IMI2-PainCare-BioPain-RCT3: a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by electroencephalography (EEG)

Background IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity. Methods This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory. Discussion LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. Trial registration This trial was registered 25/06/2019 in EudraCT (2019%2D%2D001204-37).

Methodological foundations of psychological reliability and professional suitability to work in dangerous conditions

The article discusses the experimental data obtained during the professional selection of persons in hazardous occupations. The high efficiency of sharing of eytracking and polygraph has been established. To determine the socio-psychological reliability, a computer program of evoked brain potentials can be used upon presentation of drug-related slides.

New psychophysiologic approaches applied in occupational selection of candidates for dangerous professions

Introduction. In increased requirements to occupational and personal qualities of workers engaged into or applying for dangerous professions, effi ciency of occupational selection considerably depends on choice of methodic approaches adequate to the study objectives. Objective. To study psychophysiologic approaches to evaluation of social psychologic reliability and occupational fi tness of individuals with dangerous professions, for revealing prognostic facilities of new methods and for improving occupational selection for military and police offi cers. Materials and methods. Psychophysiologic studies used eye-tracker SMI-RED–250 and polygraph “Diana” and covered 201 candidates for service in various divisions of RF Investigating Committ ee. Major part of the examinees consisted of individuals aged under 30 years (134 males and 67 females). All the candidates had normal vision or corrected to normal one. Evoked brain potentials study covered 114 candidates for military service (2 females and 112 males) aged 17 to 52 years. According to polygraph study, 51.8% of the examinees demonstrated a risk factor of “drug use”. Results. Th e authors presented results of psychophysiologic studies of occupational fi tness in candidates for military and police service. Nowadays, polygraph study remains a reliable method to reveal reactions proving presence of concealed information. Using evoked brain potentials for disclosing individuals who conceal drug usage is an important procedure in security maintenance. Within a standard polygraph procedure, videooculography (eye-tracker) seems the most interesting. Th e studies covered possible use of evoked EEG potentials and eye-tracker along with polygraph study for personnel checkups. Conclusions. Occupational selection in individuals with dangerous professions obtained experimental data indicating high effi ciency of combined use of eye-tracking and polygraph, for diagnosis of social psychologic reliability one can use soft ware of evoked brain potentials with demonstration of drugs-associated slides.

Electrophysiology of Human Personality

In this section an overview on evoked brain potentials will be introduced, same as the bases of electrophysiology of the brain. The main research findings on evoked potentials and other psychological variables such as cognition, emotion, motivation and personality will be presented. The emphasis will be given to the relationship between evoked brain potentials and personality operationalized by previously presented two personality theories: Eysenck's and Strelau's theory. Even though it is possible to expect, based on arousal theory, that introverts who had higher sensory reactivity on physical stimuli of moderate intensity and higher levels of cortical arousal than extraverts, would also show higher P300-amplitudes in both modalities, audio and visual, due to other significant variables (i.e. task type, other psychological and physiological characteristics of subjects, etc.) some other results could be expected. Therefore, all complexity about the relationship between evoked brain potentials and human personality and relevant research methodology will be presented here.

Empirical Research on the Relationship Between Personality and Evoked Brain Potentials

In this section, research aim, problems and hypothesis with the methods and determined research results will be presented. This correlational design research that has been run on a sample of N=54 students in Croatia will be described. The main findings regarding the relationship between personality traits extraversion and evoked brain potentials will be presented. Personality traits that were explored are: extraversion, neuroticism, psychoticism, social desirability, addiction, criminality, empathy, impulsivity, adventurousness, strength of excitation, strength of inhibition, mobility, and depression. Latencies and amplitudes in two trials were investigated for the following evoked brain potentials: N1, P2, N2, P3, and Slow wave activity. Visual oddball paradigm was used for evoking brain activity measured on two occipital and two parietal electrodes. Results on controlled variables, such as: age, sight characteristics, coffee drinking, smoking, taking medications, alcohol and drug consumption, and body exercise, are introduced as well. The correlation analyses revealed a significant relationship between personality traits and evoked brain potentials, especially trait adventurousness and social desirability, due to a too simple and monotonous visual task that was use. The determined findings from the PCA factor analysis with Varimax rotation determined 15 factors that explained 79,611% of the total variance. Series of Hierarchical regression analyses for each personality trait individually revealed, as it was expected, certain visual evoked potentials as significant predictors.