Itzhak Fried - US grants

DESCRIPTION (provided by applicant): Our overall goal is to provide a better understanding of the neuronal basis of human memory in health and disease. Despite considerable research, there is a critical dearth of data at the single neuron level in humans on brain mechanisms underlying declarative memory. Such data can bridge the gap between basic neuronal research in animals, and human functional magnetic resonance imaging (fMRI) research. Direct recording from depth electrodes implanted in human medial temporal lobe (MIL) areas is possible because our subjects are epilepsy patients who require electrode placement to identify the seizure focus for later resection. Our NIH-funded studies to date have elucidated key characteristics of single neuron responses to complex visual stimuli during encoding and retrieval. Now our primary objective is to characterize single neuronal responses and local field potentials (LFPs) during all three major aspects of human declarative memory processes: (1) associative representations, (2) temporal sequential organization of events, and (3) abstraction of common features among related memories. We propose to use tasks that more closely approximate human episodic memory, including sequences of stimuli and stimulus associations and an immersive virtual reality navigational task. The central hypothesis of this study is that neurons in the medial temporal lobe use two codes for declarative memory: (1) a rate code, based on neuronal firing rate, which is sparse, accentuated by inhibition, highly specific to complex stimuli, yet strikingly abstract. It is this code that underlies associative representations and abstraction of common features. And (2) a temporal code, based on timing of spikes that is driven by oscillatory patterns and phase locking of neuronal firing. It is this code that underlies temporal sequential organization of events. We remain the main group in a position to address these fundamental questions about human memory at both the single neuron level and the level of local field potentials. Our studies pave the way to understanding and managing memory impairment in Alzheimer's, temporal lobe epilepsy and other neurological diseases.

Project Summary/Abstract Loss of the ability to form new memories and retrieve old ones is one of the most dreaded afflictions of the human condition. It is present in various neurological disorders, including temporal lobe epilepsy, traumatic brain injury and is one of the first features of Alzheimer?s Disease (AD) affecting millions of people in the US and many more worldwide. Decades of research have established that declarative memory, the ability to remember recently experienced facts and events, depends on the hippocampus and associated structures in the medial temporal lobe (MTL), including the entorhinal cortex. Our laboratory has been a leader in single neuron physiology of the human MTL for last two decades and was the first group to publish findings using deep brain stimulation (DBS) of the entorhinal-hippocampal circuitry in humans to modulate human memory. Our approach is based on the unique opportunity to record activity of single neurons, neuronal assemblies and local field potentials (LFPs), as well as to apply deep brain stimulation of neural circuits in neurosurgical patients. These are patients with intractable epilepsy who have intracranial depth electrodes implanted in order to identify their seizure focus for possible surgical cure. Our initial findings showed dramatic spatial memory enhancement when DBS was applied to the entorhinal area during learning [1]. In the initial funding period of this project, we built on this success by testing DBS across a wide variety of hippocampal-dependent memory tasks and demonstrating that the critical predictor of whether stimulation would improve memory was the precise spatial targeting of the stimulating electrode to the white matter of the entorhinal area (angular bundle). In the renewed grant, we will further refine our modulation of the entorhinal?hippocampal circuitry by using microstimulation to more precisely identify the spatial and temporal features of applied DBS that lead to enhanced memory. Through simultaneous microstimulation and recording, the project will elucidate the complex relationship between single neuronal responses, LFP oscillations, and DBS that underlies memory enhancement. A primary objective will be to expand the investigation of DBS from encoding to the critical memory phases of consolidation and retrieval, across three memory tasks. Importantly, we will probe the effects of DBS on consolidation during sleep which provides an intriguing and feasible time window for potential clinical intervention. A critical component of our modulation will involve the use of novel closed-loop technology to provide stimulation coordinated in time with endogenous oscillations that have been shown to be critically important for encoding, retrieval, and for consolidation during sleep. The project aims at developing critical insights into the mechanisms of human memory and its enhancement through closed-loop DBS in humans, and thus may contribute significantly to the development of novel therapeutic approaches to human memory disorders.

