ORIGINAL RESEARCH published: 21 July 2022 doi: 10.3389/fnhum.2022.881291 Reliability of Upper Limb Pin-Prick Stimulation With Electroencephalography: Evoked Potentials, Spectra and Source Localization Lisa Tedesco Triccas 1,2,3,4* , Kenneth P. Camilleri 2,4 , Camilleri Tracey 2,4 , Fahimi Hnazaee Mansoureh 5,6 , Wittevrongel Benjamin 5 , Muscat Francesca 2,4 , Boccuni Leonardo 7,8,9 , Mantini Dante 10 and Verheyden Geert 1 1 Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium, 2 Department of Systems and Control Engineering, University of Malta, Msida, Malta, 3 REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, Hasselt, Belgium, 4 Centre for Biomedical Cybernetics, University of Malta, Msida, Malta, 5 Laboratory for Neuro- Edited by: and Psychophysiology, KU Leuven, Leuven, Belgium, 6 The Wellcome Trust Centre for Neuroimaging, University College Carsten Dahl Mørch, London Institute of Neurology, London, United Kingdom, 7 Institut Guttmann, Institut Universitari de Neurorehabilitació Aalborg University, Denmark Adscrit a la Universitat Autónoma de Barcelona, Barcelona, Spain, 8 Universitat Autònoma de Barcelona, Cerdanyola del Reviewed by: Vallès, Spain, 9 Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain, 10 Lin Yao, Department of Movement Sciences, KU Leuven, Leuven, Belgium Cornell University, United States Bernadette Ann Murphy, Ontario Tech University, Canada In order for electroencephalography (EEG) with sensory stimuli measures to be used *Correspondence: in research and neurological clinical practice, demonstration of reliability is needed. Lisa Tedesco Triccas However, this is rarely examined. Here we studied the test-retest reliability of the EEG lisa.tedescotriccas@uhasselt.be latency and amplitude of evoked potentials and spectra as well as identifying the sources Specialty section: during pin-prick stimulation. We recorded EEG in 23 healthy older adults who underwent This article was submitted to a protocol of pin-prick stimulation on the dominant and non-dominant hand. EEG was Sensory Neuroscience, a section of the journal recorded in a second session with rest intervals of 1 week. For EEG electrodes Fz, Cz, Frontiers in Human Neuroscience and Pz peak amplitude, latency and frequency spectra for pin-prick evoked potentials Received: 22 February 2022 was determined and test-retest reliability was assessed. Substantial reliability ICC scores Accepted: 23 May 2022 (0.76–0.79) were identified for evoked potential negative-positive amplitude from the left Published: 21 July 2022 hand at C4 channel and positive peak latency when stimulating the right hand at Cz Citation: Tedesco Triccas L, Camilleri KP, channel. Frequency spectra showed consistent increase of low-frequency band activity Tracey C, Mansoureh FH, (< 5 Hz) and also in theta and alpha bands in first 0.25 s. Almost perfect reliability scores Benjamin W, Francesca M, Leonardo B, Dante M and Geert V were found for activity at both low-frequency and theta bands (ICC scores: 0.81–0.98). (2022) Reliability of Upper Limb Sources were identified in the primary somatosensory and motor cortices in relation to Pin-Prick Stimulation With the positive peak using s-LORETA analysis. Measuring the frequency response from the Electroencephalography: Evoked Potentials, Spectra and Source pin-prick evoked potentials may allow the reliable assessment of central somatosensory Localization. impairment in the clinical setting. Front. Hum. Neurosci. 16:881291. doi: 10.3389/fnhum.2022.881291 Keywords: psychometric, exteroception, hand, cortical activity, event-related potentials, frequency band, sources Frontiers in Human Neuroscience | www.frontiersin.org 1 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation INTRODUCTION to researchers administering only 15 pin-prick stimuli. A higher number of stimuli of >500 is recommended for recording After an unexpected stimulus such as a pin-prick, the human somatosensory-evoked potentials (Cruccu et al., 2008). van den brain integrates that input in the somatosensory system. Broeke et al. (2017) also explored a time-frequency analysis Specifically, the primary and secondary somatosensory cortex, from PPEPs resulting in a phase-locked low frequency response, the thalamus, the insula, the posterior parietal cortex and the followed by a drop in the alpha-band oscillations. They concluded cerebellum all play important parts in processing somatosensory that time-frequency analysis is more sensitive than time-domain information (Abraira and Ginty, 2013; Limanowski et al., 2020). analysis. However, they did not examine the reliability of this Understanding the changes in cortical mechanisms involved in assessment using time-frequency analysis (Asadzadeh et al., somatosensory processing in neurological conditions could be 2020). the next step in predicting recovery and identifying different Identifying the sources in the brain through source treatment programs for patients. localization analysis from N-P response from pin-prick Routine measurement involving behavioral assessments in stimuli though also warranted, has never been conducted to our neurological conditions such as stroke could predict the knowledge. EEG source localization is