Applications of minimally invasive multimodal telemetry for continuous monitoring of brain function and intracranial pressure in macaques with acute viral encephalitis

PLoS One. 2020 Jun 25;15(6):e0232381. doi: 10.1371/journal.pone.0232381. eCollection 2020.

Abstract

Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics can mitigate CNS infection or disease in this model. The documentation of alphavirus encephalitis in animals relies on traditional physiological biomarkers and behavioral/neurological observations by veterinary staff; quantitative measurements such as electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naïve macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-infection in a cohort of twelve adult cynomolgus macaques. Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 - 4Hz); theta: [4 - 8Hz); alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to alphavirus infection. This novel enhancement of the cynomolgus macaque model offers utility for timely determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and therapeutic candidates.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alphavirus / isolation & purification
  • Alphavirus / pathogenicity
  • Alphavirus Infections / metabolism
  • Alphavirus Infections / pathology*
  • Animals
  • Biomarkers / metabolism
  • Brain / physiology*
  • Circadian Rhythm
  • Disease Models, Animal
  • Electroencephalography / methods
  • Encephalitis, Viral / metabolism
  • Encephalitis, Viral / pathology*
  • Female
  • Intracranial Pressure / physiology*
  • Macaca
  • Male
  • Severity of Illness Index
  • Telemetry

Substances

  • Biomarkers

Grants and funding

This research was funded by Defense Threat Reduction Agency (DTRA, https://www.dtra.mil/), grant number W911QY-15-1-0019 and The APC was funded by the same. Disclaimer: This project was sponsored by the Department of the Army, U.S. Army Contracting Command, Aberdeen Proving Ground, Natick Contracting Division, Ft. Detrick, MD under grant no. W911QY-15-1-0019, awarded to ALH, WK, and DSR. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the position or the policy of the government and no official endorsement should be inferred. Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.