Investigating the neural mechanisms of human cognitive function through intracranial recordings

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FY2020 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 drug resistant epilepsy receiving intracranial electrodes and surgical treatment at the Clinical Center have been recruited for these studies. Our work takes advantage of the opportunities to record both intracranial EEG and single unit spiking activity from these implanted electrodes as participants perform a variety of cognitive tasks during the monitoring period. 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 represent information and how they communicate with one another across spatial scales. In our recent work, we have identified traveling waves of low frequency activity at both the larger spatial scale and at the smaller micro-scale that 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 Revision). We have related activity across spatial scales, and have recently examined how discrete high frequency oscillations known as ripples that are observed in the iEEG and local field potential signal in fact reflect bursts of coordinated spiking activity (Tong AP, Vaz A, Inati SK, Zaghloul KA (2020) In Preparation). We also have explored how such connectivity at the smallest spatial scales may provide insights into the functional organization and structure of the human cortex. Specifically, we have found that small local patches of cortex, which we refer to as modules, are highly connected and that activity within these modules is differentially modulated by different stimuli, suggesting that these modules encode different functional information (Chapeton JI, Wittig JH, Inati SK, Zaghloul KA (2020) In Preparation). 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, using a paired associates episodic memory task, we have directly explored the neural mechanisms that underlie our ability to form and retrieve memories. Our primary recent focus has been on understanding how patterns of individual neuronal spiking are related to successful memory. We have previously shown that fast oscillations, known as ripples are associated with successful memory retrieval. In our recent work, we demonstrated that these ripples reflect underlying bursts of neuronal spiking that occur in a specific temporal order. Importantly, our work demonstrated that the sequence of neuronal firing observed when individual are studying items are actually replayed when they recall those items from memory. This provides the first direct evidence that sequence replay is involved in human memory retrieval. We have described this work in a recent manuscript (Vaz AP, Wittig JH, Inati SK, Zaghloul KA (2020) Replay of neural sequences in the human cortex during memory retrieval Science 367(6842): 1131-1134). Building upon this work, we have also found that the order of firing is specific to the individual item that is being studied and recall. As such, we have developed a new set of tasks designed to explore how semantic concepts and categories are represented, and have obtained preliminary data suggesting that indeed sequences can separate different semantic information. We are currently preparing this work for submission (Wittig JH, Vaz AP, Inati SK, Zaghloul KA (2020) In Preparation). 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. We have been particularly interested in whether we can modulate the state of the brain through direct electrical stimulation. To do so, however, requires a careful understanding of how direct electrical stimulation can affect neural activity. We recently explored the use of single pulse electrical stimulation to identify stereotypical responses to stimulation in the human brain. We developed an approach that allows us to predict the responses to novel sequences of pulses with good fidelity. We have published this work in a recent manuscript (Steinhardt C, Sacre P, Sheehan TC, Wittig JH, Inati SK, Sarma SV, Zaghloul KA (2020) Reliable control of neural responses to single pulse stimulation in the human brain Brain Stimulation). We have now extended this work to examine whether we can also understand the effects of stimulation on individual neuronal spiking activity. We have found that applying local micro-stimulation through our microelectrode array can evoke both excitatory and inhibitory responses in nearby neurons. The effects of stimulation on the inhibitory responses are related to the distance between the stimulation and recording site, whereas the effects on excitatory responses appear more diffuse. We have completed this work and are preparing a manuscript describing these efforts for publication (Wittig JH, Youssef D, Inati SK, Zaghloul KA (2020) In Preparation). Finally, in a third set of studies, we have focused on understanding the interaction between the human memory and decision systems and how memory may be used for future cognitive behavior. In our paired associates data, we found that some words were more likely to be recalled successfully, no matter which word they were paired with, across all participants. These words are memorable, and we hypothesized that such memorability may be related to how semantically related those words are to all other semantic concepts. In our work, we found that the words that are the most memorable are those that are most semantically related to all other words, suggesting that our previous experiences can help guide our ability to search for a particular memory. In parallel, we found that patterns of activity that are reinstated when individuals successful recall words are reinstated more quickly in the cases when the words are more memorable. We have recently published this work in a manuscript (Xie W, Bainbridge W, Inati SK, Baker CI, Zaghloul KA (2020) Memorability of words in arbitrary verbal associations modulates memory retrieval in the anterior temporal lobe Nature Human Behavior In Press). In a separate study, we examined the hypothesis that recent episodes that we experience can be used to construct an internal model of the world that we then use to predict future events. We presented our participants with images of natural scenes that they had previously seen, but we manipulated some of the images by adding or removing an item from each image. In order to recognize this change, individuals must draw upon their memory of the initial experience and compare that memory to their current visual experience. We found that when individuals successfully identify this manipulation, we observe a prediction error signal that first emerges in regions of higher order visual cortex and that then propagates to the medial temporal lobe. Our data therefore suggest that even a single exposure to an event or episode is sufficient to establish a representation of a memory of that event in cortical regions that can be used for subsequent comparisons. Our manuscript detailing these efforts is currently under review (Haque RU, Inati SK, Levey AI, Zaghloul KA (2020) In Review).