particularly theta band power in posterior electrodes. Learning also led to distinct neural representations for stimuli within the temporal communities, while neural activity at Learned boundary nodes showed predictive evidence for the adjacent community. The data show that people segment experiences at both learned and novel boundaries and suggest that learned event boundaries trigger retrieval of information about the upcoming community that could underlie anticipation of the next event in a sequence.Significance Statement People make sense of their continuous experience by segmenting it into meaningful units at event boundaries. Event boundaries influence cognitive function in a variety of ways, however it remains unclear how different forms of uncertainty affect the parsing of continuous experiences, and how such uncertainty might influence the brain's processing of ongoing events. We found that although people segment experiences at both learned and novel boundaries, brain activity diverges rapidly (250-450 ms post-stimulus) in response to different types of event boundaries. The findings suggest the brain can flexibly respond to event boundaries of distinct types, which could support dynamic modulation and updating of neural activity in response to ongoing experience.

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.

Neural Evidence for Representational Persistence Within Events.

How does the brain process continuous experiences so they can be remembered? Evidence suggests that people perceive their experience as a series of distinct and meaningful events. Information encountered within the same event shows greater temporal integration into memory as well as enhanced neural representational similarity. Although these data support the theory that the brain builds and maintains a mental model of the current event that represents recently encountered stimulus information, this hypothesis has not been directly tested. We used fMRI in humans (N = 21, 13 female) to test whether within-event neural similarity indicates the persistence of stimulus representations in a mental model. Participants viewed trial-unique visual images that were grouped into events. We calculated neural pattern similarity across time in the category-selective visual cortex to measure stimulus persistence. Pattern similarity was enhanced within, compared with between, events in the object-sensitive left lateral occipital (LO) cortex. This was specific to situations when objects could persist within a mental model, suggesting modulation of neural activity based on the features and structure of the event. Left LO object persistence was correlated with activity in a medial prefrontal cortex (mPFC) region linked to representing mental models within events. mFPC activity also correlated with pattern similarity in the hippocampus but more generally across stimulus categories. Critically, left LO similarity was related to estimates of temporal proximity in memory. The data suggest that temporal neural stability reflects stimulus persistence in mental models and highlight the importance of within-event representational stability in the transformation of experience to memory.SIGNIFICANCE STATEMENT How does the brain process continuous experiences so they can be remembered? One idea is that information persists in mental models during stable events, facilitating the organization of events in memory. Using fMRI pattern similarity analysis, we found enhanced similarity within, compared with between, events in the object-sensitive LO but only when objects could persist within a mental model. mPFC activity correlated with left LO similarity when objects persisted within an event; in contrast, mPFC activity correlated with hippocampal similarity across stimulus categories. Left LO persistence was also related to the remembered temporal proximity of stimuli. The data suggest the brain dynamically maintains stimulus information in mental models during events, supporting the transformation of experience into memory.

Differentiation of Human Medial Prefrontal Cortex Activity Underlies Long-Term Resistance to Forgetting in Memory.

It is well known that distributing study events over time leads to better memory over long time scales, compared with massing study events together. One explanation for such long-term resistance to forgetting is that distributed study leads to neural differentiation in memory, which supports retrieval of past experiences by disambiguating highly similar memory representations. Neuroanatomical models of episodic memory retrieval propose that the hippocampus and medial prefrontal cortex (MPFC) work together to enable retrieval of behaviorally appropriate memories. However, it is not known how representations in these regions jointly support resistance to forgetting long after initial learning. Using fMRI, we measured differentiation in retrieved memory representations following an extended delay in male and female human participants. After 1 week, word-object associations were better remembered if studied across 2 d (overnight), allowing associations to be learned in distinct temporal contexts, compared with learning within a single day (same day). MPFC retrieval patterns showed differentiation for overnight relative to same day memories, whereas hippocampal patterns reflected associative retrieval success. Overnight memory differentiation in MPFC was higher for associative than item memories and higher than differentiation assessed over a brain-wide set of retrieval-active voxels. The memory-related difference in MPFC pattern differentiation correlated with memory success for overnight learning and with hippocampal-MPFC functional connectivity. These results show that learning information across days leads to differentiated MPFC memory representations, reducing forgetting after 1 week, and suggest this arises from persistent interactions between MPFC and hippocampus.SIGNIFICANCE STATEMENT Neural activity in both the hippocampus and medial prefrontal cortex (MPFC) has been linked to memory-related representations, but prior work has not examined how these representations support episodic memory retrieval over extended time scales that are characteristic of everyday retrieval. We show that differentiation in MPFC activity 1 week after encoding is higher for retrieved information learned across 2 d compared with within a single day. In hippocampus, differentiation was greater for detailed memory retrieval but was not influenced by whether information had been learned over 1 or 2 d. Differentiation in MPFC predicted behavioral robustness to forgetting and was correlated with hippocampal-MPFC connectivity. The results suggest that context-based differentiation supports robust long-term memory via persistent MPFC-hippocampal interactions.

