FY2019 has seen significant progress towards realizing our goals and objectives. We have continued our efforts capturing and analyzing intracranial recordings while participants engage in cognitive tasks designed to probe memory encoding and retrieval. Patients with medically refractory epilepsy receiving intracranial electrodes and surgical treatment at the Clinical Center have been recruited for these studies. We have also continued our work analyzing local field potential and single unit spiking activity captured from the basal ganglia during deep brain stimulation surgery for patients with Parkinsons disease. Our efforts are focused on understanding changes in human brain activity across these different spatial scales. In order to properly interpret how such changes in neural activity may underlie our ability to form and retrieve memories, an important goal for our lab has been to understand how brain regions communicate with one another across spatial scales. We have developed a metric of effective connectivity that is premised on the hypothesis that communication between brain regions occurs with consistent and stable timing. We have successfully related these measures of effective connectivity to measures of oscillatory coherence, demonstrating that brain regions communicate neural activity through bursts of communication that are gated by coherent oscillations (Chapeton J, Inati SK, Zaghloul KA (2019) Large-Scale Communication in the Human Brain Is Rhythmically Modulated through Alpha Coherence, Current Biology 29: 1-11). We have also examined how traveling waves of activity at both this larger spatial scale and at the smaller micro-scale may be relevant for the ability to move information across the brain, and how this may play a role in cognition (Sreekumar V, Inati SK, Zaghloul KA (2019) Traveling waves at the macro and micro scale in the human brain, In Preparation). At the smaller scale we have successfully collected single unit spiking activity from microelectrode arrays in several patients while they have participated in our cognitive tasks, and have developed automated processing pipelines to extract out spiking information in real-time. We have recently identified several important interactions between the spiking activity of individual neurons and the broader changes in neural activity that we observe at the larger spatial scales. We are continuing to develop these methodological advances in order to use these tools on three main sets of studies. In the first set of studies, we have been interested in investigating human episodic memory formation. Using a paired associates episodic memory task, we have directly explored the neural mechanisms that underlie our ability to form and retrieve memories. We recently demonstrated that the background brain activity that forms a neural representation of the context within which memories are experienced plays a role in memory encoding. When we experience stimuli every day, we form a neural representation of both the individual items and the context within which they occur. The extent to which we can retrieve distinct memories depends on how different these representations are. In this recent study, we showed that if the background context changes more rapidly from moment to moment, which means that the neural patterns of activity from moment to moment are more different, it is easier to remember and distinguish different memories (El-Kalliny ME, Wittig JH, Sheehan TC, Sreekumar V, Inati SK, Zaghloul KA (2019) Changing temporal context in human temporal lobe promotes memory of distinct episodes Nature Communications 10: 203). We have also been interested in how interactions between the medial temporal lobe and the lateral temporal cortex may play a role in memory retrieval. Specifically, we focused on ripples, which are a form of fast oscillatory activity that has been previously identified in the medial temporal lobe and that has been hypothesized to play a role in memory retrieval. We have shown that ripples are coupled between the medial temporal lobe and the lateral temporal lobe during successful retrieval, providing a potential neural mechanism by which activity in the medial temporal lobe triggers the recovery of neural activity associated with a memory in the cortex. We have described this work in a recent manuscript (Vaz AP, Inati SK, Brunel N, Zaghloul KA (2019) Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory Science 363(6430): 975-978). In a second set of studies, we have been interested in understanding how the fidelity of memory encoding is modulated by the state of the brain and are particularly interested in whether we can modulate the state of the brain through direct electrical stimulation. This effort builds upon previous work from our lab in which we have demonstrated that neural signals that are present before items are even presented to be remembered can predict the fidelity of memory encoding. These earlier studies suggest that such neural activity may reflect other cognitive processes such as attention, or the capacity of the brain to flexibly encode information. As such, we have hypothesized that we can manipulate these signals in order to modulate memory performance. To do so, however, requires a careful understanding of how direct electrical stimulation can affect neural activity. In an initial study, we have explored the use of single pulse electrical stimulation to identify stereotypical responses to stimulation in the human brain. We have developed an approach that allows us to predict the responses to novel sequences of pulses with good fidelity. We have completed this initial project, and a manuscript describing these efforts is currently under review (Steinhardt C, Sacre P, Sheehan TC, Wittig JH, Inati SK, Sarma SV, Zaghloul KA (2019) Reliable control of neural responses to single pulse stimulation in the human brain In Review). We are extending this work to ask how such individual pulses can be combined across space and across time, and whether we can use the learned responses to single pulses to predict novel spatiotemporal combinations of pulses. We have developed a novel experimental task to explore this question, and are currently collecting data for analyses. Finally, in a third set of studies, we have focused on understanding the interaction between the human memory and decision systems. In a recent study, we have found that cognitive control, which requires adaptations both during individual trials and adaptations across trials, involves a complex interaction of oscillatory changes in both the subthalamic nucleus and prefrontal cortex. (Zavala B, Jang AI, Trotta M, Lungu CI, Brown P, Zaghloul KA (2018) Cognitive control involves theta power within trials and beta power across trials in the prefrontal-subthalamic network Brain 141(12): 3361-3376). We were motivated to pursue these questions because we were interested in whether similar circuit dynamics are present when making non-motor decisions related to memory. In a recent study, we found that oscillatory and spiking activity in the human subthalamic nucleus is modulated during non-motor decisions to encode items into memory or to ignore them. We are now currently extending this work by examining the reverse interaction between decisions and memory, specifically how memory affects our ability to make decisions. We have developed a novel task in which participants must rely upon their memory for associations that they have formed to make decisions, and are interested in how this process is represented in the human brain. We are currently collecting data for these analyses.

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