Ueli Rutishauser - US grants

Memory disorders affect millions of Americans today. Despite decades of work, we have little ability to prevent, improve or treat such memory disorders. With the support of the National Science Foundation, Dr. Ueli Rutishauser and colleagues are investigating how humans form, store, and retrieve memories. The research supported by this CAREER award is to observe the electrical activity of brain cells in the hippocampus, an area essential for the formation of new memories. This research is performed with human patients who are undergoing surgery to treat epilepsy. To localize seizures, these patients are implanted with small wires in different parts of their brain, which allows researchers to investigate the human nervous system at the cellular level. Using this technique, we will investigate how human brain cells change when new memories are formed. Specifically, we will test whether the formation of new memories is dependent on a brain rhythm called the "theta oscillation", and if disruptions of this rhythm lead to poor memory. Critically, theta oscillations can be changed by electrical stimulation, which offers a potential technique to improve memory. Through education, teaching, and mentoring, this CAREER award will enable new researchers and organizations to take advantage of the extremely valuable opportunities for basic research on the human nervous system presented by intracranial electrophysiology.

The research objective of this CAREER award is to investigate the neural mechanisms of human declarative memory at the level of individual neurons and circuits. We work with patients implanted with micro-wire electrodes who volunteer to participate in this research. The objective is to understand how the activity of networks of neurons is coordinated such that their collective action results in plasticity and long-term memories. We test the hypothesis that hippocampal theta oscillations mediate this process by combining human single-neuron recordings, behavioral testing, electrical stimulation, and computational modelling. This approach will allow us to assess the role and necessity of oscillations for the formation of human memories and thereby demonstrate the role of a specific oscillation in human cognition. We study i) how the activity of two distinct functional types of hippocampal neurons that we identified (visual and memory selective) are modulated by the theta rhythm; ii) how modulation of theta oscillations by shifts in spatial attention impacts individual neurons; and iii) whether there is a causal link between theta oscillations and memory strength. This study could provide, for the first time, a link between the cellular mechanisms of plasticity, oscillations, and human memory. The educational objective is to closely involve students in all aspects of the research, and to incorporate research results into classes, workshops and a K-12 outreach program. The resulting methods, tools, and datasets will be publicly released.

Project Summary/Abstract Deficient control and monitoring of memory processes is a key feature of major psychiatric diseases, including schizophrenia, bipolar disorder, and PTSD. The long-term goal of this research is to understand how individual brain areas within the temporal-and frontal lobes interact, how these interactions are coordinated and how disruption of such coordination results in mental disease. The proposed experiments will utilize rare neurosurgical opportunities to directly record from individual neurons in several areas of the human medial frontal cortex and the hippocampus to study the role of theta-mediated coordination in the executive control of memory. This approach is motivated by previous work from this laboratory, which has revealed a candidate microcircuit for declarative memories consisting of groups of cells that signal memory strength and a second group that signals highly processed sensory information independent of memories (VS/MS neurons). The overall objective of this application is to understand how information provided by these hippocampal neurons is utilized by areas in the medial frontal lobes to make decisions and how such memory-based decision making processes are monitored and controlled. We will achieve this objective by recording single-neurons from the hippocampus and three medial frontal cortical areas important for monitoring and control of memory processes: the ACC, pre-SMA, and vmPFC. Our central hypothesis is that Frontal-Hippocampal coordination is mediated by theta-band oscillations such that subsets of medial frontal neurons transiently phase-lock to hippocampal theta oscillations in order to gain access to task-relevant information provided by subsets of VS/MS neurons in the hippocampus. Our specific aims are to determine how medial frontal neurons accumulate evidence provided by the hippocampus (Aim 1), to determine whether medial frontal neurons exert top-down control over the hippocampus (Aim 2), and to test the causality of theta-mediated medial frontal- hippocampal coordination for memory (Aim 3). The contribution is significant because it will provide an unprecedented characterization of the role of medial frontal-hippocampal coordination in the control of memory processes through bottom-up and top-down interactions and their causal necessity. The approach is innovative because we directly test, in humans, a hypothesis of high significance for psychiatric disease which cannot be tested by non-invasive fMRI/EEG/MEG studies nor by animal models due to the unclear homologies of frontal areas. The work proposed in this application will advance knowledge on the normal mechanisms of frontal- temporal coordination by theta oscillations and might thereby enable the development of new treatments to restore or improve such coordination in cases of mental disease.

