Neural oscillations during conditional associative learning.

Associative learning requires mapping between complex stimuli and behavioural responses. When multiple stimuli are involved, conditional associative learning is a gradual process with learning based on trial and error. It is established that a distributed network of regions track associative learning, however the role of neural oscillations in human learning remains less clear. Here we used scalp EEG to test how neural oscillations change during learning of arbitrary visuo-motor associations. Participants learned to associative 48 different abstract shapes to one of four button responses through trial and error over repetitions of the shapes. To quantify how well the associations were learned for each trial, we used a state-space computational model of learning that provided a probability of each trial being correct given past performance for that stimulus, that we take as a measure of the strength of the association. We used linear modelling to relate single-trial neural oscillations to single-trial measures of association strength. We found frontal midline theta oscillations during the delay period tracked learning, where theta activity was strongest during the early stages of learning and declined as the associations were formed. Further, posterior alpha and low-beta oscillations in the cue period showed strong desynchronised activity early in learning, while stronger alpha activity during the delay period was seen as associations became well learned. Moreover, the magnitude of these effects during early learning, before the associations were learned, related to improvements in memory seen on the next presentation of the stimulus. The current study provides clear evidence that frontal theta and posterior alpha/beta oscillations play a key role during associative memory formation

Oscillations and Episodic Memory: Addressing the Synchronization/Desynchronization Conundrum

Brain oscillations are one of the core mechanisms underlying episodic memory. However, while some studies highlight the role of synchronized oscillatory activity, others highlight the role of desynchronized activity. We here describe a framework to resolve this conundrum and integrate these two opposing oscillatory behaviors. Specifically, we argue that the synchronization and desynchronization reflect a division of labor between a hippocampal and a neocortical system, respectively. We describe a novel oscillatory framework that integrates synchronization and desynchronization mechanisms to explain how the two systems interact in the service of episodic memory

Hippocampal theta activity during encoding promotes subsequent associative memory in humans

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings

Neural Mechanisms of Episodic Memory formation

In order to remember what you had for breakfast today, you must rely on episodic memory, the memory for personal events situated within a spatiotemporal context. In this dissertation, I use electroencephalographic (EEG) recordings to measure the neural correlates of successful episodic memory formation. The recorded EEG signals simultaneously sample local field potentials throughout the brain, and can be analyzed in terms of specific time-varying oscillatory or spectral components of neural activity which are thought to reflect the concerted activity of neuronal populations. I collected EEG recordings while participants engage in free recall, an episodic memory task during which participants must study and then recall a list of items. In the first chapter, I compare the spectral correlates during encoding of items later remembered to those later forgotten using two separate recording modalities, scalp and intracranial EEG. I find that memory formation is characterized by broad low frequency spectral power decreases and high frequency power increases across both datasets, suggesting that scalp EEG can resolve high frequency activity (HFA) and that low frequency decreases in intracranial EEG are unlikely due to pathology. In the next chapter, I connect these HFA increases to memory-specific processes by comparing study items based on how they are re- called, not whether they are recalled. I find increased HFA in left lateral cortex and hippocampus during the encoding of subsequently clustered items, those items recalled consecutively with their study neighbors at test. The precise time course of these results suggests that context updating mechanisms and item-to-context associative mechanisms support successful memory formation. In the third chapter, I measure how the formation of these episodic associations is modulated by pre-existing semantic associations by including a semantic orienting task during the encoding interval. I find that semantic processing interferes with the formation of new, episodic memories. In the final chapter, I show that the memory benefit for emotionally valenced items is better explained by a contextual mechanism than an attentional mechanism. Together, my work supports the theory that contextual encoding associative mechanisms, reflected by HFA increases in the memory network, support memory formation

