Okay. Next, Dr. James Caruso, who's going to talk about gamma and theta band power increases in the anterior and posterior hippocampus. Predict successful episodic memory formation. Hi, everyone. My name is James Caruso. I'm a first-year resident at UT Southwestern in Dallas. It's a pleasure to be speaking in front of everybody today. I'll be presenting some of our research focused on the use of SEG to study differences in oscillatory power across the anterior and posterior hippocampal axis during episodic memory formation. Specifically, we're going to look at theta wave changes in oscillatory power in the anterior and posterior hippocampus and examine how these data fit with theories of functional specialization throughout the hippocampus. So, these are a few of our funding sources, including the UT Brain Initiative, as well as DARPA, the Restoring Active Memory Program. Very thankful to have these funding sources, and no conflicts of interest. So, I'll start by talking about a pretty straightforward question, but why theta oscillations are important in memory. So, in rodents, theta's been implicated in numerous functions related to memory formation, including synaptic plasticity, as well as information encoding, and based on cortical and subcortical recordings in animals, theta activity is thought to bind brain regions in memory encoding and retrieval. It also occurs during navigation, storage, and retrieval of working memory items. And there's additional evidence that suggests that lesional or pharmacologic disruption of theta correlates with impaired memory function. But these are primarily rodent studies, and the human data is a little less revealing. There's some intracranial EEG studies of patients engaging in episodic memory tasks that have shown associations between episodic memory formation and gamma band activity, but no associated theta activity. And the data we do have involves relatively vague neocortical theta oscillations during successful episodic memory formation, but they're not localized to the hippocampus, which is a primary feature in rodents. So why are we talking about episodic memory? It's one way to assess theta activity, and it involves the recollection of items and events at specific time points, and episodic memory degeneration is particularly important in a variety of neurologic diseases. There's prior work that demonstrates that the hippocampus is very active in episodic memory formation, and that the hippocampus is functionally specialized. Again, this is in rodent data. There are also studies that show that the dorsal aspect of the hippocampus may be involved in spatial reasoning, whereas the ventral hippocampus is involved in characterizing the emotional and affective content of memories. But there's not much human direct electrophysiologic data to support this, and of the studies that do exist, they're not confirmed with direct brain recordings. So we know that in rodent data, theta oscillations are associated with successful episodic memory formation, and we also know that episodic memory formation involves hippocampal activity, but anterior-posterior axis specialization hasn't been well-defined, and that's primarily where our study comes in. We wanted to look at whether memory-related oscillatory changes exist in human hippocampal recordings along the anterior-posterior axis. We focused on the theta frequency. We also have some data related to the gamma frequency that I'll touch on briefly later, but we mainly wanted to look at theta. So as far as our data set, we have 23 patients with medication-resistant epilepsy that underwent SEG surgery for identification of seizure foci. Every participant with at least one anterior and posterior hippocampal electrode pair was included in the study. However, we excluded any electrodes in the anterior-posterior hippocampus that were at the site of direct seizure foci. The anterior and posterior hippocampus, we delineated that out based on where it was in relation to the uncle notch. That's consistent with prior studies in humans. And as far as our total data set, we had 71 anterior and 70 posterior hippocampal electrodes that were included. For our recall task, we had each patient perform a verbal free recall task in which they were instructed to study lists of words for a later memory test. Each word in the list was presented to them on a laptop for 1.6 seconds, and it was followed by a blank screen for four seconds. This was repeated for 15 memory items in a single list. Each list was followed by 30 seconds of simple math distractors in the format of A plus B plus C equals to basically attenuate the recency effect and limit rehearsal in their participation. During the recall period, they were instructed to recall as many items as possible in any order during a 30-second recall period. The vocal responses were recorded for analysis, and each session involved 25 lists of words with this encoding distractor recall paradigm, and each participant completed approximately one to three sessions. We sought to compare oscillatory power from successfully encoded items to that of unsuccessfully encoded items in the list to identify relationships between the difference in oscillatory power at theta and their likelihood of subsequent recall. So this is a good summary slide, but we describe our results in terms of subsequent memory effect. So a positive subsequent memory effect would represent a theta or gamma band power increase during successful item encoding that we observed, and a negative subsequent memory effect would mean that there was a power increase associated with unsuccessful encoding of the items. We compared power values derived from recall events to power values from non-recalled events using a Wilcoxon rank sum test at each time frequency point, and then we calculated the Z statistics across electrodes and subjects in the population. So this plot for both theta and gamma compares the differences in subsequent memory effects across the anterior-posterior axis. We didn't observe any differences between the anterior-posterior axis in the gamma frequency range, but at slow theta we did observe a significant difference. These time frequency plots are another representation of the aggregate subsequent memory effects in both the anterior hippocampus on the left and the posterior hippocampus, which is the time frequency plot on the