chronic-cranial-window-technique-for-repeated-cortical-recordings

Chronic Cranial Window Technique for Repeated Cortical Recordings During Anesthesia in Pigs

Cortical recordings are essential for extracting neuronal signals to inform various applications, including brain-computer interfaces and disease ...

Aalborg University

This article demonstrates the power and flexibility of linear mixed-effects models (LMEMs) to investigate high-density surface electromyography (HD-sEMG) signals. The potentiality of the model is illustrated by investigating the root mean squared value of HD-sEMG signals in the tibialis anterior muscle of healthy (n = 11) and individuals with diabetic peripheral neuropathy (n = 12). We started by presenting the limitations of traditional approaches by building a linear model with only fixed effects. Then, we showed how the model adequacy could be increased by including random effects, as well as by adding alternative correlation structures. The models were compared with the Akaike information criterion and the Bayesian information criterion, as well as the likelihood ratio test. The results showed that the inclusion of the random effects of intercept and slope, along with an autoregressive moving average correlation structure, is the one that best describes the data (p < 0.01). Furthermore, we demonstrate how the inclusion of additional variance structures can accommodate heterogeneity in the residual analysis and therefore increase model adequacy (p < 0.01). Thus, in conclusion, we suggest that adopting LMEM to repeated measures such as electromyography can provide additional information from the data (e.g. test for alternative correlation structures of the RMS value), and hence provide new insights into HD-sEMG-related work.

Linear mixed-effects models for the analysis of high-density electromyography with application to diabetic peripheral neuropathy.

This study implements the use of Danish Landrace pigs as subjects for the long-term potentiation (LTP)-like pain model. This is accomplished by analyzing changes in the primary somatosensory cortex (S1) in response to electrical stimulation on the ulnar nerve after applying high-frequency electrical stimulation (HFS) on the ulnar nerve. In this study, eight Danish Landrace pigs were electrically stimulated, through the ulnar nerve, to record the cortically evoked response in S1 by a 16-channel microelectrode array (MEA). Six of these pigs were subjected to HFS (four consecutive, 15 mA, 100 Hz, 1000 µs pulse duration) 45 min after the start of the experiment. Two pigs were used as control subjects to compare the cortical response to peripheral electrical stimulation without applying HFS. Low-frequency components of the intracortical signals (0.3-300 Hz) were analyzed using event-related potential (ERP) analysis, where the minimum peak during the first 30-50 ms (N1 component) in each channel was detected. The change in N1 was compared over time across the intervention and control groups. Spectral analysis was used to demonstrate the effect of the intervention on the evoked cortical oscillations computed between 75 ms and 200 ms after stimulus. ERP analysis showed an immediate increase in N1 amplitude that became statistically significant 45 mins after HFS ( < 0.01) for the intervention group. The normalized change in power in frequency oscillations showed a similar trend. The results show that the LTP-like pain model can be effectively implemented in pigs using HFS since the cortical responses are comparable to those described in humans.

The effect of peripheral high-frequency electrical stimulation on the primary somatosensory cortex in pigs.

Decoding information from the peripheral nervous system via implantable neural interfaces remains a significant challenge, considerably limiting the advancement of neuromodulation and neuroprosthetic devices. The velocity selective recording (VSR) technique has been proposed to improve the classification of neural traffic by combining temporal and spatial information through a multi-electrode cuff (MEC). Therefore, this study investigates the feasibility of using the VSR technique to characterise fibre type based on the electrically evoked compound action potentials (eCAP) propagating along the ulnar nerve of pigs in vivo. A range of electrical stimulation parameters (amplitudes of 50 μA-10 mA and pulse durations of 100 μs, 500 μs, 1000 μs, and 5000 μs) was applied on a cutaneous and a motor branch of the ulnar nerve in nine Danish landrace pigs. Recordings were made with a 14 ring MEC and a delay-and-add algorithm was used to convert the eCAPs into the velocity domain. The results revealed two fibre populations propagating along the cutaneous branch of the ulnar nerve, with mean velocities of 55 m/s and 21 m/s, while only one dominant fibre population was found for the motor branch, with a mean velocity of 63 m/s. Because of its simplicity to provide information on the fibre selectivity and direction of propagation of nerve fibres, VSR can be implemented to advance the performance of the bidirectional control of neural prostheses and bioelectronic medicine applications.

