Biology subjects

Mamelak, A. N.

Publications and source records attributed to Mamelak, A. N..

17 recordsLinked to original sources

bioRxiv2026

Cellular code for mnemonic pattern separation in the human hippocampus is revealed by false memories

Theoretical models propose that pattern separation, a computation thought to be implemented by the hippocampus, allows us to differentiate between familiar and novel items. However, whether pattern separation operates in the human hippocampus remains contested, with no established single-cell correlate. We recorded the single neuron activity of 3506 neurons in the human brain while 97 patients performed a recognition memory task in which novel images similar to previously seen images led to false memories and associated behavioral errors. We identified two kinds of memory selective neurons distributed across the brain: those responding differently to falsely recognized novel and correctly recognized familiar images in a manner compatible with pattern separation, and the other signaling the subject's choice. At the population level, these cells predicted mnemonic ground truth in the hippocampus and the decision in the pre-supplementary motor area, illustrating the progression from mnemonic signals to decisions. Removing pattern separation-signaling cells abolished the continuous memory strength gradient present in the hippocampus, suggesting a role of these cells in separating memories of different strength. These results establish a single cell correlate for mnemonic pattern separation in the human hippocampus and show its behavioral relevance in episodic memory.

neuroscience↗

bioRxiv2026

Criterion-selective neurons in the human medial frontal cortex track decision thresholds during memory-based decision making

The decision criterion is foundational to theories of decision-making, yet little is known about its neural underpinnings. In memory-based decision making, the criterion sets the minimal memory strength for something to be familiar, but whether or how it is distinctly represented from memory strength is unknown. We recorded single neurons in the medial frontal cortex (MFC) and medial temporal lobe (MTL), both implicated in memory-based decisions, while participants made decisions under different decision criteria. We identified criterion-selective (CS) neurons in the MFC that tracked the criterion regardless of memory strength, and memory-selective (MS) neurons in both regions that tracked memory strength regardless of the criterion. CS neurons signaled the criterion before MS neurons signaled memory strength, and a race model incorporating both neuron types outperformed one using MS neurons alone. These findings reveal two independent cellular substrates, one for the decision criterion and one for memory strength, whose joint activity underlies memory-based decisions.

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bioRxiv2026

Choice-driven remapping of action- and stimulus-anchored value in human single neurons

Whether stimulus- and action-based choices rely on a shared neural architecture remains intensely debated. While lesion and fMRI studies show conflicting regional dissociation and overlap, the underlying single neuron substrates remain unknown. We recorded single neuron activity from the human ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), pre-supplementary motor area (preSMA), and amygdala during distinct action- and stimulus-based reward tasks. Prior to decision-making, neurons across all regions broadly encode value for both choice domains. However, choice commitment triggers domain segregation across the prefrontal cortex. While ACC and vmPFC neurons flexibly track both chosen actions and stimuli, they exhibit a double dissociation for chosen valuation: ACC neurons selectively maintain action-based values, whereas vmPFC neurons selectively maintain stimulus-based values. Conversely, preSMA neurons invariant to task domain track chosen action identity and value. These findings reveal how prefrontal networks transition from domain-general evaluation to domain-segregated choice execution.

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bioRxiv2026

Task goals reorganize visual codes in human ventral temporal cortex via medial frontal modulation

How sensory representations in the sensory cortex are dynamically and rapidly modulated to support flexible, goal-directed behavior remains a fundamental open question. Using rare simultaneous single-neuron recordings across multiple human brain regions, including the ventral temporal cortex (VTC), a high-level visual area not traditionally associated with context-dependent coding, we show that visual representations in VTC are rapidly reconfigured by the presence or absence of preceding verbal task instructions. Identical visual stimuli evoked distinct responses in VTC depending on whether task instructions were provided or not, with categorical representations sharpened when goals were specified in advance. In contrast, dorsal anterior cingulate cortex (dACC) and the hippocampus carried strong signals related to instruction timing, consistent with known regional specialization in top-down control. Coupling between dACC and VTC increased during periods of instructional uncertainty and high cognitive demand on a rapid timescale during stimulus presentation, and its strength predicted correct performance. Together, these findings uncover a rapid, online feedback mechanism through which the medial frontal cortex dynamically reorganizes sensory population codes in VTC, linking flexible cortical coordination to successful goal-directed computation.

