Participants with stimulating and recording electrodes implanted within the brain for clinical evaluation and treatment provide a rare opportunity to unravel the neuronal correlates of human memory, as well as offer potential for modulation of behavior. Recent intracranial stimulation studies of memory have been inconsistent in methodologies employed and reported conclusions, which renders generalizations and construction of a framework impossible. In an effort to unify future study efforts and enable larger meta-analyses we propose in this mini-review a set of guidelines to consider when pursuing intracranial stimulation studies of human declarative memory and summarize details reported by previous relevant studies. We present technical and safety issues to consider when undertaking such studies and a checklist for researchers and clinicians to use for guidance when reporting results, including targeting, placement, and localization of electrodes, behavioral task design, stimulation and electrophysiological recording methods, details of participants, and statistical analyses. We hope that, as research in invasive stimulation of human declarative memory further progresses, these reporting guidelines will aid in setting standards for multicenter studies, in comparison of findings across studies, and in study replications.

Functional magnetic resonance imaging (fMRI) is a powerful research tool to understand the neural underpinnings of human memory. However, as memory is known to be context-dependent, differences in contexts between naturalistic settings and the MRI scanner environment may potentially confound neuroimaging findings. Virtual reality (VR) provides a unique opportunity to mitigate this issue by allowing memories to be formed and/or retrieved within immersive, navigable, visuospatial contexts. This can enhance the ecological validity of task paradigms, while still ensuring that researchers maintain experimental control over critical aspects of the learning and testing experience. This mini-review surveys the growing body of fMRI studies that have incorporated VR to address critical questions about human memory. These studies have adopted a variety of approaches, including presenting research participants with VR experiences in the scanner, asking participants to retrieve information that they had previously acquired in a VR environment, or identifying neural correlates of behavioral metrics obtained through VR-based tasks performed outside the scanner. Although most such studies to date have focused on spatial or navigational memory, we also discuss the promise of VR in aiding other areas of memory research and facilitating research into clinical disorders.

Extracting meaning from a dynamic and variable flow of incoming information is a major goal of both natural and artificial intelligence. Computer vision (CV) guided by deep learning (DL) has made significant strides in recognizing a specific identity despite highly variable attributes. This is the same challenge faced by the nervous system and partially addressed by the concept cells-neurons exhibiting selective firing in response to specific persons/places, described in the human medial temporal lobe (MTL) ⁠. Yet, access to neurons representing a particular concept is limited due to these neurons' sparse coding. It is conceivable, however, that the information required for such decoding is present in relatively small neuronal populations. To evaluate how well neuronal populations encode identity information in natural settings, we recorded neuronal activity from multiple brain regions of nine neurosurgical epilepsy patients implanted with depth electrodes, while the subjects watched an episode of the TV series "24". First, we devised a minimally supervised CV algorithm (with comparable performance against manually-labeled data) to detect the most prevalent characters (above 1% overall appearance) in each frame. Next, we implemented DL models that used the time-varying population neural data as inputs and decoded the visual presence of the four main characters throughout the episode. This methodology allowed us to compare "computer vision" with "neuronal vision"-footprints associated with each character present in the activity of a subset of neurons-and identify the brain regions that contributed to this decoding process. We then tested the DL models during a recognition memory task following movie viewing where subjects were asked to recognize clip segments from the presented episode. DL model activations were not only modulated by the presence of the corresponding characters but also by participants' subjective memory of whether they had seen the clip segment, and by the associative strengths of the characters in the narrative plot. The described approach can offer novel ways to probe the representation of concepts in time-evolving dynamic behavioral tasks. Further, the results suggest that the information required to robustly decode concepts is present in the population activity of only tens of neurons even in brain regions beyond MTL.

Background

While deep brain stimulation has been successful in treating movement disorders, such as in Parkinson's disease, its potential application in alleviating memory disorders is inconclusive.

Objective/hypothesis

We investigated the role of the location of the stimulating electrode on memory improvement and hypothesized that entorhinal white versus gray matter stimulation would have differential effects on memory.

Methods

Intracranial electrical stimulation was applied to the entorhinal area of twenty-two participants with already implanted electrodes as they completed visual memory tasks.

Results

We found that stimulation of right entorhinal white matter during learning had a beneficial effect on subsequent memory, while stimulation of adjacent gray matter or left-sided stimulation was ineffective. This finding was consistent across three different visually guided memory tasks.

Conclusions

Our results highlight the importance of precise stimulation site on modulation of human hippocampal-dependent memory and suggest that stimulation of afferent input into the right hippocampus may be an especially promising target for enhancement of visual memory.

Everyday tasks in social settings require humans to encode neural representations of not only their own spatial location, but also the location of other individuals within an environment. At present, the vast majority of what is known about neural representations of space for self and others stems from research in rodents and other non-human animals^1-3. However, it is largely unknown how the human brain represents the location of others, and how aspects of human cognition may affect these location-encoding mechanisms. To address these questions, we examined individuals with chronically implanted electrodes while they carried out real-world spatial navigation and observation tasks. We report boundary-anchored neural representations in the medial temporal lobe that are modulated by one's own as well as another individual's spatial location. These representations depend on one's momentary cognitive state, and are strengthened when encoding of location is of higher behavioural relevance. Together, these results provide evidence for a common encoding mechanism in the human brain that represents the location of oneself and others in shared environments, and shed new light on the neural mechanisms that underlie spatial navigation and awareness of others in real-world scenarios.

The theta rhythm-a slow (6-12 Hz) oscillatory component of the local field potential-plays a critical role in spatial navigation and memory by coordinating the activity of neuronal ensembles within the medial temporal lobe (MTL). Although theta has been extensively studied in freely moving rodents, its presence in humans has been elusive and primarily investigated in stationary subjects. Here we used a unique clinical opportunity to examine theta within the human MTL during untethered, real-world ambulatory movement. We recorded intracranial electroencephalographic activity from participants chronically implanted with the wireless NeuroPace responsive neurostimulator (RNS) and tracked their motion with sub-millimeter precision. Our data revealed that movement-related theta oscillations indeed exist in humans, such that theta power is significantly higher during movement than immobility. Unlike in rodents, however, theta occurs in short bouts, with average durations of ∼400 ms, which are more prevalent during fast versus slow movements. In a rare opportunity to study a congenitally blind participant, we found that both the prevalence and duration of theta bouts were increased relative to the sighted participants. These results provide critical support for conserved neurobiological characteristics of theta oscillations during ambulatory spatial navigation, while highlighting some fundamental differences across species in these oscillations between humans and rodents.

Uncovering the neural mechanisms underlying human natural ambulatory behavior is a major challenge for neuroscience. Current commercially available implantable devices that allow for recording and stimulation of deep brain activity in humans can provide invaluable intrinsic brain signals but are not inherently designed for research and thus lack flexible control and integration with wearable sensors. We developed a mobile deep brain recording and stimulation (Mo-DBRS) platform that enables wireless and programmable intracranial electroencephalographic recording and electrical stimulation integrated and synchronized with virtual reality/augmented reality (VR/AR) and wearables capable of external measurements (e.g., motion capture, heart rate, skin conductance, respiration, eye tracking, and scalp EEG). When used in freely moving humans with implanted neural devices, this platform is adaptable to ecologically valid environments conducive to elucidating the neural mechanisms underlying naturalistic behaviors and to the development of viable therapies for neurologic and psychiatric disorders.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.