Brain Electrical Activity

Aksharkumar Dobariya

Overview

• Why study electrical activity
• Why large animal brain model
• Current state of the art for epilepsies
• Approach
• Mechanism of ischemia physiology
• Some preliminary data
• Troubleshooting optimal parameters
• Summary

Functional Unit of Brain

Image: https://en.wikipedia.org/wiki/Neural_circuit

Approaches: Micro vs Macro

Micro-electrode implant and recording

EEG implant and recording

• Extracellular recording from very local area
• Useful for understanding the local circuit phenomenon
• Mainly an experimental approach

• Net synaptic activity over a brain region
• Useful for understanding Macro circuit phenomenon
• More viable clinically

Wang et al, 2023 and Courtesy: ©UNIGE

Large animal brain model

• You can only do so much with human subject ethically.
• You can only do so much with rodent models experimentally.

EEG/ECoG comparison of Humans, Pigs and Mice

- Anesthetized pig achieved extremely similar brain neurophysiology to an awake human. Awake mice data on the other hand looks very different from awake human being despite being not anesthetized.

Unpublished

Dobariya et al 2022

Why we need alternative model/approach?

State of current drug failure rate.

• It take a billion dollar to take drug to market.
• In cancer biology more than 85% targets fails in just preclinical trials. And those that survive Phase III, only half makes it to clinical use. (Mak, 2014)
• Clinical failure rate of Neurodegenerative diseases is much worse, nearly 100% disease modifying treatments that slow or stop disease progression fails. (Vissers, 2021)

We already have what it takes to do it effectively

We don’t need to reinvent the wheel.

- Century old experience of running Pig farms

- Established Clinical expertise and hospital systems that could easily be used for large animal research.

• Ischemia/Stroke leads to epilepsies.
• Pharmacologics – generally only good for maintenance of disease, personality modifying
• Drug resistant epilepsies are treated with surgery post-identification of seizure locus.
• Of-those in about 50% cases, seizures recur without potential solution.

State of the art treatment option

Approach: Accessing the brain

ECoG

Microelectrode

recording

Approach: Vessel occlusion

Arikan F, Martínez-Valverde T, Sánchez-Guerrero Á, Campos M, Esteves M, et al. (2017) Malignant infarction of the middle cerebral artery in a porcine model. A pilot study. PLOS ONE 12(2): e0172637. https://doi.org/10.1371/journal.pone.0172637

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172637

Arikan F, Martínez-Valverde T, Sánchez-Guerrero Á, Campos M, Esteves M, et al. (2017) Malignant infarction of the middle cerebral artery in a porcine model. A pilot study. PLOS ONE 12(2): e0172637. https://doi.org/10.1371/journal.pone.0172637

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172637

Kentar et al, 2020

2,3,5-Triphenyltetrazolium chloride (TTC)

Measuring mitochondrial enzyme succinate dehydrogenase

Sequence of Events

• During ischemia cell shifts to anaerobic metabolism
• Insufficient energy balance occurs in cell post small period of ischemia
• Ionic dysregulation occurs due to pump (NA+/K+) failures since they require ATP
• Leads to overload of NA+ and Ca+ causing cell swelling, morphological and functional disruption of cellular organelles particularly Mitochondria
• Continued ischemia leads to activation of microglia cells producing pro-inflammatory chemokines and cytokines such as tumor necrosis factor (TNF)-α or interleukin(IL)-1β.
• Activated neutrophils produces Reactive oxygen species (ROS) post-ischemia
• Restoration of oxygen exacerbates an already compromised neurovascular and brain parenchymal milieu.

1^st

Point of intervention

2^nd

Point of intervention

Right – Injury side

Left – Contralateral side

Occlusion

Reperfuse

Preliminary data

Ischemic region

Choosing correct parameter

• Signal processing principles such as Nyquist theorem is very important.
• Band pass filter according to what we plan to deduce is important as well.
• Using multi-taper spectrogram choosing correct amount of time and tapers according to our required level of resolution is very crucial.

https://chronux.org/

%% Parameters for Time-Frequency Spectral Analysis

params.tapers = [3 5]; % Time-bandwidth product and number of tapers

params.Fs = 1000; % Sampling Hz

params.err = [2 0.05]; % Jackknife error bars, 95% CI

params.fpass = [1 300]; % Bandpass filtering

movingwin = [1 0.1]; % Moving window of 1 sec with 0.1 sec step

Parameter selection

Filtering

params.tapers = [3 5]

params.tapers = [10 19]

params.tapers = [15 29]

Time-bandwidth

Dobariya et al 2022

Summary

• Brain electrical recordings are reliable markers of physiological changes in disease condition.
• Using changes in electrical recording, metabolism, immunostaining, we plan to attempt to understand the mechanism.
• Interventions targeting the specific physiological aspects thus should improve the biomarkers such as electrical activity.

Questions?