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bioRxiv2025

Stimulus-specific recruitment of human amygdala neurons predicts episodic memory encoding success

Controlling whether a given experience is encoded into long-term memory and thus later remembered is a crucial component of our memory system whose failure is often at the root of memory disorders. One brain area that takes part in controlling which experiences are remembered is the amygdala, but the mechanisms by which it does so remain poorly understood. Here we examined single-neuron activity and local field potentials as human participants performed recognition memory tasks with visual stimuli. Category-selective amygdala neurons exhibited elevated firing rates during encoding of later remembered items versus forgotten items. This subsequent memory effect was restricted to images of the preferred category of a given cell, was stronger and appeared earlier in the amygdala compared to the hippocampus, and did not depend on the valence and arousal of the stimuli. In contrast, category selective cells immediately upstream in the ventral temporal cortex did not exhibit a subsequent memory effect, highlighting specificity to the amygdala. Successful memory formation was accompanied by enhanced spike-field coherence between the activity of category cells in the amygdala and hippocampal field potentials. These findings, replicated in two large independent datasets with two different tasks, demonstrate that recruitment of stimulus-specific amygdala representations predicts episodic memory formation, particularly in the right amygdala. This data suggests category cells in the right amygdala as a cellular target for interventions to treat memory disorders in humans.

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bioRxiv2025

Order-Selective Cells Tile Temporal Space and Predict Order Memory in Humans

Remembering the temporal order of events is critical for episodic memory, allowing us to link individual events into sequences. While the medial temporal lobe and prefrontal cortex are essential for this process, the underlying neural mechanisms remain poorly understood. Here we characterized the representation of order information at the level of single neurons and field potentials recorded from human neurosurgical patients watching naturalistic videos of everyday events and later recalling the order and content of the events depicted. We found order-selective cells (OSCs) in the human hippocampus, amygdala, and orbitofrontal cortex that responded selectively to specific event orders, independent of event content or absolute time. OSCs exhibited transient theta phase precession following their preferred order during both memory encoding and retrieval, the strength of which predicted participants order memory accuracy. During retrieval, OSC spike timing relative to theta varied with the relative position of their preferred event within the recalled event sequence, enabling selective retrieval of relevant events. These findings reveal a neural substrate for representing, encoding into and retrieving from memory absolute and relative ordinal relationships between discrete events. OSCs tile temporal space into discrete ordinal positions, thereby weaving episodic experiences into coherent temporal narratives.

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bioRxiv2025

Hippocampal stimulation reveals causal role of persistent neural activity in human working memory

Working memory (WM) enables the temporary maintenance and manipulation of information, supporting flexible, goal-directed behavior. While converging evidence suggests that persistent activity in the hippocampus and other areas of the brain contributes to WM storage, this link has not been examined by manipulating neural activity experimentally. Here, we combined simultaneous intracranial single-neuron recordings with focal electrical stimulation in the human hippocampus to test the role of memoranda-selective persistent neural activity for WM. Thirty patients with implanted hybrid depth electrodes performed a WM task with images as memoranda. Electrical stimulation (2 s, 50 Hz, 1 mA) was delivered to the hippocampus during the maintenance period on a subset of trials. Behaviorally, stimulation impaired WM performance, increasing response times especially in low-load conditions. Neuronally, stimulation reduced memoranda-selective activity in hippocampus and ventral temporal cortex (VTC), thereby disrupting content-specific neural representations of WM content. The extent of stimulation-induced change in firing rate mediated trial-by-trial impaired WM-related behavior, linking disrupted neural selectivity to impaired WM. At the population level, stimulation shifted neural trajectories farther from attractor states, consistent with degraded mnemonic fidelity. Together, these data provide evidence that selective persistent activity of individual neurons in hippocampus and VTC supports WM maintenance in humans. Our results demonstrate that hippocampal stimulation disrupts both single-neuron coding and population-level attractor stability, linking cellular mechanisms to behavior and highlighting the contributions of persistent activity to WM maintenance.

