Information flows from hippocampus to auditory cortex during replay of verbal working memory items

  1. Vasileios Dimakopoulos
  2. Pierre Mégevand
  3. Lennart H Stieglitz
  4. Lukas Imbach
  5. Johannes Sarnthein

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    Evaluation Summary:

    The basis for working memory is controversial in terms of any basis related to neuronal or synaptic activity in sensory cortex during maintenance and the involvement of non-sensory areas especially the frontal cortex and hippocampus. This work uses rare human intracranial recordings to examine another aspect, connectivity between areas, and demonstrates connectivity from sensory cortex to hippocampus during encoding in one frequency band and connectivity in a reverse sense during maintenance. The work has the potential to inform models of working memory.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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Abstract

The maintenance of items in working memory (WM) relies on a widespread network of cortical areas and hippocampus where synchronization between electrophysiological recordings reflects functional coupling. We investigated the direction of information flow between auditory cortex and hippocampus while participants heard and then mentally replayed strings of letters in WM by activating their phonological loop. We recorded local field potentials from the hippocampus, reconstructed beamforming sources of scalp EEG , and – additionally in four participants – recorded from subdural cortical electrodes. When analyzing Granger causality, the information flow was from auditory cortex to hippocampus with a peak in the [4 8] Hz range while participants heard the letters. This flow was subsequently reversed during maintenance while participants maintained the letters in memory. The functional interaction between hippocampus and the cortex and the reversal of information flow provide a physiological basis for the encoding of memory items and their active replay during maintenance.

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  1. Version published to 10.7554/elife.78677 on eLife
  2. Version published to 10.1101/2021.03.11.434989v2 on bioRxiv
  3. eLife

    Evaluation Summary:

    The basis for working memory is controversial in terms of any basis related to neuronal or synaptic activity in sensory cortex during maintenance and the involvement of non-sensory areas especially the frontal cortex and hippocampus. This work uses rare human intracranial recordings to examine another aspect, connectivity between areas, and demonstrates connectivity from sensory cortex to hippocampus during encoding in one frequency band and connectivity in a reverse sense during maintenance. The work has the potential to inform models of working memory.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  4. eLife

    Reviewer #1 (Public Review):

    The authors have shown a unique set of recordings, wherein they have collected intracranial data from parietal cortex and hippocampus, as well as scalp EEG in a number of subjects. With this unique advantage, they have examined directionality of connectivity between various regions during a working memory task. Given the growing evidence for the role of hippocampus in working memory, understanding its connectivity to the rest of the brain provides a crucial insight into the network involved in such a fundamental process. Whilst the existing content is generally of a high standard, and the analyses seem sound, there are some areas of considerable brevity that would benefit from expansion. Below are my comments on the manuscript.

    Discussion: This is surprisingly short discussion section. I feel this should be expanded considerably, such as including some of the information that I have discussed below regarding potential considerations of the task (e.g bimodal nature), discussion of the PLV results in the context of previous non-directional findings, the differences observed between correct and incorrect trials, considering in more detail the other behavioral consequences of these results. These suggestions are not necessarily exhaustive but are all points I believe should be included.

    Comments on results section in general:

    ~All the results in this section seem to refer to a single electrode for each subject. It would be beneficial to know whether these electrodes were representative of activity from surrounding electrodes or not. That is, how generalizable are the PSD results shown here.

    ~Also, many of these results are very descriptive. Whilst in some specific scenarios this is unavoidable, for the purposes of reporting results from PSD (for example) it is definitely possible to report details such as the degree of power increase. At present, this reads more like a discussion section that an informative results section.

    ~It would be helpful to see an overlay of the parietal electrode with a topographic map of the scalp EEG recording, to truly appreciate the spatial overlap between the electrode and the generator.

    Figures in general: many of the figures appear to refer only to single subjects. It would be useful to have more detailed summary information across subjects to understand how reliable/variable these effects are.

    Data availability section: The bit on previously published datasets confused me a little. Is this published dataset included as part of this article? It isn't so clear in the manuscript whether these are previously published data. If they are, this should be made more apparent.

    Line 29: Phrasing - I would add the words "rather than sequentially" here to help readers with interpretation of why this separates out encoding from maintenance

    Line 64: This can actually extend as low as delta band (see Leszczynski et al., 2015, Cell Reports; Kumar et al., 2021, Neuropsychologia).

    Line 88: Do the authors have behavioral data or prior knowledge of how long it takes (on average) to encode 4, 6 or 8 letters? That is, how much of the 'encoding' period is truly encoding, rather than an initial encoding followed by maintenance. Or in a similar manner, how much of maintenance is still residual encoding.

    Line 90: Was there a particular reason as to why the encoding phase was bimodal? Do the authors think this may have influenced their results?

    Line 94-95: Was this an instruction to the participants? If so, I would put this more explicitly, i.e. "participants were instructed to rehearse...". Of course, one cannot know for certain whether individual subjects employed this strategy.

    Figure 2f: Where is this change in Granger relative to? A particular baseline window?

    Line 293: Were any electrodes here included in a seizure foci? Was anything done to ensure that seizure activity did not affect recordings (e.g. not recording within xxx hours of a seizure)?

    Line 301: Was anything done to deal with artefacts on the ECoG/sEEG electrodes? I.e. were trials with unusually large amplitudes, potentially indicative of muscle artefact (a known contaminant) removed?

    Line 325-326: I am confused by this. You say that the individual frequencies may differ between participants - do you mean in terms of the peak frequency, or were different bands used for each subject? If different bands, why?

    All power spectral density plots: I assume these are relative to baseline. Are they statistically-thresholded in any way?

  5. eLife

    Reviewer #2 (Public Review):

    Dimakopoulos et al. use intracranial data in humans to ask whether information flow is primarily cortical to hippocampal or the reverse during the encoding and retrieval stages of a working memory task. They find a highly reliable pattern where information in the alpha/beta range flows from auditory cortex to hippocampus during encoding and in the reverse direction during maintenance of items in WM. The authors show this pattern in a sub-selection of ECoG recordings and go on to show it is present in virtually all subjects at the EEG to intracranial hippocampus level. In addition, this directional pattern breaks down during incorrect trials. However, the current analysis suffers from possible contamination by volume conduction.

    The study is unique in its data set and provides a valuable look into hippocampal cortical interactions during WM. However, there are multiple technical questions remaining. One of the limitations is that the study investigated primarily interactions in the alpha/beta range when looking at interactions. In contrast, their power spectral results show increases in gamma during encoding, and other studies have emphasized a role for gamma in feedforward routing. Did the authors perform a granger causality analysis in gamma?

  6. eLife

    Reviewer #3 (Public Review):

    Dimakopoulos and colleagues investigate connectivity and flow of information during encoding and maintenance of Working Memory. They use unique data, which combine human intracranial recordings from depth electrodes with ECOG and EEG. This data, combined with Granger causality analysis (GC), provides interesting results that signal from cortex (mostly from EEG electrodes located over temporal cortex) is flowing to hippocampus during encoding and this flow is reversed during maintenance. Authors interpret this as a sign of bottom-up and top-down processing. I believe that chosen methods for signal analysis are appropriate.

    However, paper contains several statements that are unsupported by statistics and there is no clear information about why some decisions in the analysis process were made. This could give an impression that the analysis is built from arbitrarily chosen single case examples. I believe that because of below listed flaws results of the analysis do not support conclusions.

    1. Authors do not use correction for multiple comparisons - this cast doubts on the strength of obtained results.

    2. There is no criterion given for ECOG electrodes selected to the analysis.
      For instance, authors state that for participant 1 for C2 electrode, increased gamma power during encoding proves that this electrode was over auditory cortex but there is no systematic analysis of gamma power. From the results we can observe that this electrode has the strongest GC with hippocampus what suggests that it was used because of this characteristic what looks like double dipping.

    3. Why frequencies observed in PLV and GC are so different? For instance, in supplementary Figure 1 PLV shows significant differences in 18-30 Hz but GC is calculated for 8-18 Hz. Such large differences in frequencies suggest some inconsistencies in the analysis.

    4. For analyses depicted in Fig 4 and 5 it is unknown how the highest GC is defined (is it a mean from all frequencies?) Furthermore, there is no systematic measurement or criterion that would support that indeed chosen electrodes have the highest GC.

    5. All analysis conducted in the time domain (time to frequency and GC) does not contain any statistics supporting validity of the proposed conclusions.

    6. There is no data that supports statement that patients used verbalization. Although material is verbal authors cannot rule out that subject uses different modalities to support information maintenance.

  7. Version published to 10.1101/2021.03.11.434989v1 on bioRxiv