Task design of the encoding and recall periods of the memory experiments, and iEEG recording sites in AI, with DMN and FPN nodes.

(a) Experiment 1, Verbal free recall (VFR): (i) Task design of memory encoding and recall periods of the verbal free recall experiment (see Methods for details). Participants were first presented with a list of words in the encoding block and asked to recall as many as possible from the original list after a short delay. (ii) Electrode locations for AI with DMN nodes (top panel) and AI with FPN nodes (bottom panel), in the verbal free recall experiment. Proportion of electrodes for AI, PCC/Pr, mPFC, dPPC, and MFG were 9%, 8%, 19%, 32%, and 32% respectively, in the VFR experiment. (b) Experiment 2, Categorized verbal free recall (CATVFR): (i) Task design of memory encoding and recall periods of the categorized verbal free recall experiment (see Methods for details). Participants were presented with a list of words with consecutive pairs of words from a specific category (for example, JEANS-COAT, GRAPE-PEACH, etc.) in the encoding block and subsequently asked to recall as many as possible from the original list after a short delay. (ii) Electrode locations for AI with DMN nodes (top panel) and AI with FPN nodes (bottom panel), in the categorized verbal free recall experiment. Proportion of electrodes for AI, PCC/Pr, mPFC, dPPC, and MFG were 10%, 7%, 11%, 35%, and 37% respectively, in the CATVFR experiment. (c) Experiment 3, Paired associates learning verbal cued recall (PALVCR): (i) Task design of memory encoding and recall periods of the paired associates learning verbal cued recall experiment (see Methods for details). Participants were first presented with a list of 6 word-pairs in the encoding block and after a short post-encoding delay, participants were shown a specific word-cue and asked to verbally recall the cued word from memory. (ii) Electrode locations for AI with DMN nodes (top panel) and AI with FPN nodes (bottom panel), in the paired associates learning verbal cued recall experiment. Proportion of electrodes for AI, PCC/Pr, mPFC, dPPC, and MFG were 14%, 5%, 13%, 33%, and 35% respectively, in the PALVCR experiment. (d) Experiment 4, Water maze spatial memory (WMSM): (i) Task design of memory encoding and recall periods of the water maze spatial memory experiment (see Methods for details). Participants were shown objects in various locations during the encoding period and asked to retrieve the location of the objects during the recall period. Modified from Jacobs et. al. (2018) with permission. (ii) Electrode locations for AI with DMN nodes (top panel) and AI with FPN nodes (bottom panel), in the water maze spatial memory experiment. Proportion of electrodes for AI, PCC/Pr, mPFC, dPPC, and MFG were 10%, 15%, 13%, 38%, and 24% respectively, in the WMSM experiment. Overall, proportion of electrodes for VFR, CATVFR, PALVCR, and WMSM experiments were 43%, 27%, 15%, and 15% respectively. AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Anterior insula electrode locations (red) visualized on insular regions based on the atlas by Faillenot and colleagues (Faillenot, Heckemann, Frot, & Hammers, 2017).

Anterior insula is shown in blue, and posterior insula mask is shown in green (see Methods for details). This atlas is based on probabilistic analysis of the anatomy of the insula with demarcations of the AI based on three short dorsal gyri and the PI which encompasses two long and ventral gyri.

iEEG evoked response, quantified using high-gamma (HG) power, for AI (red) and PCC/precuneus (blue) during (a) VFR, (b) CATVFR, (c) PALVCR, and (d) WMSM experiments.

Green horizontal lines denote greater high-gamma power for AI compared to PCC/precuneus (ps < 0.05). Red horizontal lines denote increase of AI response compared to the resting baseline during the encoding and recall periods (ps < 0.05). Blue horizontal lines denote decrease of PCC/precuneus response compared to the baseline during the encoding periods and increase of PCC/precuneus response compared to the baseline during the recall periods (ps < 0.05).

Causal directed information flow between the anterior insula and the PCC/precuneus and mPFC nodes of the default mode network (DMN), across verbal and spatial memory domains, measured using phase transfer entropy (PTE).

(a) Experiment 1, VFR: The anterior insula showed higher causal directed information flow to the PCC/precuneus (AI → PCC/Pr) compared to the reverse direction (PCC/Pr → AI) (n=142) during both encoding and recall. The anterior insula also showed higher causal directed information flow to the mPFC (AI → mPFC) compared to the reverse direction (mPFC → AI) (n=112) during both memory encoding and recall. (b) Experiment 2, CATVFR: The anterior insula showed higher causal directed information flow to the PCC/precuneus (AI → PCC/Pr) compared to the reverse direction (PCC/Pr → AI) (n=46) during both encoding and recall. (c) Experiment 3, PALVCR: The anterior insula showed higher causal directed information flow to the PCC/precuneus (AI → PCC/Pr) compared to the reverse direction (PCC/Pr → AI) (n=10) during both encoding and recall. (d) Experiment 4, WMSM: The anterior insula showed higher causal directed information flow to PCC/precuneus (AI → PCC/Pr) than the reverse (PCC/Pr → AI) (n=91), during both spatial memory encoding and recall. The anterior insula also showed higher causal directed information flow to mPFC (AI → mPFC) than the reverse (mPFC → AI) (n=23), during both spatial memory encoding and recall. In each panel, the direction for which PTE is higher, is underlined. White dot in each violin plot represents median PTE across electrode pairs. *** p < 0.001, * p < 0.05.

Replicability of findings of causal interactions of the AI with the DMN and FPN nodes for different memory experiments during (a) Memory Encoding and (b) Memory Recall.