Electrical Stimulation in Hippocampus and Entorhinal Cortex Impairs Spatial and Temporal Memory.

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.SIGNIFICANCE STATEMENT Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex.

Direct electrical stimulation of the human brain can elicit sensory and motor perceptions as well as recall of memories. Stimulating higher order association areas of the lateral temporal cortex in particular was reported to activate visual and auditory memory representations of past experiences (Penfield and Perot, 1963). We hypothesized that this effect could be used to modulate memory processing. Recent attempts at memory enhancement in the human brain have been focused on the hippocampus and other mesial temporal lobe structures, with a few reports of memory improvement in small studies of individual brain regions. Here, we investigated the effect of stimulation in four brain regions known to support declarative memory: hippocampus, parahippocampal neocortex, prefrontal cortex and temporal cortex. Intracranial electrode recordings with stimulation were used to assess verbal memory performance in a group of 22 patients (nine males). We show enhanced performance with electrical stimulation in the lateral temporal cortex (paired t-test, P = 0.0067), but not in the other brain regions tested. This selective enhancement was observed both on the group level, and for two of the four individual subjects stimulated in the temporal cortex. This study shows that electrical stimulation in specific brain areas can enhance verbal memory performance in humans.awx373media15704855796001.

Similar patterns of neural activity predict memory function during encoding and retrieval.

Neural networks that span the medial temporal lobe (MTL), prefrontal cortex, and posterior cortical regions are essential to episodic memory function in humans. Encoding and retrieval are supported by the engagement of both distinct neural pathways across the cortex and common structures within the medial temporal lobes. However, the degree to which memory performance can be determined by neural processing that is common to encoding and retrieval remains to be determined. To identify neural signatures of successful memory function, we administered a delayed free-recall task to 187 neurosurgical patients implanted with subdural or intraparenchymal depth electrodes. We developed multivariate classifiers to identify patterns of spectral power across the brain that independently predicted successful episodic encoding and retrieval. During encoding and retrieval, patterns of increased high frequency activity in prefrontal, MTL, and inferior parietal cortices, accompanied by widespread decreases in low frequency power across the brain predicted successful memory function. Using a cross-decoding approach, we demonstrate the ability to predict memory function across distinct phases of the free-recall task. Furthermore, we demonstrate that classifiers that combine information from both encoding and retrieval states can outperform task-independent models. These findings suggest that the engagement of a core memory network during either encoding or retrieval shapes the ability to remember the past, despite distinct neural interactions that facilitate encoding and retrieval.

The end point of the ventral visual stream: face and non-face perceptual deficits following unilateral anterior temporal lobe damage.

While it has been claimed that the ventral visual stream ends in the inferior aspects of the anterior temporal lobe (ATL), little is known about whether this region is important for visual perception. Here the performance of two patients with unilateral ATL damage was assessed across four visual perception tasks that parametrically varied stimulus similarity. Patients performed normally on difficult judgments of circle size or face age but were impaired on face identity and dot pattern matching tasks. Portions of the ATL, most likely the ventral surface, may have a functional role in visual perception tasks requiring detailed configural processing, most commonly used to discern facial identity.

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.

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.

What constitutes an episode in episodic memory?

The idea of episodic memory implies the existence of a process that segments experience into episodes so that they can be stored in memory. It is therefore surprising that the link between event segmentation and the organization of experiences into episodes in memory has not been addressed. We found that after participants read narratives containing temporal event boundaries at varying locations in the narrative, their long-term associative memory for information across event boundaries was lower than their memory for information within an event. This suggests that event segmentation during encoding resulted in segmentation of those same events in memory. Further, functional imaging data revealed that, across participants, brain activity consistent with the ongoing integration of information within events correlated with this pattern of mnemonic segmentation. These data are the first to address the mechanisms that support the organization of experiences into episodes in long-term memory.

Distinct cortical systems reinstate the content and context of episodic memories.

Episodic recall depends upon the reinstatement of cortical activity present during the formation of a memory. Evidence from functional neuroimaging and invasive recordings in humans suggest that reinstatement organizes our memories by time or content, yet the neural systems involved in reinstating these unique types of information remain unclear. Here, combining computational modeling and intracranial recordings from 69 epilepsy patients, we show that two cortical systems uniquely reinstate the semantic content and temporal context of previously studied items during free recall. Examining either the posterior medial or anterior temporal networks, we find that forward encoding models trained on the brain's response to the temporal and semantic attributes of items can predict the serial position and semantic category of unseen items. During memory recall, these models uniquely link reinstatement of temporal context and semantic content to these posterior and anterior networks, respectively. These findings demonstrate how specialized cortical systems enable the human brain to target specific memories.