right. Now, at theta, in around two-and-a-half to five hertz range, which is the low end of theta or slow theta, there's a significantly greater power increase in the posterior hippocampus compared to the anterior hippocampus. This power increase is significantly greater approximately 500 milliseconds after presentation of a recalled item. In the anterior hippocampus, there's actually a negative memory effect, which would be a power increase associated with non-recalled items that's strongest in the second half of the cycle, as represented by the blue here. Prior studies may have sampled from the anterior hippocampus more than the posterior hippocampus, mainly because of differences in size. But if you're sampling from the anterior hippocampus nearly exclusively, it's likely that prior studies have underestimated a slow theta memory effect during item encoding. And it also implies that there may be functional differences along the anterior or posterior axis of the hippocampus. So, I'll talk about some of, there have been a variety of models that have been proposed for differential hippocampal function. I'll focus on some that are more relevant to our data, as well as why we weren't necessarily able to delineate that. One model proposes that the anterior region exhibits sensitivity to emotional content of successfully encoded memory items. But the dorsal aspect may be involved in encoding non-emotional or contextual related content. We didn't address this proposal because we didn't manipulate the effective content of individual memory items. It was recalling words from a list. We would need a separate memory task for that. We had, there's another view that posits that there's a gain of representation along the anterior or posterior axis, in which more general information about an item that needs to be recalled is represented in the anterior hippocampus, whereas more specific and contextual information is represented in the posterior hippocampus. One thing that we would need to establish this further in our study would be a definitive assessment of the relative contribution of theta versus gamma oscillations in supporting episodic memory. We would also need a memory task that, again, manipulates the specificity of memories during encoding and retrieval, and includes additional item and category information to help answer this question. Namely, whether the theta oscillations we observed in the posterior hippocampus are related to a functional specialization that involves increased contextual contents in memory. It's also important to note, you know, speaking to a room of neurosurgeons, the neurosurgical applications of functional specialization of the hippocampus. In brief, if we can elucidate exactly what the individual regions of the hippocampus are and how they contribute to episodic memory formation and retrieval, we can better counsel patients regarding the effects of seizure foci that involve the hippocampus in terms of memory difficulties, as well as better estimate postoperative memory loss subtleties, and it'll allow us to further refine our surgical planning at later points. So, in conclusion, we studied 141 electrodes in 23 patients who underwent SCEG surgery and performed a verbal free recall task to assess gamma and theta frequency activity during episodic memory formation. We saw a power increase in successfully encoded items in the posterior, but not the anterior hippocampus at the slow theta range. These differences in slow theta activity may symbolize functional specialization, but again, we would need further study with more specific memory tasks to confirm this. It may be essential knowledge for counseling patients later on, and we look forward to seeing more of the clinical applications of these results. And some acknowledgments, we have departments at the University of Pennsylvania, as well as UT Dallas and UT Southwestern, who've contributed to the work, and we're very grateful for all the different input. Thank you very much. Yes? Was there a difference, or do you notice it between the dominant versus the dominant? Absolutely. So, we did look at dominant versus non-dominant hemispheres. I primarily focused on anterior and posterior for the sake of this talk, but the results are interesting. We didn't observe any differences in theta between the two hemispheres, but gamma, we did. During item encoding, we got a very much more robust gamma response in the anterior hippocampus, and in item retrieval, we saw increased gamma activation in the non-dominant hippocampus. So, it was kind of a reversal of the paradigm in encoding versus retrieval for gamma, but in theta, the results were a little more nonspecific. So, we'd like to be able to look into that further. I don't know the exact location of the electrodes or how you controlled for power differences, but is there a chance that the different anatomical orientation of the head of the hippocampus, how it wraps back on itself, could affect the power compared to the tail or the more posterior aspect of the hippocampus? That's interesting. We thought a little bit about that, and one of the ways that that plays in, as well as like spatial orientation of the hippocampus, but subfield localization as well, whether CA1 or CA3 were involved, and we know that CA1 is relatively expanded in the anterior hippocampus as opposed to the posterior. We did have some further subsets of our analysis where we analyzed anterior-only CA1 and CA3 regions, and we didn't find any significant difference in theta. So, we do believe that rather than it being a primarily subfield-related phenomenon or hippocampal orientation phenomenon, we're thinking it has more to do with the anterior-posterior axis, but one of our directions going forward is to further isolate where our electrodes are placed in terms of anterior and posterior electrodes for all different subfields. So. I guess, follow-up, did any of your electrodes come from the back? Because one way to address this would be to compare electrodes that come from orthogonal compared to electrodes that come more down the axis of the hippocampus and comparing the contacts that are anterior versus more posterior. Yeah. No, that makes perfect sense. Certainly something we could factor into our further analysis. Absolutely. Thank you.

scalp EEG

oscillatory power

anterior hippocampus

posterior hippocampus

episodic memory formation