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Working memory (WM) and long-term memory (LTM) are often viewed as separate cognitive systems. Little is known about how these systems interact when forming memories. We recorded single neurons in the human medial temporal lobe while patients maintained novel items in WM and completed a subsequent recognition memory test for the same items. In the hippocampus, but not in the amygdala, the level of WM content-selective persistent activity during WM maintenance was predictive of whether the item was later recognized with high confidence or forgotten. By contrast, visually evoked activity in the same cells was not predictive of LTM formation. During LTM retrieval, memory-selective neurons responded more strongly to familiar stimuli for which persistent activity was high while they were maintained in WM. Our study suggests that hippocampal persistent activity of the same cells supports both WM maintenance and LTM encoding, thereby revealing a common single-neuron component of these two memory systems., Competing Interests: Declaration of interests W.S.A. serves as a compensated consultant to Globus Medical, Turing Medical, UniQure, and iota Biosciences. He receives royalty payments from Globus Medical., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference 1,2 . However, how cognitive control regulates working memory storage is unclear. Here we show that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase-amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory 1,2 , with frontal control managing maintenance of working memory content in storage-related areas 3-5 . Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes., (© 2024. The Author(s).)

We present a dataset of 1809 single neurons recorded from the human medial temporal lobe (amygdala and hippocampus) and medial frontal lobe (anterior cingulate cortex, pre-supplementary motor area, ventral medial prefrontal cortex) across 41 sessions from 21 patients that underwent seizure monitoring with depth electrodes. Subjects performed a screening task (907 neurons) to identify images for which highly selective cells were present. Subjects then performed a working memory task (902 neurons), in which they were sequentially presented with 1-3 images for which highly selective cells were present and, following a maintenance period, were asked if the probe was identical to one of the maintained images. This Neurodata Without Borders formatted dataset includes spike times, extracellular spike waveforms, stimuli presented, behavior, electrode locations, and subject demographics. As validation, we replicate previous findings on the selectivity of concept cells and their persistent activity during working memory maintenance. This large dataset of rare human single-neuron recordings and behavior enables the investigation of the neural mechanisms of working memory in humans., (© 2024. The Author(s).)

Maintaining multiple items in working memory (WM) is central to human behavior. Persistently active neurons are thought to be a mechanism to maintain WMs, but it remains unclear how such activity is coordinated when multiple items are kept in memory. We show that memoranda-selective persistently active neurons in the human medial temporal lobe phase lock to ongoing slow-frequency (1-7 Hz) oscillations during WM maintenance. The properties of phase locking are dependent on memory content and load. During high memory loads, the phase of the oscillatory activity to which neurons phase lock provides information about memory content not available in the firing rate of the neurons. We provide a computational model that reveals that inhibitory-feedback-mediated competition between multiple persistently active neurons reproduces this phenomenon. This work reveals a mechanism for the active maintenance of multiple items in WM that relies on persistently active neurons whose activation is orchestrated by oscillatory activity., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recent work has revealed important new discoveries on the cellular mechanisms of working memory (WM). These findings have motivated several seemingly conflicting theories on the mechanisms of short-term memory maintenance. Here, we summarize the key insights gained from these new experiments and critically evaluate them in light of three hypotheses: classical persistent activity, activity-silent, and dynamic coding. The experiments discussed include the first direct demonstration of persistently active neurons in the human medial temporal lobe that form static attractors with relevance to WM, single-neuron recordings in the macaque prefrontal cortex that show evidence for both persistent and more dynamic types of WM representations, and noninvasive neuroimaging in humans that argues for activity-silent representations. A key insight that emerges from these new results is that there are several neural mechanisms that support the maintenance of information in WM. Finally, based on established cognitive theories of WM, we propose a coherent model that encompasses these seemingly contradictory results. We propose that the three neuronal mechanisms of persistent activity, activity-silent, and dynamic coding map well onto the cognitive levels of information processing (within focus of attention, activated long-term memory, and central executive) that Cowan's WM model proposes., (© 2019 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