potentially capable of functional outcome of the upper limb (Boccuni et al., 2018; identifying sources that are not captured by functional Magnetic Zandvliet et al., 2020). However, they mostly lead to dichotomous Resonance Imaging (fMRI). EEG has a high temporal resolution results and are sometimes unable to detect change. EEG is an and unlike fMRI, it is also a direct reflection of neural activity accessible, safe and non-invasive method that measures changes (Cohen, 2017; Michel and He, 2019). In comparison, laser evoked in brain activation from sensory stimuli (Shiner et al., 2015; potentials, which stimulate type II Aδ mechano-heat receptors, Van Diessen et al., 2015). EEG also has almost no contra- have also resulted in an initial negative–positive complex in indications, which makes it a safe application in healthy adults which sources have been contradictory in either the parasylvian or any clinical population (Borich et al., 2015b). Identifying high region or the contralateral S1 contribution using both dipole reliability of sensory modalities in combination with EEG could and source estimation analysis (LORETA) (Treede et al., 2000; be a promising tool for prediction models of recovery from a Valentini et al., 2012). Similarly, EEG dipole analysis after median brain injury (Triccas et al., 2019). This study aimed to evaluate the nerve stimulation also resulted in early sources (at P50) located reliability of the combination of measures to be further used in in the contralateral S1, medial frontal gyrus, the insula, and also people with stroke with upper limb somatosensory impairments. hippocampus (Bak et al., 2011). A somatosensory modality that could be combined with EEG Therefore, the novelty of this research was to assess the is exteroception, induced by electrical nerve stimulation, heat, variability of EEG in combination with pin-prick assessment laser, vibration or pin-prick. Mechanical pin-prick stimulates on separate days (test-retest reliability) in two different the type I A-fiber mechano-heat (I-AMH) nociceptors and has populations using time-domain and time-frequency analyses. been combined with EEG in a few studies involving healthy Based on similar research using a similar somatosensory young adults (Iannetti et al., 2013; van den Broeke et al., 2015, modality, we hypothesized that substantial reliability will 2016). From pin-prick stimulation, oscillatory activity at different be identified in the time-domain (Özgül et al., 2017) and frequency bands and evoked potentials, which are linked to time-frequency analysis. Additionally, to estimate the sources short and immediate neuronal response, can also be sensitively and their variability in the brain from the N-P complex measured and analyzed. Study of change in frequency band from pin-prick stimulation using standardized low-resolution activity gives information about the functional state of the brain electromagnetic tomography source analysis (sLORETA) sensorimotor cortex (Illman et al., 2020). The advantage of using (Pascual-Marqui, 2002). We hypothesized that similar sources to pin-prick stimulation over median nerve electrical stimulation as laser evoked potentials in the contralateral S1 (Valentini et al., a tactile stimulus, is that the latter targets both muscle efferent 2012) will be identified from pin-prick stimulation in sessions and joint afferent fibers resulting muscle contraction could 1 and 2. The research involved healthy adults above the age of be elicited upon stimulation disturbing the sensory response 40 to be used as age-and-gender matched to patients with stroke, (Fujii et al., 1994; Kandel et al., 2000; Mauguiere, 2005). In presented in a separate study. stroke rehabilitation, it is sometimes necessary to separate the somatosensory analysis from the motor one for example exploring the effect of a somatosensory rehabilitation program on MATERIALS AND METHODS upper limb function. Pin-prick evoked potentials (PPEP) have been shown to Participants consist of a biphasic negative-positive (N-P) wave with average Twenty-three healthy adult participants from two different peak latencies of 111 and 245 ms and average amplitudes of centers, Malta and Belgium, participated in this study. Each 3.5 and 11.1 µV in young healthy adults (Iannetti et al., 2013). subject participated in two sessions of EEG with pin-prick Recently, Rosner et al. (2020) explored the reliability of PPEP stimulation in 1 week. All participants were provided an measurement. They identified a poor reliability (ICC = 0.27) information pack explaining the aim of the study and of N-P amplitude measurement at dermatome C6 but higher they all gave informed consent according to the declaration reliability of N2-latency (ICC = 0.63) in healthy younger and of Helsinki. The participants had no previous peripheral older adults. The poor to moderate reliability values could be due nerve injury in the upper limbs and were screened by the Frontiers in Human Neuroscience | www.frontiersin.org 2 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation reliable Erasmus Modified Nottingham Sensory Assessment electrode cap was placed so that Cz electrode was exactly in the (EmNSA) (Stolk-Hornsveld et al., 