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.

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.

Human hippocampal responses to network intracranial stimulation vary with theta phase.

Hippocampal-dependent memory is thought to be supported by distinct connectivity states, with strong input to the hippocampus benefitting encoding and weak input benefitting retrieval. Previous research in rodents suggests that the hippocampal theta oscillation orchestrates the transition between these states, with opposite phase angles predicting minimal versus maximal input. We investigated whether this phase dependence exists in humans using network-targeted intracranial stimulation. Intracranial local field potentials were recorded from individuals with epilepsy undergoing medically necessary stereotactic electroencephalographic recording. In each subject, biphasic bipolar direct electrical stimulation was delivered to lateral temporal sites with demonstrated connectivity to hippocampus. Lateral temporal stimulation evoked ipsilateral hippocampal potentials with distinct early and late components. Using evoked component amplitude to measure functional connectivity, we assessed whether the phase of hippocampal theta predicted relatively high versus low connectivity. We observed an increase in the continuous phase-amplitude relationship selective to the early and late components of the response evoked by lateral temporal stimulation. The maximal difference in these evoked component amplitudes occurred across 180 degrees of separation in the hippocampal theta rhythm; that is, the greatest difference in component amplitude was observed when stimulation was delivered at theta peak versus trough. The pattern of theta-phase dependence observed for hippocampus was not identified for control locations. These findings demonstrate that hippocampal receptivity to input varies with theta phase, suggesting that theta phase reflects connectivity states of human hippocampal networks. These findings confirm a putative mechanism by which neural oscillations modulate human hippocampal function.

Looking for the neural basis of memory.

Memory neuroscientists often measure neural activity during task trials designed to recruit specific memory processes. Behavior is championed as crucial for deciphering brain-memory linkages but is impoverished in typical experiments that rely on summary judgments. We criticize this approach as being blind to the multiple cognitive, neural, and behavioral processes that occur rapidly within a trial to support memory. Instead, time-resolved behaviors such as eye movements occur at the speed of cognition and neural activity. We highlight successes using eye-movement tracking with in vivo electrophysiology to link rapid hippocampal oscillations to encoding and retrieval processes that interact over hundreds of milliseconds. This approach will improve research on the neural basis of memory because it pinpoints discrete moments of brain-behavior-cognition correspondence.

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.

Rapid coordination of effective learning by the human hippocampus.

Although the human hippocampus is necessary for long-term memory, controversial findings suggest that it may also support short-term memory in the service of guiding effective behaviors during learning. We tested the counterintuitive theory that the hippocampus contributes to long-term memory through remarkably short-term processing, as reflected in eye movements during scene encoding. While viewing scenes for the first time, short-term retrieval operative within the episode over only hundreds of milliseconds was indicated by a specific eye-movement pattern, which was effective in that it enhanced spatiotemporal memory formation. This viewing pattern was predicted by hippocampal theta oscillations recorded from depth electrodes and by shifts toward top-down influence of hippocampal theta on activity within visual perception and attention networks. The hippocampus thus supports short-term memory processing that coordinates behavior in the service of effective spatiotemporal learning.

Enhanced reinstatement of naturalistic event memories due to hippocampal-network-targeted stimulation.

Episodic memory involves the reinstatement of distributed patterns of brain activity present when events were initially experienced. The hippocampus is thought to coordinate reinstatement via its interactions with a network of brain regions, but this hypothesis has not been causally tested in humans. The current study directly tested the involvement of the hippocampal network in reinstatement using network-targeted noninvasive stimulation. We measured reinstatement of multi-voxel patterns of functional magnetic resonance imaging (fMRI) activity during encoding and retrieval of naturalistic video clips depicting everyday activities. Reinstatement of video-specific activity patterns was robust in posterior parietal and occipital areas previously implicated in event reinstatement. Theta-burst stimulation targeting the hippocampal network increased video-specific reinstatement of fMRI activity patterns in occipital cortex and improved memory accuracy relative to stimulation of a control out-of-network location. Furthermore, stimulation targeting the hippocampal network influenced the trial-by-trial relationship between hippocampal activity during encoding and later reinstatement in occipital cortex. These findings implicate the hippocampal network in the reinstatement of spatially distributed patterns of event-specific activity and identify a role for the hippocampus in encoding complex naturalistic events that later undergo cortical reinstatement.

Temporal context guides visual exploration during scene recognition.

Memories for episodes are temporally structured. Cognitive models derived from list-learning experiments attribute this structure to the retrieval of temporal context information that indicates when a memory occurred. These models predict key features of memory recall, such as the strong tendency to retrieve studied items in the order in which they were first encountered. Can such models explain ecological memory behaviors, such as eye movements during encoding and retrieval of complex visual stimuli? We tested predictions from retrieved-context models using three data sets involving recognition memory and free viewing of complex scenes. Subjects reinstated sequences of eye movements from one scene-viewing episode to the next. Moreover, sequence reinstatement decayed over time and was associated with successful memory. We observed memory-driven reinstatement even after accounting for intrinsic scene properties that produced consistent eye movements. These findings confirm predictions of retrieved-context models, suggesting retrieval of temporal context influences complex behaviors generated during naturalistic memory experiences. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Hippocampal theta coordinates memory processing during visual exploration.