Project Summary The rapid formation of new memories and the recall of old memories to inform decisions is essential for human cognition, but the underlying neural mechanisms remain poorly understood. The long-term goal of this research is a circuit-level understanding of human memory to enable the development of new treatments for the devastating effects of memory disorders. Our experiments utilize the rare opportunity to record in-vivo from human single neurons simultaneously in multiple brain areas in patients undergoing treatment for drug resistant epilepsy. The overall objective is to assemble a multi-institutional (Cedars-Sinai/Caltech, Johns Hopkins, U Toronto, Children?s/Harvard), integrated, and multi-disciplinary team. Jointly, we have the expertise and patient volume to test key predictions on the neural substrate of human memory. We will utilize a combination of (i) in- vivo recordings in awake behaving humans assessing memory strength through confidence ratings, (ii) focal electrical stimulation to test causality, and (iii) computational analysis and modeling. We will apply these techniques to investigate three overarching hypothesis on the mechanisms of episodic memory. First, we will test the prediction that stimulus-specific persistent activity is essential for memory formation (Aim 1). Second, we will determine whether neurons accumulate memory-derived evidence to inform retrieval decisions and/or the confidence (a type of metacognition) about retrieval decisions (Aim 2). Third, we will test the hypothesis that visually-and memory selective cells emerge gradually during temporally extended episodes of experience to gradually create and solidify memories (Aim 3). The expected outcomes of this research are an unprecedented characterization of how declarative memories are formed and used in the human brain. This work is significant because we move beyond a ?parts list? of neurons and brain areas by testing circuit-based hypothesis by simultaneously recording single-neurons from multiple frontal cortical and subcortical temporal lobe areas in humans who are forming, declaring and describing their memories. The proposed work is unusually innovative because we combine single-neuron recordings in multiple areas in behaving humans, develop new methods for non-invasive localization of implanted electrodes and electrical stimulation and directly test long-standing theoretical predictions on the role of evidence accumulation in memory retrieval. A second significant innovation is our team, which combines the patient volume and expertise of several major centers to maximally utilize the rare neurosurgical opportunities available to directly study the human nervous system. This innovative approach permits us to investigate circuit-level mechanisms of human memory that cannot be studied non-invasively in humans nor in animal models due to their unclear relevance to human memory and its diseases. This integrated multi-disciplinary combination of human in-vivo single-neuron physiology, behavior, and modeling will contribute significantly to our understanding of the circuits and patterns of neural activity that give rise to human memory, which is a central goal of human neuroscience in general and the BRAIN initiative in particular.

How do we monitor our actions? We notice quickly when we dial a wrong number, get off the elevator at the wrong floor, blurt out something inappropriate, or send an email that we really didn’t mean to send, even when no one tells us that we made a mistake. These behaviors are everyday examples of monitoring our own performance, which is critical for us to learn from our mistakes. Although external feedback can also play an important role in monitoring our actions, remarkably, noticing that we made an error often occurs from self-monitoring alone. This research project utilizes rare opportunities to record individual human brain cells to decipher how the brain achieves this extraordinary feat. Determining how the brain enables us to detect our own errors is of broad significance because it may enable us to develop new training and teaching strategies to help those who fail to detect their own errors or, conversely, are overly sensitive to their own mistakes. Also, it will provide fundamental knowledge about the brain mechanisms underlying error-monitoring that may facilitate the development of a non-invasive biomarker that might allow us to assess the success or failure of training strategies and also enable the creation of artificial intelligence systems with better abilities at performance monitoring. The research team is involved in several outreach educational activities to under-represented groups aimed at providing enrichment classes at the middle and high school level, to teach students about exciting recent advances in cognitive neuroscience, and also bringing opportunities for STEM research experiences in neuroscience for high school and undergraduate students.<br/><br/>To understand how the brain enables us to detect our own errors, this proposal aims to test the predictions of three prominent theories of error monitoring. While these theories are at the core of a large number of studies in psychology and cognitive neuroscience, we do not know at present which (if any) of these theories actually reflects how our brain enables this critical ability of performance monitoring. Motivated by their recent discovery of single neurons which signal error in the medial prefrontal cortex (mPFC) of the human brain, the research team will examine the response of individual mPFC neurons (in patients being monitored for epilepsy prior to neurosurgery to remove epileptic brain tissue, who have volunteered to participate in this study). Participants will perform cognitive tasks to test the differing predictions of the three extant theories which may resolve which theory is correct. Along with the single neuron recordings from the mPFC, researchers will also simultaneously record scalp and intercranial EEG. These tandem recording techniques will be especially useful for understanding the neural basis of the error related negativity (ERN), which is a frequently studied scalp EEG component. Combined with novel quantitative methods, the researchers expect to gain a mechanistic understanding of how the human brain monitors errors. The researchers also plan to begin development of an accurate computational model of how the human mPFC monitors errors incorporating insights gained from the research in this proposal.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.