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

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

Physiological and immunological changes in the brain associated with lethal eastern equine encephalitis virus in macaques

“…A subset of animals were implanted with telemetry devices to measure EEG, including 2 uninfected controls. The EEG leads were placed at approximate F4 and O1 positions on the 10–20 EEG map such that the two leads spanned the brain from front to back [ 16 ]. EEG measures global fluctuations in ionic electrical currents stemming from neuronal activity in the brain, and analysis of different frequency components of the waveform can aid the identification of pathological neurologic states as may be encountered in acute viral encephalitis [ 11 , 12 , 17 , 18 ].…”

“…EEG and ICP had not been previously measured during alphavirus infection of cynomolgus macaques, yet both methods can be used in the human clinical setting [ 7 , 9 ]. To determine if either physiological measurement provides an indicator of lethal EEEV disease, we developed a surgical method to implant radiotelemetry devices into macaques for infectious disease studies [ 16 ]. Significant changes in both EEG and ICP were only found in the lethally-infected macaques.…”

“…Prior to draping and fixture into a stereotaxic apparatus, the head, neck and upper back of each macaque was shaved and scrubbed in triplicate with betadine and chlorhexidine. Surgical implantation of the implant was performed as previously described [ 16 ]. Post-surgery, macaques were given analgesia and observed until recovered.…”

“…Analysis of EEG and ICP data was performed as previously described [ 16 ]. Briefly, Ponemah data was opened in NeuroScore (v.3.0.0, DSI) software package, which facilitated batch processing of data to European Data Format (.edf) for analysis.…”

Long-Term Recording of Reticulo-Rumen Myoelectrical Activity in Sheep by a Telemetry Method

“…With the development of technological advances, the availability of specific sensor-based technologies that can monitor these physiological changes increases [ 49 ]. Recently, multimodal telemetry was successfully applied to monitoring brain function and intracranial pressure in macaques [ 50 ], and may support a new approach in the minimally invasive monitoring of the reticulo-rumen activity in sheep.…”