The Use of the Velocity Selective Recording Technique to Reveal the Excitation Properties of the Ulnar Nerve in Pigs.

The aim of this study was to determine whether HD-sEMG is sensitive to detecting changes in motor unit behavior amongst healthy adults and type 2 diabetes mellitus (T2DM) patients presenting diabetic peripheral neuropathy (DPN) at different levels. Healthy control subjects (CON, n = 8) and T2DM patients presenting no DPN symptoms (ABS, n = 8), moderate DPN (MOD, n = 18), and severe DPN (SEV, n = 12) performed isometric ankle dorsiflexion at 30 % maximum voluntary contraction while high-density surface EMG (HD-sEMG) was recorded from the tibialis anterior muscle. HD-sEMG signals were decomposed, providing estimates of discharge rate, motor unit conduction velocity (MUCV), and motor unit territory area (MUTA). As a result, the ABS group presented reduced MUCV compared to CON. The groups with diabetes presented significantly larger MUTA compared to the CON group (p < 0.01), and the SEV group presented a significantly lower discharge rate compared to CON and ABS (p < 0.01). In addition, the SEV group presented significantly higher CoV compared to CON and MOD. These results support the use of HD-SEMG as a method to detect peripheral and central changes related to DPN.

Differences in motor unit behavior during isometric contractions in patients with diabetic peripheral neuropathy at various disease severities.

The knowledge of the morphology and morphometry of peripheral nerves is essential for developing neural interfaces and understanding nerve regeneration in basic and applied research. Currently, the most adopted animal model is the rat, even though recent studies have suggested that the neuroanatomy of large animal models is more comparable to humans. The present knowledge of the morphological structure of large animal models is limited; therefore, the present study aims to describe the morphological characteristics of the Ulnar Nerve (UN) in pigs. UN cross-sections were taken from seven Danish landrace pigs at three distinct locations: distal UN, proximal UN and at the dorsal cutaneous branch of the UN (DCBUN). The nerve diameter, fascicle diameter and number, number of fibres and fibre size were quantified. The UN diameter was larger in the proximal section compared to the distal segment and the DCBUN. The proximal branch also had a more significant number of fascicles (median: 15) than the distal (median: 10) and the DCBUN (median: 11) segments. Additionally, the mean fascicle diameter was smaller at the DCBUN (mean: 165 μm) than at the distal (mean: 197 μm) and proximal (mean: 199 μm) segments of the UN. Detailed knowledge of the microscopical structure of the UN in pigs is critical for further studies investigating neural interface designs and computational models of the peripheral nervous system.

Morphology and morphometry of the ulnar nerve in the forelimb of pigs.

Little research exists on extending ex-vivo systems to large animal nerves, and to the best of our knowledge, there has yet to be a study comparing these against in-vivo data. This paper details the first ex-vivo system for large animal peripheral nerves to be compared with in-vivo results.

Ex-vivo systems for neuromodulation: A comparison of ex-vivo and in-vivo large animal nerve electrophysiology.

Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation.

Porcine Model of Cerebral Ischemic Stroke Utilizing Intracortical Recordings for the Continuous Monitoring of the Ischemic Area.

Translational models of the sensitized pain system are needed to progress the understanding of involved mechanisms. In this study, long-term potentiation was used to develop a mechanism-based large-animal pain model. Event-related potentials to electrical stimulation of the ulnar nerve were recorded by intracranial recordings in pigs, 3 weeks before, immediately before and after, and 3 weeks after peripheral high-frequency stimulation (HFS) applied to the ulnar nerve in the right forelimb (7 pigs) or in control animals (5 pigs). Event-related potential recordings and peripheral HFS were done during anesthesia. Two weeks before and after the HFS, behavioral responses reflecting mechanical and thermal sensitivity were collected using brush, noxious limb-mounted pressure algometer, and noxious laser stimuli. The HFS intervention limb was progressively sensitized to noxious mechanical stimulation in week 1 and 2 compared with baseline ( P = 0.045) and the control group ( P < 0.034) but not significantly to laser or brush stimulation. The first negative (N1) peak of the event-related potential was increased 30 minutes after HFS compared with before ( P < 0.05). The N1 peak was also larger compared with control pigs 20 to 40 minutes after HFS ( P < 0.031) but not significantly increased 3 weeks after. The relative increase in N1 30 minutes after HFS and the degree of mechanical hyperalgesia 2 weeks post-HFS was correlated ( P < 0.033). These results show for the first time that the pig HFS model resembles the human HFS model closely where the profile of sensitization is comparable. Interestingly, the degree of sensitization was associated with the cortical signs of hyperexcitability at HFS induction.

High-frequency electrical stimulation increases cortical excitability and mechanical sensitivity in a chronic large animal model.

The most characteristic feature of the human electroencephalogram is the peak alpha frequency (PAF). While PAF has been proposed as a biomarker in several diseases and disorders, the disease mechanisms modulating PAF, as well as its physiological substrates, remain elusive. This has partly been due to challenges related to experimental manipulation and invasive procedures in human neuroscience, as well as the scarcity of animal models where PAF is consistently present in resting-state. With the potential inclusion of PAF in clinical screening and decision-making, advancing the mechanistic understanding of PAF is warranted. In this paper, we propose the female Danish Landrace pig as a suitable animal model to probe the mechanisms of PAF and its feature as a biomarker. We show that somatosensory alpha oscillations are present in anesthetized pigs using electrocorticography and intracortical electrodes located at the sensorimotor cortex. This was evident when looking at the time-domain as well as the spectral morphology of spontaneous recordings. We applied the FOOOF-algorithm to extract the spectral characteristics and implemented a robustness threshold for any periodic component. Using this conservative threshold, PAF was present in 18/20 pigs with a normal distribution of the peak frequency between 8-12 Hz, producing similar findings to human recordings. We show that PAF was present in 69.6 % of epochs of approximately six-minute-long resting-state recordings. In sum, we propose that the pig is a suitable candidate for investigating the neural mechanisms of PAF as a biomarker for disease and disorders such as pain, neuropsychiatric disorders, and response to pharmacotherapy.

Article	Year
Linear mixed-effects models for the analysis of high-density electromyography with application to diabetic peripheral neuropathy. Medical & biological engineering & computing\| PubMed ID: 32447652	2020
The effect of peripheral high-frequency electrical stimulation on the primary somatosensory cortex in pigs. IBRO neuroscience reports\| PubMed ID: 34541572	2021
The Use of the Velocity Selective Recording Technique to Reveal the Excitation Properties of the Ulnar Nerve in Pigs. Sensors (Basel, Switzerland)\| PubMed ID: 35009601	2021
Differences in motor unit behavior during isometric contractions in patients with diabetic peripheral neuropathy at various disease severities. Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology\| PubMed ID: 36436278	2023
Morphology and morphometry of the ulnar nerve in the forelimb of pigs. Anatomia, histologia, embryologia\| PubMed ID: 37715494	2024
Ex-vivo systems for neuromodulation: A comparison of ex-vivo and in-vivo large animal nerve electrophysiology. Journal of neuroscience methods\| PubMed ID: 38548122	2024
Porcine Model of Cerebral Ischemic Stroke Utilizing Intracortical Recordings for the Continuous Monitoring of the Ischemic Area. Sensors (Basel, Switzerland)\| PubMed ID: 38793822	2024
High-frequency electrical stimulation increases cortical excitability and mechanical sensitivity in a chronic large animal model. Pain\| PubMed ID: 39133034	2025
Pigs as a translational animal model for the study of peak alpha frequency. Neuroscience\| PubMed ID: 39694317	2025

Felipe R. Andreis

Biography

JoVE Journal Publications

Other Publications