Reporting Guidelines and Issues to Consider for Using Intracranial Brain Stimulation in Studies of Human Declarative Memory

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

Direct recordings of grid-like neuronal activity in human spatial navigation

Grid cells in the entorhinal cortex appear to represent spatial location via a triangular coordinate system. Such cells, which have been identified in rats, bats and monkeys, are believed to support a wide range of spatial behaviors. Recording neuronal activity from neurosurgical patients performing a virtual-navigation task, we identified cells exhibiting grid-like spiking patterns in the human brain, suggesting that humans and simpler animals rely on homologous spatial-coding schemes

Thickness in Entorhinal and Subicular Cortex Predicts Episodic Memory Decline in Mild Cognitive Impairment

Identifying subjects with mild cognitive impairment (MCI) most likely to decline in cognition over time is a major focus in Alzheimer's disease (AD) research. Neuroimaging biomarkers that predict decline would have great potential for increasing the efficacy of early intervention. In this study, we used high-resolution MRI, combined with a cortical unfolding technique to increase visibility of the convoluted medial temporal lobe (MTL), to assess whether gray matter thickness in subjects with MCI correlated to decline in cognition over two years. We found that thickness in the entorhinal (ERC) and subicular (Sub) cortices of MCI subjects at initial assessment correlated to change in memory encoding over two years (ERC: r = 0.34; P = .003) and Sub (r = 0.26; P = .011) but not delayed recall performance. Our findings suggest that aspects of memory performance may be differentially affected in the early stages of AD. Given the MTL's involvement in early stages of neurodegeneration in AD, clarifying the relationship of these brain regions and the link to resultant cognitive decline is critical in understanding disease progression

Theta Oscillations in the Human Medial Temporal Lobe during Real-World Ambulatory Movement

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

Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimers disease: A rationale and study design.

INTRODUCTION: Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimers disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process. METHODS: We will conduct a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimers Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short-term efficacy for memory. The first stage will involve 5 to 10 participants receiving open-label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double-blind, sham-controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures. RESULTS: We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement. DISCUSSION: Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability. HIGHLIGHTS: Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimers disease (AD), though recent methods require intensive personalization.We propose here a trial design of precuneus rTMS in mild-to-early-moderate AD dementia using exclusively off-the-shelf equipment and protocol modifications to reduce participant burden.Our two novel modifications from prior work are (1) using a larger rTMS coil, and (2) consolidating the induction phase of treatment.This trial focuses primarily on tolerability and feasibility while exploring clinical measures of efficacy and biomarkers of target engagement.Our trial is registered at ClinicalTrials.gov NCT06597942

Specific responses of human hippocampal neurons are associated with better memory

A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory

Enhancing the Ecological Validity of fMRI Memory Research Using Virtual Reality

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

Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults.

BACKGROUND: The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. METHODS: We studied healthy older adult participants (N = 21, ages 48-79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. RESULTS: Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. CONCLUSIONS: The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way

Transient topographical disorientation due to right-sided hippocampal hemorrhage

Introduction: Topographical disorientation is defined as the inability to recognize familiar or unfamiliar environments. While its slowly progressive development is a common feature of neurodegenerative processes like Alzheimer's dementia, acute presentations are less frequent and mostly caused by strategic lesions within the cerebral navigation network. Depending on the lesion site, topographical disorientation can originate from deficits in landmark recognition and utilization for route planning (egocentric navigation deficit), or disturbance of an overarching cognitive map of the spatial environment (allocentric navigation deficit). However, objective measurements of spatial navigation performance over time are largely missing in patients with topographical disorientation. Methods: We here report a 55-year-old patient with acute topographical disorientation as the single symptom of right-sided hippocampal hemorrhage and present quantitative gaze-monitoring head camera-based analyses of his path-finding strategy and visual exploration behavior in a real space navigation paradigm. Results: The patient exhibited severe allocentric and also egocentric navigation deficits during the acute phase, shown by higher error rates at finding target items. In addition, he showed a more extensive use of search saccades toward, and fixations on, landmarks that could potentially serve as spatial cues. These deficits had been completely compensated for after four months, when the patient performed unremarkably in the real space navigation task, and used even more strongly allocentric path optimization strategies than age-matched controls. Conclusions: This case report highlights the integral function and right-sided dominance of the hippocampal formation in the cerebral navigation network in humans. It shows that the cognitive map can be restored completely despite a residual hippocampal lesion, which illustrates the enormous plasticity of the cerebral navigation network in humans