Probing Network Mechanisms of Brain Stimulation in the Mood Circuit.

Direct brain stimulation has diverse effects on network activity. In this issue of Neuron, Qiao et al. (2020) demonstrate a novel approach for using stimulation to characterize and modulate interactions between areas of the mood processing network.

Tonic Resting State Hubness Supports High Gamma Activity Defined Verbal Memory Encoding Network in Epilepsy.

High gamma activity (HGA) of verbal-memory encoding using invasive-electroencephalogram has laid the foundation for numerous studies testing the integrity of memory in diseased populations. Yet, the functional connectivity characteristics of networks subserving these memory linkages remains uncertain. By integrating this electrophysiological biomarker of memory encoding from IEEG with resting-state BOLD fluctuations, we estimated the segregation and hubness of HGA-memory regions in drug-resistant epilepsy patients and matched healthy controls. HGA-memory regions express distinctly different hubness compared to neighboring regions in health and in epilepsy, and this hubness was more relevant than segregation in predicting verbal memory encoding. The HGA-memory network comprised regions from both the cognitive control and primary processing networks, validating that effective verbal-memory encoding requires integrating brain functions, and is not dominated by a central cognitive core. Our results demonstrate a tonic intrinsic set of functional connectivity, which provides the necessary conditions for effective, phasic, task-dependent memory encoding.

Does data cleaning improve brain state classification?

BACKGROUND: Neuroscientists routinely seek to identify and remove noisy or artifactual observations from their data. They do so with the belief that removing such data improves power to detect relations between neural activity and behavior, which are often subtle and can be overwhelmed by noise. Whereas standard methods can exclude certain well-defined noise sources (e.g., 50/60 Hz electrical noise), in many situations there is not a clear difference between noise and signals so it is not obvious how to separate the two. Here we ask whether methods routinely used to "clean" human electrophysiological recordings lead to greater power to detect brain-behavior relations. NEW METHOD: This, to the authors' knowledge, is the first large-scale simultaneous evaluation of multiple commonly used methods for removing noise from intracranial EEG recordings. RESULTS: We find that several commonly used data cleaning methods (automated methods based on statistical signal properties and manual methods based on expert review) do not increase the power to detect univariate and multivariate electrophysiological biomarkers of successful episodic memory encoding, a well-characterized broadband pattern of neural activity observed across the brain. COMPARISON WITH EXISTING METHODS: Researchers may be more likely to increase statistical power to detect physiological phenomena of interest by allocating resources away from cleaning noisy data and toward collecting more within-patient observations. CONCLUSIONS: These findings highlight the challenge of partitioning signal and noise in the analysis of brain-behavior relations, and suggest increasing sample size and numbers of observations, rather than data cleaning, as the best approach to improving statistical power.

Functional control of electrophysiological network architecture using direct neurostimulation in humans.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

The Enigmatic temporal pole: a review of findings on social and emotional processing.

The function of the anterior-most portion of the temporal lobes, the temporal pole, is not well understood. Anatomists have long considered it part of an extended limbic system based on its location posterior to the orbital frontal cortex and lateral to the amygdala, along with its tight connectivity to limbic and paralimbic regions. Here we review the literature in both non-human primates and humans to assess the temporal pole's putative role in social and emotional processing. Reviewed findings indicate that it has some role in both social and emotional processes, including face recognition and theory of mind, that goes beyond semantic memory. We propose that the temporal pole binds complex, highly processed perceptual inputs to visceral emotional responses. Because perceptual inputs remain segregated into dorsal (auditory), medial (olfactory) and ventral (visual) streams, the integration of emotion with perception is channel specific.

Perceptual boundaries cause mnemonic trade-offs between local boundary processing and across-trial associative binding.

Episodic memories are not veridical records of our lives, but rather are better described as organized summaries of experience. Theories and empirical research suggest that shifts in perceptual, temporal, and semantic information lead to a chunking of our continuous experiences into segments, or "events." However, the consequences of these contextual shifts on memory formation and organization remains unclear. In a series of 3 behavioral studies, we introduced context shifts (or "event boundaries") between trains of stimuli and then examined the influence of the boundaries on several measures of associative memory. In Experiment 1, we found that perceptual event boundaries strengthened associative binding of item-context pairings present at event boundaries. In Experiment 2, we observed reduced temporal order memory for items encoded in distinct events relative to items encoded within the same event, and a trade-off between the speed of processing at boundaries, and temporal order memory for items that flanked those boundaries. Finally, in Experiment 3 we found that event organization imprinted structure on the order in which items were freely recalled. These results provide insight into how boundary- and event-related organizational processes during encoding shape subsequent representations of events in episodic memory. (PsycINFO Database Record

Electrical Stimulation Modulates High γ Activity and Human Memory Performance.

Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with "poor" memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation.

Closed-loop stimulation of temporal cortex rescues functional networks and improves memory.

Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction.