Abstract

Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n=38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience.

Data availability

A source data file has been provided for the plots in Figure 2- figure supplement 1, and main figures 3-8. The participants of our study had not been asked to consent for their anonymized data to be publicly shared and be made freely available. Therefore, these data are available through a request to Dr Georgios Argyropoulos and would need to be approved by an ethics committee. Information relating to the 32 MRI datasets previously collected and made available via the Oxford Project To Investigate Memory and Aging can be found here https://www.ndcn.ox.ac.uk/research/centre-prevention-stroke-dementia/resources/optima-oxford-project-to-investigate-memory-and-ageing and requests to access made to Dr. Christopher Butler.

Article and author information

Author details

  1. Georgios P D Argyropoulos

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    For correspondence
    georgios.argyropoulos@ndcn.ox.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8267-6861
  2. Clare Loane

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  3. Adriana Roca-Fernandez

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Carmen Lage-Martinez

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Oana Gurau

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  6. Sarosh R Irani

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    Sarosh R Irani, is a coapplicant and receives royalties on patent application WO/2010/046716 (U.K. patent no., PCT/GB2009/051441) entitled 'Neurological Autoimmune Disorders'. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies..
  7. Christopher R Butler

    Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.

Funding

Medical Research Council (MR/K010395/1)

  • Christopher R Butler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All participants provided written informed consent according to the Declaration of Helsinki. Ethical approval was received from South Central Oxford Research Ethics Committee (REC no: 08/H0606/133).

Copyright

© 2019, Argyropoulos et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,839
    views
  • 375
    downloads
  • 33
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Georgios P D Argyropoulos
  2. Clare Loane
  3. Adriana Roca-Fernandez
  4. Carmen Lage-Martinez
  5. Oana Gurau
  6. Sarosh R Irani
  7. Christopher R Butler
(2019)
Network-wide abnormalities explain memory variability in hippocampal amnesia
eLife 8:e46156.
https://doi.org/10.7554/eLife.46156

Share this article

https://doi.org/10.7554/eLife.46156

Further reading

    1. Neuroscience
    Gaqi Tu, Peiying Wen ... Kaori Takehara-Nishiuchi
    Research Article

    Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.

    1. Neuroscience
    Philipp S O'Neill, Martín Baccino-Calace ... Igor Delvendahl
    Tools and Resources

    Quantitative information about synaptic transmission is key to our understanding of neural function. Spontaneously occurring synaptic events carry fundamental information about synaptic function and plasticity. However, their stochastic nature and low signal-to-noise ratio present major challenges for the reliable and consistent analysis. Here, we introduce miniML, a supervised deep learning-based method for accurate classification and automated detection of spontaneous synaptic events. Comparative analysis using simulated ground-truth data shows that miniML outperforms existing event analysis methods in terms of both precision and recall. miniML enables precise detection and quantification of synaptic events in electrophysiological recordings. We demonstrate that the deep learning approach generalizes easily to diverse synaptic preparations, different electrophysiological and optical recording techniques, and across animal species. miniML provides not only a comprehensive and robust framework for automated, reliable, and standardized analysis of synaptic events, but also opens new avenues for high-throughput investigations of neural function and dysfunction.