The hippocampus supports memory encoding and retrieval, which may occur at distinct phases of the theta cycle. These processes dynamically interact over rapid timescales, especially when sensory information conflicts with memory. The ability to link hippocampal dynamics to memory-guided behaviors has been limited by experiments that lack the temporal resolution to segregate encoding and retrieval. Here, we simultaneously tracked eye movements and hippocampal field potentials while neurosurgical patients performed a spatial memory task. Phase-locking at the peak of theta preceded fixations to retrieved locations, indicating that the hippocampus coordinates memory-guided eye movements. In contrast, phase-locking at the trough of theta followed fixations to novel object-locations and predicted intact memory of the original location. Theta-gamma phase amplitude coupling increased during fixations to conflicting visual content, but predicted memory updating. Hippocampal theta thus supports learning through two interleaved processes: strengthening encoding of novel information and guiding exploration based on prior experience.

Neural activity reveals interactions between episodic and semantic memory systems during retrieval.

Whereas numerous findings support a distinction between episodic and semantic memory, it is now widely acknowledged that these two forms of memory interact during both encoding and retrieval. The precise nature of this interaction, however, remains poorly understood. To examine the role of semantic organization during episodic encoding and retrieval, we recorded intracranial encephalographic signals as 69 neurosurgical patients studied and subsequently recalled categorized and unrelated word lists. Applying multivariate classifiers to neural recordings, we were able to reliably predict encoding success, retrieval success, and temporal and categorical clustering during recall. By assessing how these classifiers generalized across list types, we identified specific retrieval processes that predicted recall of categorized lists and distinguished between recall transitions within and between category clusters. These results particularly implicate retrieval (rather than encoding) processes in the categorical organization of episodic memories. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

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.

Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans.

People often forget information because they fail to effectively encode it. Here, we test the hypothesis that targeted electrical stimulation can modulate neural encoding states and subsequent memory outcomes. Using recordings from neurosurgical epilepsy patients with intracranially implanted electrodes, we trained multivariate classifiers to discriminate spectral activity during learning that predicted remembering from forgetting, then decoded neural activity in later sessions in which we applied stimulation during learning. Stimulation increased encoding-state estimates and recall if delivered when the classifier indicated low encoding efficiency but had the reverse effect if stimulation was delivered when the classifier indicated high encoding efficiency. Higher encoding-state estimates from stimulation were associated with greater evidence of neural activity linked to contextual memory encoding. In identifying the conditions under which stimulation modulates memory, the data suggest strategies for therapeutically treating memory dysfunction.

Decoding Episodic Retrieval Processes: Frontoparietal and Medial Temporal Lobe Contributions to Free Recall.

Neuroimaging studies of recognition memory have identified distinct patterns of cortical activity associated with two sets of cognitive processes: Recollective processes supporting retrieval of information specifying a probe item's original source are associated with the posterior hippocampus, ventral posterior parietal cortex, and medial pFC. Familiarity processes supporting the correct identification of previously studied probes (in the absence of a recollective response) are associated with activity in anterior medial temporal lobe (MTL) structures including the perirhinal cortex and anterior hippocampus, in addition to lateral prefrontal and dorsal posterior parietal cortex. Here, we address an open question in the cognitive neuroscientific literature: To what extent are these same neurocognitive processes engaged during an internally directed memory search task like free recall? We recorded fMRI activity while participants performed a series of free recall and source recognition trials, and we used a combination of univariate and multivariate analysis techniques to compare neural activation profiles across the two tasks. Univariate analyses showed that posterior MTL regions were commonly associated with recollective processes during source recognition and with free recall responses. Prefrontal and posterior parietal regions were commonly associated with familiarity processes and free recall responses, whereas anterior MTL regions were only associated with familiarity processes during recognition. In contrast with the univariate results, free recall activity patterns characterized using multivariate pattern analysis did not reliably match the neural patterns associated with recollective processes. However, these free recall patterns did reliably match patterns associated with familiarity processes, supporting theories of memory in which common cognitive mechanisms support both item recognition and free recall.

Neural activity in the medial temporal lobe reveals the fidelity of mental time travel.

Neural circuitry in the medial temporal lobe (MTL) is critically involved in mental time travel, which involves the vivid retrieval of the details of past experience. Neuroscientific theories propose that the MTL supports memory of the past by retrieving previously encoded episodic information, as well as by reactivating a temporal code specifying the position of a particular event within an episode. However, the neural computations supporting these abilities are underspecified. To test hypotheses regarding the computational mechanisms supported by different MTL subregions during mental time travel, we developed a computational model that linked a blood oxygenation level-dependent signal to cognitive operations, allowing us to predict human performance in a memory search task. Activity in the posterior MTL, including parahippocampal cortex, reflected how strongly one reactivates the temporal context of a retrieved memory, allowing the model to predict whether the next memory will correspond to a nearby moment in the study episode. A signal in the anterior MTL, including perirhinal cortex, indicated the successful retrieval of list items, without providing information regarding temporal organization. A hippocampal signal reflected both processes, consistent with theories that this region binds item and context information together to form episodic memories. These findings provide evidence for modern theories that describe complementary roles of the hippocampus and surrounding parahippocampal and perirhinal cortices during the retrieval of episodic memories, shaping how humans revisit the past.