2006). The EmNSA assesses middle of an imaginary line drawn from the occipital tuberculum tactile sensation and proprioception in the extremities. The posterior to the middle of the nasal bridge. Underlying hair and participants also confirmed that they were not diagnosed dead skin cells were minimized by using a cotton swab and with diabetes and other neurological conditions. Level of subsequently conductive gel to ensure good contact between the cognitive function was screened by the Montreal Cognitive electrodes and the scalp. Assessment (MOCA) (Nasreddine et al., 2005) in Belgium or the Mini-Mental State Examination (MMSE) (Folstein Data Acquisition et al., 1983) in Malta. Approval was obtained from the In order to administer a sharp stimulus, a pinprick stimulator University of Malta Research Ethics Committee (Registration (MRC Systems, Germany) was used, which was interfaced with number: 002/2016) and the UZ/KU Leuven Ethics Committee the EEG systems. The left or right hand was placed on a wooden (Registration number: S61174). apparatus that ensured that participants were not allowed to see when pin-prick stimulation was applied. In order to apply the Experimental Setup stimuli to each hand in a standardized manner at dermatomes C6/C7, the distance between the base of metacarpal I to the EEG data was collected by four researchers at the Experimental middle of metacarpal V was measured. The middle of this Neurology Department of Gasthuisberg University Hospital distance was set as the center of the circle that was drawn on Leuven, in Belgium and at the Biomedical Engineering the dorsum of the hand. This circle was divided in eight equal Laboratory, Faculty of Engineering, University of Malta. The EEG compartments and was drawn on both hands (Figure 1). Ten sets protocol consisted of placing electrodes on the head according of 8 stimuli (one stimulus per compartment) with approximately to the extended 10–20 international system (Homan et al., 6 s apart were applied in a random order to the dorsum of 1987). During EEG recording, participants sat in a chair as still both hands aiming to apply 160 stimuli per hand. To ensure as possible with their gaze fixed and their hand palms facing that the same force of pin-prick stimulation was applied to downwards. A BioSemi (Netherlands) EEG system, consisting the participants, a training program with all researchers was of 64 active shielded Ag-AgCl electrodes mounted in an elastic conducted. During the experiment, participants had to rate electrode-cap was used in Belgium. FCz channel was registered their level of sensation from 0 to 100% which was recorded as the reference and AFz channel as the ground. A g. tec (Austria) on a mobile phone. EEG system with 32 g. Scarabeo sintered Ag-AgCl ring electrodes also mounted in a cap was used in Malta. For this system, the AFz channel was registered as the ground and the reference clip was Data Processing and Analyses attached to the left ear lobe of the participant. Electrodes were The mean and standard deviation of level of sensation scores and concentrated on the parietal, central and frontal regions. The number of epochs per session for both hands was calculated in FIGURE 1 | Standardized hand marking for the pin-prick stimulation protocol on the dorsum of both hands. Frontiers in Human Neuroscience | www.frontiersin.org 3 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation SPSS. Wilcoxon signed rank test was used to assess the differences the standardized LORETA (sLORETA) algorithm (Pascual- in sensation scores between sessions setting a significance level at Marqui, 2002), which has been identified as an accurate method p < 0.05. EEG data was processed off-line in Matlab (Mathworks R of identifying sources and used in similar studies exploring version R2018a Update 6, Natick, Maine, United States) using somatosensory stimulation in combination with EEG (Babiloni a combination of scripts from EEGLAB (Swartz Centre for et al., 2007; Ertl et al., 2020). The noise covariance matrix required Computational Neuro-science, eeglab 14_1_2b) (Brunner et al., as input for source localization with sLORETA was obtained by 2013). The EEG signal of patients was digitized at 2,000 Hz in merging the matrices calculated from the baseline of the averaged Belgium and at 256 Hz in Malta. All data was then down sampled trials. In order to visualize in time the averaged PPEPs, contact to 256 Hz and then band pass-filtered between 1 and 50 Hz, to sheets for right and left stimulation as intraindividual analysis set remove line-noise and slow drifts, and to improve the frequency at an amplitude of 70% for the right and 60% for the left were specificity of subsequent post-processing techniques. This was generated. Regions of interest were identified using Desikan- followed by average referencing (Bertrand et al., 1985). Killiany (Desikan et al., 2006) and Brodmann areas (Kaas et al., For time-domain analysis, EEG epochs that included the 1979) and peak activity was visualized using scout time series pin-prick stimuli were extracted with a window of –0.5–1.5 s after analysis for session 1 and session 2 for both hands. stimulation. EEG epochs were averaged across trials, separately