Federico Arguissain

On the use of information theory for the analysis of synchronous nociceptive withdrawal reflexes and somatosensory evoked potentials elicited by graded electrical stimulation

BACKGROUND To date, few studies have combined the simultaneous acquisition of nociceptive withdrawal reflexes (NWR) and somatosensory evoked potentials (SEPs). In fact, it is unknown whether the combination of these two signals acquired simultaneously could provide additional information on somatosensory processing at spinal and supraspinal level compared to individual NWR and SEP signals. NEW METHOD By using the concept of mutual information (MI), it is possible to quantify the relation between electrical stimuli and simultaneous elicited electrophysiological responses in humans based on the estimated stimulus-response signal probability distributions. RESULTS All selected features from NWR and SEPs were informative in regard to the stimulus when considered individually. Specifically, the information carried by NWR features was significantly higher than the information contained in the SEP features (p<0.05). Moreover, the joint information carried by the combination of features showed an overall redundancy compared to the sum of the individual contributions. Comparison with existing methods MI can be used to quantify the information that single-trial NWR and SEP features convey, as well as the information carried jointly by NWR and SEPs. This is a model-free approach that considers linear and non-linear correlations at any order and is not constrained by parametric assumptions. CONCLUSIONS The current study introduces a novel approach that allows the quantification of the individual and joint information content of single-trial NWR and SEP features. This methodology could be used to decode and interpret spinal and supraspinal interaction in studies modulating the responsiveness of the nociceptive system.

Venlafaxine and Oxycodone Effects on Human Spinal and Supraspinal Pain Processing: a Randomized Cross‐Over Trial

Severe pain is often treated with opioids. Antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) have also shown a pain relieving effect, but for both SNRI and opioids, the specific mode of action in humans remains vague. This study investigated how oxycodone and venlafaxine affect spinal and supraspinal pain processing. Twenty volunteers were included in this randomized cross‐over study comparing 5‐day treatment with venlafaxine, oxycodone and placebo. As a proxy of the spinal pain transmission, the nociceptive withdrawal reflex (NWR) to electrical stimulation on the sole of the foot was recorded at the tibialis anterior muscle before and after 5 days of treatment. For the supraspinal activity, 61‐channel electroencephalogram evoked potentials (EPs) to the electrical stimulations were simultaneously recorded. Areas under curve (AUCs) of the EMG signals were analyzed. Latencies and AUCs were computed for the major EP peaks and brain source analysis was done. The NWR was decreased in venlafaxine arm (P = 0.02), but the EP parameters did not change. Oxycodone increased the AUC of the EP response (P = 0.04). Oxycodone also shifted the cingulate activity anteriorly in the mid‐cingulate‐operculum network (P < 0.01), and the cingulate activity was increased while the operculum activity was decreased (P = 0.02). Venlafaxine exerts its effects on the modulation of spinal nociceptive transmission, which may reflect changes in balance between descending inhibition and descending facilitation. Oxycodone, on the other hand, exerts its effects at the cortical level. This study sheds light on how opioids and SNRI drugs modify the human central nervous system and where their effects dominate.

Effects of conditioned pain modulation on the withdrawal pattern to nociceptive stimulation in humans – Preliminary results

Abstract Aims Conditioned pain modulation (CPM) is a paradigm employed to assess descending control of spinal nociception. Previous studies have shown that CPM affects the nociceptive withdrawal reflex (NWR) threshold (RTh), typically assessed in one muscle. However, the NWR activates not one but a group of synergistic muscles, which are recruited by common neural commands to achieve the limb withdrawal. In this regard, synergy analysis can provide the minimum coordinated recruitment of groups of muscles with specific activation balances that describe a movement. The aim was to assess how CPM modulate the global withdrawal strategy of the lower limb expressed by synergy analysis. Methods Sixteen healthy subjects received electrical stimulation in the arch of the foot at 2 × RTh intensity assessed at the biceps femoris muscle, to elicit the NWR at three time points: before, during and after immersion of the hand in cold water at 2.6 ± 0.4° (cold pressor test, CPT) to trigger CPM. Electromyographic signals (EMG) were recorded from 2 distal muscles (tibialis anterior, soleus) and 2 proximal muscles (biceps femoris, rectus femoris). Muscle synergies were identified by a non-negative matrix factorization algorithm for the EMG envelope in the 60–180 ms post-stimulus interval. Data were analyzed by a point-by-point Wilcoxon test using a permutation strategy. Results The overall withdrawal pattern was explained by two main synergies (Syn1 and Syn2). Syn1 mainly contributes to EMG of distal muscles, whereas Syn2 contributes to EMG of proximal muscles. During CPT, the magnitude of Syn2 was reduced in the 160–180ms post-stimulus interval (p < 0.05), whereas no changes were found for Syn1. Conclusions At least two synergies are required to explain the NWR. Furthermore, results suggest that CPM might differentially affect proximal and distal muscles. Further analysis is needed to provide additional information about the behavior of the individual muscles.

On the Agreement between Manual and Automated Methods for Single-Trial Detection and Estimation of Features from Event-Related Potentials.

The agreement between humans and algorithms on whether an event-related potential (ERP) is present or not and the level of variation in the estimated values of its relevant features are largely unknown. Thus, the aim of this study was to determine the categorical and quantitative agreement between manual and automated methods for single-trial detection and estimation of ERP features. To this end, ERPs were elicited in sixteen healthy volunteers using electrical stimulation at graded intensities below and above the nociceptive withdrawal reflex threshold. Presence/absence of an ERP peak (categorical outcome) and its amplitude and latency (quantitative outcome) in each single-trial were evaluated independently by two human observers and two automated algorithms taken from existing literature. Categorical agreement was assessed using percentage positive and negative agreement and Cohen’s κ, whereas quantitative agreement was evaluated using Bland-Altman analysis and the coefficient of variation. Typical values for the categorical agreement between manual and automated methods were derived, as well as reference values for the average and maximum differences that can be expected if one method is used instead of the others. Results showed that the human observers presented the highest categorical and quantitative agreement, and there were significantly large differences between detection and estimation of quantitative features among methods. In conclusion, substantial care should be taken in the selection of the detection/estimation approach, since factors like stimulation intensity and expected number of trials with/without response can play a significant role in the outcome of a study.

Investigating mechanisms behind offset analgesia: Effect on spinal responses during thermal stimulation

Abstract Introduction Offset analgesia (OA) is a temporal perceptual mechanism in which subjective pain ratings decrease disproportionally when a noxious heat stimulus is decreased by 1–3 ◦C. Whether OA is a peripheral, spinal or supraspinal mechanism remains unknown. The stimulation of afferent nociceptors in the foot, leads to a spinal nociceptive withdrawal reflex (NWR) which is mediated through the wide dynamic range (WDR) neurons and therefore under descending control. We hypothesized that OA affects the spinal nociceptive neurons resulting in an attenuation of the NWR during OA. Methods Four heat stimulations profiles were applied to the lower legs divided into four segments of 5 s, 5 s, 5 s, and 15 s, respectively: Offset Analgesia Trial (OAT) (48, 49, 48, 48 ◦C), Offset Baseline Trial (OBT) (48, 49, 32, 32 ◦C), Constant Heat Trial (CHT) (4 × 48 ◦C), and Baseline Trial (BT) (4 × 32 ◦C). Subjects rated the pain intensity continuously using a visual analog scale (VAS). NWR were evoked by electrical stimulation of the plantar foot and assessed once during each segment by recording EMG from the tibialis anterior muscle. Results VAS-ratings were lower during the third period of OAT compared to CHT (p < 0.001). However, there was no difference (p > 0.05) comparing the NWR size between OAT, OBT, CHT, and BT throughout the time periods. Conclusions The NWR was not affected by OA suggesting that spinal WDR plays a limited role in the OA mechanism. Whether peripheral- or supraspinal mechanisms are responsible the OA phenomenon remains unknown.

Modulatory Effect on Spinal and Supraspinal Responses during Cognitive Attentional and Distraction Tasks

The aim of the present study was to investigate the influence of modulatory mechanisms on spinal and supraspinal responses triggered by changes in the cognitive state. Simultaneous nociceptive withdrawal reflex (NWR) and somatosensory evoked potentials (SEP) in response to electrical stimuli were acquired during two attentional tasks: attention to the stimuli vs. attention to a cognitive task (modified Stroop test). Single-trial SEP peaks (N1, N2 and P2) and NWR root-mean-squared (NWR RMS) were obtained for both experimental conditions. The present results showed larger N1 (p<0.007), lower P2 (p<0.001) and larger NWR RMS (p<0.001) during the Stroop task compared to when the subjects paid attention to the stimulus. This mechanism could be thought as a protective system that increases the responsiveness of the NWR, in order to react under the minimum risk of tissue damage when the brain is distracted by demanding cognitive tasks. The present methodology could be potentially used for assessment of motor learning.