Project Summary/Abstract Memory is critical for cognitive well-being, and sleep is critical for memory consolidation, yet the underlying mechanisms in the human brain are poorly understood. Research on memory and sleep so far has suffered from a substantial gap between non-invasive cognitive research in humans and detailed electrophysiological research in animals. This proposal seeks a breakthrough by capitalizing on a highly unique opportunity to record and modulate activity of single neurons and neuronal assemblies in the human medial temporal lobe and neocortex during memory tasks and sleep. Recording from depth electrodes in neurosurgical patients, the study will investigate the role of information exchange between hippocampus and neocortex in memory consolidation. To bridge the gap between cognitive human research and mechanistic animal research, two essential approaches will be used. (a) Establish the neural correlates of sleep activities that predict successful memory, using paired-associate learning and object-location association tasks. The leading hypothesis is that coordinated coupling between neocortical slow waves, sleep spindles and hippocampal ripples, co-occurring with reactivation of neuronal ensembles that were selectively engaged in the learning task, will be maximally correlated with successful memory performance after sleep. (b) Test the causal role of these sleep events by modulating them via sensory or direct electrical brain stimulation. This causal approach will involve (1) Auditory Targeted Memory Reactivation. We will examine the neural and behavioral effects of repeating, during slow wave sleep, auditory cues that had been paired with selected stimuli during learning. A widely-held but untested hypothesis is that this will cause reactivation of the neuronal assemblies that encoded those memories. Our ability to record single neurons and hippocampal oscillatory activity during learning and sleep positions us uniquely to test this hypothesis. (2) Locking bursts of intracranial electrical brain stimulation or auditory stimulation to endogenous oscillations. We will achieve well-timed stimulation through the development of a closed-loop system that drives stimulation in the neocortex based on real-time sleep activity in the hippocampus. We will examine the effects of stimulation on memory and electrophysio- logical activity, such as slow waves and ripples. It is anticipated that about 25 patients with depth electrodes will be studied during the 2-year project. This exploratory study builds on the unique capabilities of our center at UCLA to stimulate and record in the human brain, not only intracranial EEG but also well-localized field potentials and single neurons whose response-specificity can be followed before, during, and after sleep. Assembling a group of experts from a wide array of disciplines?including neurobiology of sleep and memory in humans and rodents, neuroengineering, psychology, neurology, and neurosurgery?the proposed study will probe the underlying neuronal mechanisms of memory consolidation in sleep using correlative and causal measures, employing a systematic and reliable approach.

PROJECT SUMMARY/ABSTRACT Episodic memories integrate the content of human experience in space and time and constitute the core of one's identity. Memory formation involves processing, and constructing interpretations of the incoming information in our daily lives and is one of the first functions compromised in neurodegenerative diseases such as Alzheimer's Disease. With population aging, we face a ?Cognitive Tsunami? of millions of people with memory disorders. Thus, understanding neural mechanisms of memory, and finding interventions that enhance these processes is a critical endeavor with the potential to improve the lives of countless people world-wide. Although it is established that memory is critical for cognitive well-being, and sleep is critical for memory consolidation, the underlying mechanisms in the human brain are poorly understood. Research on memory and sleep so far has suffered from a gap between non-invasive cognitive research in humans and detailed electrophysiological research in animals. Moreover, most human studies are dominated by stimulus response methodologies where the presented stimuli constitute limited, discretized, aspects of memory. This approach, albeit well-controlled, is far from the rich narrative of episodes we experience. Thus, to mechanistically probe human memory consolidation, it is imperative to (a) employ methodologies that incorporate the continuous and multimodal nature of experience; (b) identify relevant neural activation patterns and how they are transformed and reactivated during sleep; (c) establish means to causally modulate memory processes during sleep. Building upon our exploratory U01 project, this proposal seeks a breakthrough in our understanding by going beyond the state-of-the-art, and via the application of integrative and multidisciplinary approaches. It capitalizes on a highly unique opportunity to record and modulate neuronal activity of a large number of single neurons and neuronal assemblies in the human brain. In parallel, it exploits the high dimensionality of the data as an asset through the use of cutting-edge Deep Learning (DL) algorithms, which have emerged as promising analysis tools. Specifically, the project will investigate the presence, and decoding, of distributed neural patterns associated with memory for different aspects of experience during wakefulness and identify their reactivation during sleep. The proposal aims to selectively modulate memory via application of novel closed-loop stimulation in sleep in concert with the DL model predictions. We anticipate that this project is poised to shed light on the relationship between sleep and memory, and its modulation from a novel perspective. Such an ambitious goal can only be achieved with unrivaled combination of experience, access to a clinical setting, and interdisciplinary collaborations such as those proposed in this project. By combining the opportunity to stimulate and record neural activity with the computational power of artificial intelligence, this project aims to offer findings with far reaching implications for basic neuroscience and contribute to the development of novel therapies for human memory disorders.