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bioRxiv2024

A shared code for perceiving and imagining objects in human ventral temporal cortex

Mental imagery is a remarkable phenomenon that allows us to remember previous experiences and imagine new ones. Animal studies have yielded rich insight into mechanisms for visual perception, but the neural mechanisms for visual imagery remain poorly understood. Here, we first determined that [~]80% of visually responsive single neurons in human ventral temporal cortex (VTC) use a distributed axis code to represent objects. We then used that code to reconstruct objects and generate maximally effective synthetic stimuli. Finally, we recorded responses from the same neural population while subjects imagined specific objects and found that [~]40% of axis-tuned VTC neurons recapitulated the visual code. Our findings reveal that visual imagery is supported by reactivation of the same neurons involved in perception, providing single neuron evidence for the existence of a generative model in human VTC. One Sentence SummarySingle neurons in human temporal cortex use feature axes to encode objects, and imagery reactivates this code.

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bioRxiv2024

Neural dynamics underlying minute-timescale persistent behavior in the human brain

The ability to pursue long-term goals relies on a representations of task context that can both be maintained over long periods of time and switched flexibly when goals change. Little is known about the neural substrate for such minute-scale maintenance of task sets. Utilizing recordings in neurosurgical patients, we examined how groups of neurons in the human medial frontal cortex and hippocampus represent task contexts. When cued explicitly, task context was encoded in both brain areas and changed rapidly at task boundaries. Hippocampus exhibited a temporally dynamic code with fast decorrelation over time, preventing cross-temporal generalization. Medial frontal cortex exhibited a static code that decorrelated slowly, allowing generalization across minutes of time. When task context needed to be inferred as a latent variable, hippocampus encoded task context with a static code. These findings reveal two possible regimes for encoding minute-scale task-context representations that were engaged differently based on task demands.

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bioRxiv2024

Persistent activity during working memory maintenance predicts long-term memory formation in the human hippocampus

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 a subsequent recognition memory test for the same items. In the hippocampus but not the amygdala, the level of WM content-selective persist activity during WM maintenance was predictive of whether the item was later recognized with high confidence or forgotten. In 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 cell supports both WM maintenance and LTM encoding, thereby revealing a common single-neuron component of these two memory systems.

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bioRxiv2023

Abstract representations emerge in human hippocampal neurons during inference behavior

Humans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning, and how they relate to behavior2,3. Here we characterized the representational geometry of populations of neurons (single-units) recorded in the hippocampus, amygdala, medial frontal cortex, and ventral temporal cortex of neurosurgical patients who are performing an inferential reasoning task. We find that only the neural representations formed in the hippocampus simultaneously encode multiple task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consisted of disentangled directly observable and discovered latent task variables. Interestingly, learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behavior suggests that abstract/disentangled representational geometries are important for complex cognition.

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bioRxiv2023

Hippocampal Theta Phase Precession Supports Memory Formation and Retrieval of Naturalistic Experience in Humans

Linking different experiences together is a key aspect of episodic memory. A potential neural mechanism for linking sequential events over time is phase precession, which causes neurons to fire progressively earlier in time relative to theta-frequency local field potential oscillations. However, no direct link between phase precession and behaviorally assessed memory encoding or retrieval success has been established. We recorded the activity of single neurons and local field potentials in the human medial temporal lobe (MTL) while participants encoded and retrieved memories of movie clips. Transient brief theta bouts and theta phase precession were observed following cognitive boundaries during movie watching as well as following stimulus onset during memory retrieval. Phase precession was dynamic, with different neurons exhibiting phase precession in different task periods. The strength of phase precession provided information about memory encoding and retrieval success that was not available in firing rates, thereby linking the temporal code established by phase precession to behaviorally assessed memory strength. These data reveal phase precession during non spatial memory in humans and provide direct neural evidence for a functional role of phase precession in episodic memory.