Holding information in working memory (WM) is an active and effortful process that is accompanied by sustained load-dependent changes in oscillatory brain activity. These proportional power increases are often reported in EEG studies recording theta over frontal midline sites. Intracranial recordings, however, yield mixed results, depending on the brain area being recorded from. We recorded intracranial EEG with depth electrodes in 13 patients with epilepsy who were performing a Sternberg WM task. Here, we investigated patterns of theta power changes as a function of memory load during maintenance in three areas critical for WM: dorsolateral prefrontal cortex (DLPFC), dorsal ACC (dACC), and hippocampus. Theta frequency power in both hippocampus and dACC increased during maintenance. In contrast, theta frequency power in the DLPFC decreased during maintenance, and this decrease was proportional to memory load. Only the power decreases in DLPFC, but not the power increases in hippocampus and dACC, were predictive of behavior in a given trial. The extent of the load-related theta power decreases in the DLPFC in a given participant predicted a participant's RTs, revealing that DLPFC theta explains individual differences in WM ability between participants. Together, these data reveal a pattern of theta power decreases in the DLPFC that is predictive of behavior and that is opposite of that in other brain areas. This result suggests that theta band power changes serve different cognitive functions in different brain areas and specifically that theta power decreases in DLPFC have an important role in maintenance of information.

Persistent neural activity is a putative mechanism for the maintenance of working memories. Persistent activity relies on the activity of a distributed network of areas, but the differential contribution of each area remains unclear. We recorded single neurons in the human medial frontal cortex and medial temporal lobe while subjects held up to three items in memory. We found persistently active neurons in both areas. Persistent activity of hippocampal and amygdala neurons was stimulus-specific, formed stable attractors and was predictive of memory content. Medial frontal cortex persistent activity, on the other hand, was modulated by memory load and task set but was not stimulus-specific. Trial-by-trial variability in persistent activity in both areas was related to memory strength, because it predicted the speed and accuracy by which stimuli were remembered. This work reveals, in humans, direct evidence for a distributed network of persistently active neurons supporting working memory maintenance.

The dynamic pattern of functional connectivity during a working memory task was investigated by means of the short-time directed transfer function. A clear-cut picture of transmissions was observed with the main centres of propagation located in the frontal and parietal regions, in agreement with imaging studies and neurophysiological hypotheses concerning the mechanisms of working memory. The study of the time evolution revealed that most of the time short-range interactions prevailed, whereas the communication between the main centres of activity occurred more sparsely and changed dynamically in time. The patterns of connectivity were quantified by means of a network formalism based on assortative mixing--an approach novel in the field of brain networks study. By means of application of the above method, we have demonstrated the existence of a modular structure of brain networks. The strength of interaction inside the modules was higher than between modules. The obtained results are compatible with theories concerning metabolic energy saving and efficient wiring in the brain, which showed that preferred organization includes modular structure with dense connectivity inside the modules and more sparse connections between the modules. The presented detailed temporal and spatial patterns of propagation are in line with the neurophysiological hypotheses concerning the role of gamma and theta activity in information processing during a working memory task.

The number of items that can be held in human short-term memory (STM) is limited to 7 (± 2) elements. Lisman and Idiart's theoretical model of STM proposes that this value depends on the number of gamma cycles that can fit in one theta cycle. Previous studies on animals and humans provided support for this hypothesis but direct evidence from human EEG scalp recordings has not previously been reported. We recorded spontaneous EEG activity from 17 participants and measured their verbal STM capacity with a modified digit span task from the Wechsler battery. The strong and positive correlation we found between verbal STM capacity and theta/gamma cycle length ratio thus provides a direct argument in favor of this STM theoretical model. In this study we also demonstrated a new method for assessing individual theta and gamma frequencies by detecting functional coupling between these oscillations., (Copyright © 2010 Elsevier Inc. All rights reserved.)