A statistical framework to assess cross-frequency coupling while accounting for confounding analysis effects

  1. Jessica K Nadalin
  2. Louis-Emmanuel Martinet
  3. Ethan B Blackwood
  4. Meng-Chen Lo
  5. Alik S Widge
  6. Sydney S Cash
  7. Uri T Eden
  8. Mark A Kramer  Is a corresponding author
  1. Boston University, United States
  2. Massachusetts General Hospital, United States
  3. University of Minnesota, United States

Abstract

Cross frequency coupling (CFC) is emerging as a fundamental feature of brain activity, correlated with brain function and dysfunction. Many different types of CFC have been identified through application of numerous data analysis methods, each developed to characterize a specific CFC type. Choosing an inappropriate method weakens statistical power and introduces opportunities for confounding effects. To address this, we propose a statistical modeling framework to estimate high frequency amplitude as a function of both the low frequency amplitude and low frequency phase; the result is a measure of phase-amplitude coupling that accounts for changes in the low frequency amplitude. We show in simulations that the proposed method successfully detects CFC between the low frequency phase or amplitude and the high frequency amplitude, and outperforms an existing method in biologically-motivated examples. Applying the method to in vivo data, we illustrate how CFC evolves during seizure and is affected by electrical stimuli.

Data availability

In vivo human data available at https://github.com/Eden-Kramer-Lab/GLM-CFCIn vivo rat data available at https://github.com/tne-lab/cl-example-data

Article and author information

Author details

  1. Jessica K Nadalin

    Department of Mathematics and Statistics, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Louis-Emmanuel Martinet

    Department of Neurology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ethan B Blackwood

    Department of Psychiatry, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3049-0640
  4. Meng-Chen Lo

    Department of Psychiatry, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3913-3233
  5. Alik S Widge

    Department of Psychiatry, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8510-341X
  6. Sydney S Cash

    Department of Neurology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Uri T Eden

    Department of Mathematics and Statistics, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mark A Kramer

    Department of Mathematics and Statistics, Boston University, Boston, United States
    For correspondence
    mak@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9979-7202

Funding

National Science Foundation (NSF DMS #1451384)

  • Jessica K Nadalin
  • Mark A Kramer

National Science Foundation (GRFP)

  • Jessica K Nadalin

National Institutes of Health (R21 MH109722)

  • Alik S Widge

National Institutes of Health (R01 EB026938)

  • Alik S Widge
  • Uri T Eden
  • Mark A Kramer

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

Ethics

Animal experimentation: The animal experimentation received IACUC approval from the University of Minnesota (IACUC Protocol # 1806-36024A).

Human subjects: All patients were enrolled after informed consent, and consent to publish, was obtained and approval was granted by local Institutional Review Boards at Massachusetts General Hospital and Brigham Women's Hospitals (Partners Human Research Committee), and at Boston University according to National Institutes of Health guidelines (IRB Protocol # 1558X).

Copyright

© 2019, Nadalin 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

  • 4,368
    views
  • 616
    downloads
  • 11
    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. Jessica K Nadalin
  2. Louis-Emmanuel Martinet
  3. Ethan B Blackwood
  4. Meng-Chen Lo
  5. Alik S Widge
  6. Sydney S Cash
  7. Uri T Eden
  8. Mark A Kramer
(2019)
A statistical framework to assess cross-frequency coupling while accounting for confounding analysis effects
eLife 8:e44287.
https://doi.org/10.7554/eLife.44287

Share this article

https://doi.org/10.7554/eLife.44287

Further reading

    1. Neuroscience
    François Kroll, Joshua Donnelly ... Jason Rihel
    Research Article

    By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer’s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer’s risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3677 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.

    1. Neuroscience
    Christopher Bell, Lukas Kilo ... Stefanie Ryglewski
    Research Article

    At many vertebrate synapses, presynaptic functions are tuned by expression of different Cav2 channels. Most invertebrate genomes contain only one Cav2 gene. The Drosophila Cav2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Caβ and Gβγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Cav2 gene.