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

  • 1,009
    views
  • 155
    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
    Ana Maria Ichim, Harald Barzan ... Raul Cristian Muresan
    Review Article

    Gamma oscillations in brain activity (30–150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a ‘servicing’ rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.

    1. Medicine
    2. Neuroscience
    LeYuan Gu, WeiHui Shao ... HongHai Zhang
    Research Article

    The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.