The verbal free recall (VFR) task was considered the original dataset and the categorized verbal free recall (CATVFR), paired associates learning verbal cued recall (PALVCR), and water maze spatial memory (WMSM) tasks were considered replication datasets and Bayes factor (BF) for replication was calculated for pairwise tasks (verbal free recall vs. T, where T can be categorized verbal free recall, paired associates learning verbal cued recall, or water maze spatial memory task). Significant BF results (BF>3) are indicated in bold. AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Causal directed information flow between the anterior insula and the dPPC and MFG nodes of the frontoparietal network (FPN), across verbal and spatial memory domains.

(a) Experiment 1, VFR: The anterior insula showed higher causal directed information flow to the dorsal PPC (AI → dPPC) compared to the reverse direction (dPPC → AI) (n=586) during both encoding and recall. The anterior insula also showed higher causal directed information flow to the MFG (AI → MFG) compared to the reverse direction (MFG → AI) (n=642) during both memory encoding and recall. (b) Experiment 2, CATVFR: The anterior insula showed higher causal directed information flow to the dorsal PPC (AI → dPPC) compared to the reverse direction (dPPC → AI) (n=327) during both encoding and recall. (c) Experiment 3, PALVCR: The anterior insula showed higher causal directed information flow to the dorsal PPC (AI → dPPC) compared to the reverse direction (dPPC → AI) (n=242) during both encoding and recall. The anterior insula also showed higher causal directed information flow to the MFG (AI → MFG) compared to the reverse direction (MFG → AI) (n=362) during memory recall. (d) Experiment 4, WMSM: The anterior insula showed higher causal directed information flow to MFG (AI → MFG) than the reverse (MFG → AI) (n=177), during both spatial memory encoding and recall. In each panel, the direction for which PTE is higher, is underlined. *** p < 0.001, ** p < 0.01.

The anterior insula is a causal outflow hub in its interactions with the DMN and FPN, during encoding and recall periods, and across memory experiments.

In each panel, the net direction of information flow between the AI and the DMN and FPN nodes are indicated by green arrows on the right. *** p < 0.001, ** p < 0.01, * p < 0.05.

Schematic illustration of key findings related to the intracranial electrophysiology of the triple network model in human episodic memory.

(a) High-gamma response: Our analysis of local neuronal activity revealed consistent suppression of high-gamma power in the PCC/precuneus compared to the AI during encoding periods across all four episodic memory experiments. We did not consistently observe any significant differences in high-gamma band power between AI and the mPFC node of the DMN or the dPPC and MFG nodes of the FPN during the encoding periods across the four episodic memory experiments. In contrast, we detected similar high-gamma band power in the PCC/precuneus relative to the AI during the recall periods. (b) Directed information flow: Despite variable patterns of local activation and suppression across DMN and FPN nodes during memory encoding and recall, we found stronger causal influence (denoted by green arrows, thickness of arrows denotes degree of replicability across experiments, see Table 1) by the AI on both the DMN as well as the FPN nodes than the reverse, across all four memory experiments, and during both encoding and recall periods.

iEEG evoked response for AI (red) and mPFC (cyan) in the four experiments.

Green horizontal lines denote time periods where high-gamma power between the AI and mPFC were significantly different from each other. Red and cyan horizontal lines denote increase of high-gamma power compared to the resting baseline in the AI and mPFC respectively.

iEEG evoked response for AI (red) and dPPC (purple) in the four experiments.

Green horizontal lines denote time periods where high-gamma power between the AI and dPPC were significantly different from each other. Red and purple horizontal lines denote increase of high-gamma power compared to the resting baseline in the AI and dPPC respectively.

iEEG evoked response for AI (red) and MFG (orange) in the four experiments.

Green horizontal lines denote time periods where high-gamma power between the AI and MFG were significantly different from each other. Red and orange horizontal lines denote increase of high-gamma power compared to the resting baseline in the AI and MFG respectively.

Directed information flow from the IFG to the DMN nodes and the reverse, in broadband frequencies (0.5-80 Hz).

*** p < 0.001, ** p < 0.01, * p < 0.05.

Directed information flow from the IFG to the FPN nodes and the reverse, in broadband frequencies (0.5-80 Hz).

*** p < 0.001, ** p < 0.01, * p < 0.05.

Differential directed information flow from the anterior insula to the DMN nodes during task versus resting-state, in broadband frequencies (0.5-80 Hz).

*** p < 0.001, ** p < 0.01, * p < 0.05.

Differential directed information flow from the anterior insula to the FPN nodes during task versus resting-state, in broadband frequencies (0.5-80 Hz).

*** p < 0.001, ** p < 0.01, * p < 0.05.

iEEG evoked response for PCC/precuneus (blue) and dPPC (purple) in the four experiments.

Green horizontal lines denote time periods where high-gamma power between the PCC/precuneus and dPPC were significantly different from each other.

iEEG evoked response for PCC/precuneus (blue) and MFG (orange) in the four experiments.

Green horizontal lines denote time periods where high-gamma power between the PCC/precuneus and MFG were significantly different from each other.

Participant demographic information (total 177 participants).

Number of electrode pairs used in phase transfer entropy (PTE) analysis in the verbal free recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrode pairs used in phase transfer entropy (PTE) analysis in the categorized verbal free recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrode pairs used in phase transfer entropy (PTE) analysis in the paired associates learning verbal cued recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrode pairs used in phase transfer entropy (PTE) analysis in the water maze spatial memory task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrodes in each node used in high-gamma power analysis in the verbal free recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrodes in each node used in high-gamma power analysis in the categorized verbal free recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrodes in each node used in high-gamma power analysis in the paired associates learning verbal cued recall task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.

Number of electrodes in each node used in power spectral density (PSD) analysis in the water maze spatial memory task.

AI: anterior insula, PCC: posterior cingulate cortex, Pr: precuneus, mPFC: medial prefrontal cortex, dPPC: dorsal posterior parietal cortex, MFG: middle frontal gyrus.