성공기억에서의 해마의 특징적 뇌 기전

학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 뇌인지과학과, 2020. 8. 정천기.One of the most intriguing of the human brain's complex functions is the ability to store information provided by experience and to retrieve much of it at will. This capability of memory processing is critical to humans survival – that is, humans guide their actions based on a given stimulus (e.g., item) in an environment, and can do so even when the stimulus is no longer present owing to the memory of the stimulus. A fundamental question of memory is why some experiences are remembered whereas others are forgotten. Since Scoville and Milners characterization of patient H.M., who demonstrated severe recognition memory deficits following damage to the medial temporal lobe (MTL), the hippocampus has been extensively studied as one of the key neural substrates for memory. In line with this, several experiments have been conducted on exploring the roles of the hippocampus in various ways. One is confirming the causality of the hippocampus in the memory process using direct electrical stimulation to the hippocampal region. The other is investigating the neural correlates of hippocampus using intracranial electroencephalography (iEEG) field potential and single neurons action potential known as spike recorded directly from the hippocampus. The present thesis is focused on providing direct electrophysiological evidence of human hippocampus in episodic memory that may help fill the gap that remained in the field for several years. Here, I will show how direct hippocampal stimulation affect human behavior and present characterized neural correlates of successful memory in the hippocampus. In the first study, building on the previous findings on the hippocampus, I sought to address whether the hippocampus would show functional causality with memory tasks and elicit different neural characteristics depending on memory tasks applied. I found hippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. These results of the task-specific memory modulation suggest that the associative task elicited stronger theta oscillations than the single-item task. In the second study, I tested whether successful memory formation relies on the hippocampal neuronal activity that engaged preceding an event. I found that hippocampal pre-stimulus spiking activity (elicited by a cue presented just before a word) predicted subsequent memory. Stimulus activity during encoding (during-stimulus) also showed a trend of predicting subsequent memory but was simply a continuation of pre-stimulus activity. These findings indicate that successful memory formation in human is predicted by a pre-stimulus activity and suggests that the preparatory mobilization of neural processes before encoding benefits episodic memory performance. Throughout the study, the current finding suggests the possibility that the intervals of poor memory encoding can be identified even before the stimulus presented and may be rescued with targeted stimulation to the hippocampus even before the stimulus presented.인간의 복잡한 뇌 기능 중 흥미로운 하나는 경험에 의거하여 정보를 저장하고 의지에 따라 저장된 정보를 재인하는 기억 능력 이다. 인간은 주어진 자극에 기반하여 행동을 정하며 심지어 자극이 없는 상황에서도 자극에 대한 기억을 바탕으로 행동을 결정하기 때문에 기억 능력은 생존에 있어 매우 결정적이며, 이러한 기억과 관련된 가장 기본적인 질문은 기억의 저장 메커니즘, 즉, 어떤 기억은 저장이 되고 어떤 기억은 잊혀지는 가일 것이다. 스코빌과 밀너가 처음 보고한 기억상실증 환자 H.M.은 측두영역의 손상을 입은 후 심각한 인지 기억 능력의 장애를 보였고, 이후 사람 뇌의 해마 영역은 기억을 관장하는 뇌의 중요한 영역 중 하나로 널리 연구되었다. 해마가 기억에 미치는 영향과 역할에 대해서는 다양한 방법으로 실험이 진행되어 왔다. 