Neural networks that span the medial temporal lobe (MTL), prefrontal cortex, and posterior cortical regions are essential to episodic memory function in humans. Encoding and retrieval are supported by the engagement of both distinct neural pathways across the cortex and common structures within the medial temporal lobes. However, the degree to which memory performance can be determined by neural processing that is common to encoding and retrieval remains to be determined. To identify neural signatures of successful memory function, we administered a delayed free-recall task to 187 neurosurgical patients implanted with subdural or intraparenchymal depth electrodes. We developed multivariate classifiers to identify patterns of spectral power across the brain that independently predicted successful episodic encoding and retrieval. During encoding and retrieval, patterns of increased high frequency activity in prefrontal, MTL, and inferior parietal cortices, accompanied by widespread decreases in low frequency power across the brain predicted successful memory function. Using a cross-decoding approach, we demonstrate the ability to predict memory function across distinct phases of the free-recall task. Furthermore, we demonstrate that classifiers that combine information from both encoding and retrieval states can outperform task-independent models. These findings suggest that the engagement of a core memory network during either encoding or retrieval shapes the ability to remember the past, despite distinct neural interactions that facilitate encoding and retrieval.

22Based on rodent models, researchers have theorized that the hippocampus supports episodic 23 memory and navigation via the theta oscillation, a ∼4-10-Hz rhythm that coordinates brain-wide 24 neural activity. However, recordings from humans have indicated that hippocampal theta oscillations 25 are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in 26 theta's function. To characterize human hippocampal theta, we examined the properties of theta 27 oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects 28 performed a virtual spatial navigation task. During virtual movement, we observed hippocampal 29 oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently 30 displayed oscillations at ∼8-Hz and the precise frequency of these oscillations correlated with the 31 speed of movement, implicating these signals in spatial navigation. We also observed slower ∼3-Hz 32 oscillations, but these signals were more prevalent in the anterior hippocampus and their frequency 33 did not vary with movement speed. Our results converge with recent findings to suggest an updated 34 view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a 35 single general role, high-and low-theta oscillations, respectively, may reflect spatial and non-spatial 36 cognitive processes. 38The theta oscillation is a large-scale network rhythm that appears at ∼4-10 Hz in rodents and is 39 hypothesized to play a fundamental role in mammalian spatial navigation and memory (Kahana et 40 al., 2001; Buzsáki, 2005). However, in humans, there is mixed evidence regarding the relevance and 41 properties of hippocampal theta. Some studies in humans show hippocampal oscillations at 1-5 Hz that 42 have similar functional properties as the theta oscillations seen in rodents (e.g., Arnolds et al., 1980; 43 There is also evidence that human movement-related hippocampal theta oscillations vary substantially 45 in frequency according to whether a subject is in a physical or virtual environment (Aghajan et al., 2016; 46 Bohbot et al., 2017; Yassa, 2018). Together, these studies have been interpreted to suggest that the 47 human hippocampus does show a signal analogous to theta oscillations observed in rodents but that 48 this oscillation is more variable and slower in frequency (Jacobs, 2014). These apparent discrepancies 49 in the frequency of theta between species and behaviors shed doubt on the notion that theta exists as 50 a single general oscillatory phenomenon that coordinates brain-wide neural activity consistently across 51 species and tasks. 52Our study aimed to resolve these discrepancies by characterizing the properties of human hip-53 pocampal oscillations in spatial cognition. We analyzed intracranial electroencephalographic (iEEG) 54 recordings from the hippocampi of fourteen neurosurgical subjects performing a virtual-reality (VR) 55 spatial navigation task, in which subjects were aske...

Significance Statement (120/120 words)Cognitive impairment and memory loss are critical public health challenges. Deep brain stimulation (DBS) is a promising tool for developing strategies to ameliorate memory disorders by targeting brain regions involved in mnemonic processing. Using DBS, our study sheds light on the lesser--known role of the posterior cingulate cortex (PCC) in memory encoding. Stimulating the PCC during encoding impairs subsequent recall memory. The degree of impairment is predicted by stimulation--induced hippocampal gamma oscillations and functional connectivity between PCC and hippocampus. Our findings provide the first causal evidence implicating PCC in memory encoding and highlight the PCC as a favorable target for neuromodulation strategies, using a--priori connectivity measures to predict stimulation effects. This has significant implications for developing therapies for memory diseases. Abstract (250/250)Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role PCC plays in memory encoding is lacking. In patients undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography (stereo EEG). These techniques allow precise targeting of deep cortical structures including the PCC, and simultaneous acquisition of oscillatory recordings from neighboring regions such as the hippocampus. We used a free recall experiment in which PCC was stimulated during item encoding period of half of the study lists, while no stimulation was 2 applied during encoding period of the remaining lists. We evaluated if stimulation affected memory and/or modulated hippocampal activity. Results revealed four main findings. (i) Stimulation during encoding impaired memory for early items on the study lists. (ii) Stimulation increased hippocampal gamma band power. (iii) Stimulation--induced gamma power predicted memory impairment. (iv) Functional connectivity between the hippocampus and PCC predicted the degree of stimulation effect on memory. Our findings offer the first causal evidence implicating the PCC in episodic memory encoding.Importantly, results highlight that stimulation targeted outside of the temporal lobe can modulate hippocampal activity with implications on behavior. Furthermore, a--priori measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapies to treat diseases of memory loss and cognitive impairment using DBS.