Abstract

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Data availability

The sensitive nature of patients' data and our current ethics protocol do not permit open data sharing. However, anonymized, pre-processed, group-level data used to generate the figures have been uploaded to NeuroVault [https://neurovault.org/collections/FTKQLDFP/]. The clinical and neuroimaging data used in the current paper are available from the Senior Author (S.N.), upon formal request indicating name and affiliation of the researcher as well as a brief description of the use that will be done of the data. All requests will undergo UCSF regulated procedure thus require submission of a Material Transfer Agreement (MTA) which can be found at https://icd.ucsf.edu/material-transfer-and-data-agreements No commercial use would be approved.

Article and author information

Author details

  1. Valentina Borghesani

    Neurology, University of California, San Francisco, San Francisco, United States
    For correspondence
    valentina.borghesani@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7909-8631
  2. Corby L Dale

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sladjana Lukic

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Leighton BN Hinkley

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Lauricella

    Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Wendy Shwe

    Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Danielle Mizuiri

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Susanna Honma

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Zachary Miller

    Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Bruce L Miller

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. John F Houde

    Radiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Maria Luisa Gorno-Tempini

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Srikantan Nagarajan

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute of Health (R01NS050915)

  • Maria Luisa Gorno-Tempini

Global Brain Health Institute

  • Maria Luisa Gorno-Tempini

University of California Office of the President (MRP-17-454755)

  • Srikantan Nagarajan

National Institute of Health (K24DC015544)

  • Maria Luisa Gorno-Tempini

National Institute of Health (R01NS100440)

  • John F Houde

National Institute of Health (R01DC013979)

  • Srikantan Nagarajan

National Institute of Health (R01DC176960)

  • Srikantan Nagarajan

National Institute of Health (R01DC017091)

  • Srikantan Nagarajan

National Institute of Health (R01EB022717)

  • Srikantan Nagarajan

National Institute of Health (R01AG062196)

  • Srikantan Nagarajan

Larry Hillblom Foundation

  • Maria Luisa Gorno-Tempini

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

Ethics

Human subjects: The study was approved by the UCSF Committee on Human Research and all subjects provided written informed consent.(IRB # 11-05249).

Copyright

© 2021, Borghesani 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

  • 1,020
    views
  • 159
    downloads
  • 5
    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. Valentina Borghesani
  2. Corby L Dale
  3. Sladjana Lukic
  4. Leighton BN Hinkley
  5. Michael Lauricella
  6. Wendy Shwe
  7. Danielle Mizuiri
  8. Susanna Honma
  9. Zachary Miller
  10. Bruce L Miller
  11. John F Houde
  12. Maria Luisa Gorno-Tempini
  13. Srikantan Nagarajan
(2021)
Neural dynamics of semantic categorization in semantic variant of Primary Progressive Aphasia
eLife 10:e63905.
https://doi.org/10.7554/eLife.63905

Share this article

https://doi.org/10.7554/eLife.63905

Further reading

    1. Neuroscience
    David Oestreicher, Shashank Chepurwar ... Tina Pangrsic
    Research Article

    To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage- and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.

    1. Neuroscience
    Lian Hollander-Cohen, Omer Cohen ... Berta Levavi-Sivan
    Research Article

    Life histories of oviparous species dictate high metabolic investment in the process of gonadal development leading to ovulation. In vertebrates, these two distinct processes are controlled by the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), respectively. While it was suggested that a common secretagogue, gonadotropin-releasing hormone (GnRH), oversees both functions, the generation of loss-of-function fish challenged this view. Here, we reveal that the satiety hormone cholecystokinin (CCK) is the primary regulator of this axis in zebrafish. We found that FSH cells express a CCK receptor, and our findings demonstrate that mutating this receptor results in a severe hindrance to ovarian development. Additionally, it causes a complete shutdown of both gonadotropins secretion. Using in-vivo and ex-vivo calcium imaging of gonadotrophs, we show that GnRH predominantly activates LH cells, whereas FSH cells respond to CCK stimulation, designating CCK as the bona fide FSH secretagogue. These findings indicate that the control of gametogenesis in fish was placed under different neural circuits, that are gated by CCK.