그 중의 하나는 뇌에 직접적인 전기자극을 가해 기억 과정 중 해마의 역할을 확인하는 방법인데, 이는 뇌전증 환자의 모델을 통해 사람의 뇌에 접근이 가능해지면서 이루어져 왔다. 두 번째 방법은 전기생리학적 방법을 통하는 것인데 세포 외 활동 전위인 스파이크를 통해 성공기억에서의 뉴런의 활동성을 밝히는 것이다. 이 논문은 이 분야에서 오랫동안 논란이 되었고 부족했던 성공 기억에 관련된 해마의 역할과 기전을 물리적 자극 및 신경세포의 신호를 측정해서 전기생리학적 특성을 제시하는데 초점을 맞추고 있다. 논문에서 본 저자는 사람의 성공기억형성과 재인에 대해 뇌 자극과 단위세포활동을 보고할 것이다. 해마와 기억의 인과관계 및 기억 과정 중의 해마의 뇌 기전과 관련된 기존의 실험적, 행동적 발견들에 근거하여 본 저자는 (ㄱ) 해마에 직접적인 전기 자극을 주고 기억 수행능력의 차이 및 기억 과제에 따른 해마의 신경 기전을 밝히고, (ㄴ) 성공 기억이 형성되는 과정에서 나타나는 신경세포의 발화 패턴의 특성을 살펴보았다. 본 연구를 통해 저자는 향후 기억의 형성 과정에서, 자극이 제시되는 구간뿐 만 아니라 자극이 주어지기 전 단계에서도 해마를 타깃 하여 전기 자극을 줌으로써 기억 실패로 이어질 수 있는 자극을 성공 기억으로 저장할 수 있도록 유도할 수 있을 것이라 기대한다.SECTION 1. INTRODUCTION 1 CHAPTER 1: Human Memory System 1 1.1. The hippocampus and memory 2 1.2. The structure of the hippocampus 3 CHAPTER 2: Human Memory Research: how to see a memory 4 2.1 Clinical rationale for invasive recordings with intracranial electrodes 4 2.2. Human intracranial EEG 6 2.3. Single unit activity recording and spike sorting in human 7 2.4. Direct brain stimulation study 9 CHAPTER 3: Human Memory Research: hippocampal activity for understanding successful memory formation 11 3.1. Functional role of human intracranial oscillatory activity in successful memory mechanism 11 3.1.1. Theta Oscillations 11 3.1.2. Gamma oscillations 13 3.2. Brain stimulation for memory enhancement 14 3.3. Single unit activity study in memory 15 CHAPTER 4: Purpose of the Present Study 17 SECTION 2. EXPERIMENTAL STUDY 19 CHAPTER 5: The importance of the hippocampal oscillatory activity for successful memory: direct brain stimulation study 19 5.1. Abstract 20 5.2. Introduction 22 5.3. Materials and Methods 25 5.3.1. Patients 25 5.3.2. Electrode localization 25 5.3.3. Memory task 29 5.3.4. Brain stimulation 30 5.3.5. Neuropsychological memory test 31 5.3.6. Analysis of memory performance and electrophysiological data 32 5.4. Results 37 5.4.1. Hippocampal stimulation improves associative memory but impairs item memory 37 5.4.2. Stimulation-induced memory enhancement is reflected in increased theta power during retrieval 38 5.4.3. Associative memory elicits higher theta power than item memory during encoding 42 5.4.4. Successful memory encoding elicits higher theta power in both memory task 44 5.4.5. Stimulation-mediated memory effect is greater in subject with poorer baseline cognitive function 46 5.5. Discussion 48 5.5.1. Summary 48 5.5.2. Task-dependent effects of hippocampal stimulation on memory 49 5.5.3. Theta activity as a neural signature for memory enhancement 51 5.5.4. Clinical implications 52 5.5.5. Limitations 54 5.5.6. Conclusion 55 CHAPTER 6: Hippocampal pre-stimulus activity predicts later memory success 57 6.1. Abstract 58 6.2. Introduction 59 6.3. Materials and Methods 62 6.3.1. Patients 62 6.3.2. Electrodes 63 6.3.3. Task and Stimuli 64 6.3.4. Electrophysiological recordings and Spike sorting 65 6.3.5. Analysis of iEEG field potentials 66 6.4. Results 68 6.4.1. Behavioral results 68 6.4.2. Spiking properties of hippocampal neurons 68 6.4.3. Hippocampal pre-stimulus activity correlates with successful memory 70 6.4.4. Hippocampal pre-stimulus spiking activity correlates with high gamma field potentials 74 6.5. Discussion 78 6.5.1. Summary 78 6.5.2. Comparison with previous findings 78 6.5.3. Possible mechanism underlying pre-stimulus activity 79 6.5.4. Conclusion 82 SECTION 3. GENERAL CONCLUSION 83 CHAPTER 7: General Conclusion and Perspective 83 Bibliography 84 Abstract in Korean (국문초록) 93Docto