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bioRxiv2023

Control of working memory maintenance by theta-gamma phase amplitude coupling of human hippocampal neurons

Retaining information in working memory (WM) is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference. How cognitive control regulates WM storage, however, remains unknown. We hypothesized 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 WM. In the hippocampus, TG-PAC was indicative of WM load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. These PAC neurons were more strongly coordinated with frontal theta activity when cognitive control demand was high, and they introduced information-enhancing and behaviorally relevant noise correlations with persistently active neurons in the hippocampus. We show that TG-PAC integrates cognitive control and WM storage to improve the fidelity of WM representations and facilitate behavior.

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bioRxiv2021

Neurons in human pre-supplementary motor area encode key computations for value-based choice

Adaptive behavior in real-world environments demands that choices integrate over several variables, including the novelty of the options under consideration, their expected value, and uncertainty in value estimation. We recorded neurons from the human pre-supplementary motor area (preSMA), ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate to probe how integration over decision variables occurs during decision-making. In contrast to the other areas, preSMA neurons not only represented separate pre-decision variables for each choice option, but also encoded an integrated utility signal and, subsequently, the decision itself. Conversely, post-decision related encoding of variables for the chosen option was more widely distributed and especially prominent in vmPFC. Our findings position the human preSMA as central to the implementation of value-based decisions.

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bioRxiv2021

The geometry of domain-general performance monitoring representations in the human medial frontal cortex

Controlling behavior to flexibly achieve desired goals depends on the ability to monitor ones own performance. It is unknown how performance monitoring can be both flexible to support different tasks and specialized to perform well on each. We recorded single neurons in the human medial frontal cortex while subjects performed two tasks that involve three types of cognitive conflict. Neurons encoding predicted conflict, conflict, and error in one or both tasks were intermixed, forming a representational geometry that simultaneously allowed task specialization and generalization. Neurons encoding conflict retrospectively served to update internal estimates of control demand. Population representations of conflict were compositional. These findings reveal how representations of evaluative signals can be both abstract and task-specific and suggest a neuronal mechanism for estimating control demand.

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bioRxiv2020

Distinct roles of dorsal and ventral subthalamic neurons in action selection and cancellation

The subthalamic nucleus (STN) supports action selection by inhibiting all motor programs except the desired one. Recent evidence suggests that STN can also cancel an already selected action when goals change, a key aspect of cognitive control. However, there is little neurophysiological evidence for a dissociation between selecting and cancelling actions in the human STN. We recorded single neurons in the STN of humans performing a stop-signal task. Movement-related neurons suppressed their activity during successful stopping whereas stop-signal neurons activated at low-latencies regardless of behavioral outcome. In contrast, STN and motor-cortical beta-bursting occurred only later in the stopping process. Task-related neuronal properties varied by recording location from dorsolateral movement to ventromedial stop-signal tuning. Therefore, action selection and cancellation coexist in STN but are anatomically segregated. These results show that human ventromedial STN neurons carry fast stop-related signals suitable for implementing cognitive control.

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bioRxiv2019

Value-related neuronal responses in the human amygdala during observational learning

AbstractThe amygdala plays an important role in many aspects of social-cognition and reward-learning. Here we aimed to determine whether human amygdala neurons are involved in the computations necessary to implement learning through observation. We performed single-neuron recordings from the amygdalae of human neurosurgical patients (male and female) while they learned about the value of stimuli through observing the outcomes experienced by another agent interacting with those stimuli. We used a detailed computational modeling approach to describe patients behavior in the task. Then, using both population-level decoding and single neuron analyses we found evidence to implicate amygdala neurons in two key computations relevant for observational-learning: tracking the expected future reward associated with a given stimulus, and in tracking outcome values received by oneself or other agents. Encoding and decoding analyses suggested observational value coding in amygdala neurons occurred in a different subset of neurons than experiential value coding. Collectively, these findings support a key role for the human amygdala in the computations underlying the capacity for learning through observation. Significance statementSingle neuron studies of the human brain provide a unique window into the computational mechanisms of cognition. In this study, epilepsy patients implanted intracranially with depth microelectrodes performed an observational learning task. We measured activity bilaterally in the amygdala and found a representation for observational rewards as well as observational expected reward values. Additionally, the representation of self-experienced and observational values was performed by distinct subsets of amygdala neurons. This study thus provides a rare glimpse into the role of human amygdala neurons in social cognition.

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