Functional interactions between large-scale networks during memory search.

Neuroimaging studies have identified two major large-scale brain networks, the default mode network (DMN) and the dorsal attention network (DAN), which are engaged for internally and externally directed cognitive tasks respectively, and which show anticorrelated activity during cognitively demanding tests and at rest. We identified these brain networks using independent component analysis (ICA) of functional magnetic resonance imaging data, and examined their interactions during the free-recall task, a self-initiated memory search task in which retrieval is performed in the absence of external cues. Despite the internally directed nature of the task, the DAN showed transient engagement in the seconds leading up to successful retrieval. ICA revealed a fractionation of the DMN into 3 components. A posteromedial network increased engagement during memory search, while the two others showed suppressed activity during memory search. Cooperative interactions between this posteromedial network, a right-lateralized frontoparietal control network, and a medial prefrontal network were maintained during memory search. The DAN demonstrated heterogeneous task-dependent shifts in functional coupling with various subnetworks within the DMN. This functional reorganization suggests a broader role of the DAN in the absence of externally directed cognition, and highlights the contribution of the posteromedial network to episodic retrieval.

The neural dynamics of task context in free recall.

Multivariate pattern analysis (MVPA) is a powerful tool for relating theories of cognitive function to the neural dynamics observed while people engage in cognitive tasks. Here, we use the Context Maintenance and Retrieval model of free recall (CMR; Polyn et al., 2009a) to interpret variability in the strength of task-specific patterns of distributed neural activity as participants study and recall lists of words. The CMR model describes how temporal and source-related (here, encoding task) information combine in a contextual representation that is responsible for guiding memory search. Each studied word in the free-recall paradigm is associated with one of two encoding tasks (size and animacy) that have distinct neural representations during encoding. We find evidence for the context retrieval hypothesis central to the CMR model: Task-specific patterns of neural activity are reactivated during memory search, as the participant recalls an item previously associated with a particular task. Furthermore, we find that the fidelity of these task representations during study is related to task-shifting, the serial position of the studied item, and variability in the magnitude of the recency effect across participants. The CMR model suggests that these effects may be related to a central parameter of the model that controls the rate that an internal contextual representation integrates information from the surrounding environment.

The architecture of cross-hemispheric communication in the aging brain: linking behavior to functional and structural connectivity.

Contralateral recruitment remains a controversial phenomenon in both the clinical and normative populations. To investigate the neural correlates of this phenomenon, we explored the tendency for older adults to recruit prefrontal cortex (PFC) regions contralateral to those most active in younger adults. Participants were scanned with diffusion tensor imaging and functional magnetic rresonance imaging during a lateralized word matching task (unilateral vs. bilateral). Cross-hemispheric communication was measured behaviorally as greater accuracy for bilateral than unilateral trials (bilateral processing advantage [BPA]) and at the neural level by functional and structural connectivity between contralateral PFC. Compared with the young, older adults exhibited 1) greater BPAs in the behavioral task, 2) greater compensatory activity in contralateral PFC during the bilateral condition, 3) greater functional connectivity between contralateral PFC during bilateral trials, and 4) a positive correlation between fractional anisotropy in the corpus callosum and both the BPA and the functional connectivity between contralateral PFC, indicating that older adults' ability to distribute processing across hemispheres is constrained by white matter integrity. These results clarify how older adults' ability to recruit extra regions in response to the demands of aging is mediated by existing structural architecture, and how this architecture engenders corresponding functional changes that allow subjects to meet those task demands.

Overlapping parietal activity in memory and perception: evidence for the attention to memory model.

The specific role of different parietal regions to episodic retrieval is a topic of intense debate. According to the Attention to Memory (AtoM) model, dorsal parietal cortex (DPC) mediates top-down attention processes guided by retrieval goals, whereas ventral parietal cortex (VPC) mediates bottom-up attention processes captured by the retrieval output or the retrieval cue. This model also hypothesizes that the attentional functions of DPC and VPC are similar for memory and perception. To investigate this last hypothesis, we scanned participants with event-related fMRI whereas they performed memory and perception tasks, each comprising an orienting phase (top-down attention) and a detection phase (bottom-up attention). The study yielded two main findings. First, consistent with the AtoM model, orienting-related activity for memory and perception overlapped in DPC, whereas detection-related activity for memory and perception overlapped in VPC. The DPC overlap was greater in the left intraparietal sulcus, and the VPC overlap in the left TPJ. Around overlapping areas, there were differences in the spatial distribution of memory and perception activations, which were consistent with trends reported in the literature. Second, both DPC and VPC showed stronger connectivity with medial-temporal lobe during the memory task and with visual cortex during the perception task. These findings suggest that, during memory tasks, some parietal regions mediate similar attentional control processes to those involved in perception tasks (orienting in DPC vs. detection in VPC), although on different types of information (mnemonic vs. sensory).