Characterization And Perturbation Of Functional Networks That Support Human Memory

Episodic memory is essential to our daily lives, as it attaches meaning to the constant stream of sensory inputs to the brain. However, episodic memory often fails in a number of common neurocognitive disorders. Effective therapies remain elusive, owing to the complexity of brain networks and neural processes that support episodic encoding and retrieval. In particular, it is not understood how inter-regional communication within the brain supports memory function, though such communication may be critical to the highly integrative nature of episodic memory. To uncover the patterns of memory-related functional connectivity, we asked a large cohort of neurosurgical patients with indwelling electrodes to perform a verbal free-recall task, in which patients viewed lists of simple nouns and recalled them a short time later. As patients performed this task, we collected intracranial EEG (iEEG) from electrodes placed on the cortical surface and within the medial temporal lobe (MTL). First, we examined whole-brain functional networks that emerged during the encoding and retrieval phases of this task, using spectral methods to correlate frequency-specific signals between brain regions. We identified a dynamic network of regions that exhibited enhanced theta (3-8 Hz) connectivity during successful memory processing, whereas regions tended to desynchronize at high frequencies (30-100 Hz). Next, using only electrodes placed within the MTL, we asked whether functional coupling was also observed among this mesoscale subnetwork of highly specialized regions that play an outsize role in memory. Recapitulating our earlier findings, we noted broadly enhanced theta connectivity within the MTL, centering on the left entorhinal cortex during successful encoding operations. Finally, to determine whether such low-frequency functional connections reflect correlative or causal relations in the brain, we applied direct electrical stimulation via electrodes placed within the MTL. We found that low-frequency connections (5-13 Hz) predicted the emergence of theta activity at distant regions in the brain – particularly when stimulation occurred near white matter – indicating the potential causal relevance of iEEG-based functional connections. Taken together, these studies underscore the importance of low-frequency functional coupling to memory across spatial scales, and suggest this form of coupling indicates a causal relation between brain regions

Hippocampal CA1 gamma power predicts the precision of spatial memory judgments.

The hippocampus plays a critical role in spatial memory. However, the exact neural mechanisms underlying high-fidelity spatial memory representations are unknown. We report findings from presurgical epilepsy patients with bilateral hippocampal depth electrodes performing an object-location memory task that provided a broad range of spatial memory precision. During encoding, patients were shown a series of objects along the circumference of an invisible circle. At test, the same objects were shown at the top of the circle (0°), and patients used a dial to move the object to its location shown during encoding. Angular error between the correct location and the indicated location was recorded as a continuous measure of performance. By registering pre- and postimplantation MRI scans, we were able to localize the electrodes to specific hippocampal subfields. We found a correlation between increased gamma power, thought to reflect local excitatory activity, and the precision of spatial memory retrieval in hippocampal CA1 electrodes. Additionally, we found a similar relationship between gamma power and memory precision in the dorsolateral prefrontal cortex and a directional relationship between activity in this region and in the CA1, suggesting that the dorsolateral prefrontal cortex is involved in postretrieval processing. These results indicate that local processing in hippocampal CA1 and dorsolateral prefrontal cortex supports high-fidelity spatial memory representations

EEG, MEG and neuromodulatory approaches to explore cognition: Current status and future directions

Neural oscillations and their association with brain states and cognitive functions have been object of extensive investigation over the last decades. Several electroencephalography (EEG) and magnetoencephalography (MEG) analysis approaches have been explored and oscillatory properties have been identified, in parallel with the technical and computational advancement. This review provides an up-to-date account of how EEG/MEG oscillations have contributed to the understanding of cognition. Methodological challenges, recent developments and translational potential, along with future research avenues, are discussed. Keywords: Cognition; Electrophysiology; Event-related-potentials; Neural oscillations; Neural synchronisation; Neuromodulatio