Combining data from Belgium and Malta, the test-retest for each hand. Filtered epochs were then baseline-corrected reliability of peak power amplitudes and latencies and peak with a reference interval of –0.5–0 s. Epochs contaminated by frequency latencies at ranges 0–5, 6–10, 8–12.5, and 13–30 Hz, artifacts due to eye blinks or movements were corrected with for matched trials of relative amplitude 0.4 and above of the an independent component analysis (ICA) algorithm (Comon, PPEPs for both sessions were analyzed by Intraclass Correlation 1994). The elicited PPEPs were first visually assessed in EEGLAB Coefficient (ICC). The latter involved using single measures in (Lee et al., 2013). A script was used to calculate the amplitudes a two-way mixed model (Model 3, 1) followed by Bland and (max/min) and corresponding latencies of different peaks of the Altman Analysis in IBM SPSS Statistic 25. ICC was calculated PPEPs on channels Cz, C3, C4, Fz and Pz channels. by mean squares (i.e., estimates of the population variances Time-frequency analysis involved two stages. First, based on the variability among a given set of measures) obtained time-frequency representations (TFRs) were calculated in through analysis of variance. ICC scores were evaluated on the Brainstorm (Tadel et al., 2011) within the frequency range of following agreement level: 0.2–0.4 fair, 0.4–0.6 moderate, 0.6–0.8 3–40 Hz for a time window from –500 to 1,500 ms for each substantial, and > 0.8 almost perfect (Landis and Koch, 1977). subject using the Morlet wavelet transformation for the right and Bland and Altman figures were plotted for ICC scores > 0.75 left hands, sessions 1 and 2 (Tallon-Baudry et al., 1997; Illman to allow for a visual interpretation of measurement agreement et al., 2020). This was followed by spectrum (1/f compensation) focusing on a reference range within which 95% of all differences and baseline normalization (–500–0.5 ms), choosing the method between measurements could lie (Bland and Altman, 1986; Event-related perturbation: ERS/ERD. From the ERS/ERD Mansournia et al., 2021). plots, frequency band activity was observed. Further time- frequency analysis was then carried out in Matlab to explore spontaneous frequency band activity (Illman et al., 2020). Specifically, the power spectral density (psd) was computed RESULTS using short-time Fourier transform and then the peaks within Overall the data quality was good for all participants. The mean the 0–1 s window, for the 0–5 Hz, 6–10 Hz (van den Broeke epochs for the right hand session 1 were 139 (SD: 31) and et al., 2017), 8–12.5 and 13–30 frequency bands, were identified session 2 were 143 (SD: 28). The mean epochs for the left hand for both sessions. The time at which these peaks occurred, as well as the relative amplitudes, were also recorded. The session 1 were 149 (SD: 23) and session 2 were 150 (SD: 23). relative amplitude is defined as the amplitude of the peak Demographics of the participants constituted of: mean (SD) age relative to the highest peak within the analysis time window, of the participants was 62.48 (± 11.47) years, 13 were females giving a measure of the significance of the detected peak with and 10 were males and 21 were right-handed and 2 were left- the 0 –1 s window. handed. The mean (SD) MOCA score for participants in Belgium Source imaging analysis for all participants was performed was 26.38 (3.57) and mean (SD) MMSE for participants in Malta using Brainstorm (Tadel et al., 2011). The standard ICBM152 was 29.44 (0.83). The mean pain rating scores for the right anatomy included in Brainstorm was used to construct the hand at sessions 1 and 2 were 34.83 (SD: 24.05) and 31.29 (SD: forward solution using a realistic three-layer head model 25.41) and for the left hand 35.96 (SD: 21.21) and 30.77 (SD: (OpenMEEG BEM) where the source space was constrained 23.83), respectively. The differences in the mean pain rating to a template MRI volume with 15,000 vertices and relative scores between sessions were non-significant (p = 0.051 right; conductivities of 1, 0.0125 and 1 for the scalp, skull, and brain p = 0.333 left). layers, respectively (Gramfort et al., 2010; Hnazaee et al., 2020). Source localization of EEG data recorded at the scalp can be Time-Domain Analysis a challenging problem. Different algorithms using alternative The averaged PPEP for all participants comprised of N-P complex approaches have been developed to estimate the location of followed by a smaller second peak (Figure 2). For the right hand, EEG sources (Grech et al., 2008). In our analysis, we used N-P mean amplitude for Cz, C3, and Fz channels ranged from Frontiers in Human Neuroscience | www.frontiersin.org 4 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation FIGURE 2 | Grand-averaged pin-prick evoked potential response at Cz, C3/C4, Fz, and Pz channels for right and left hand. Response in color red is depicted for session 1 and response in color blue is depicted for session 2. TABLE 1 | The mean N-P amplitude and latency with respective intraclass correlation coefficient values of the first peak of the PPEP at the Cz, C3/C4, Fz, and Pz channels. Right hand Left hand Channel N-P amplitude N-Latency P-Latency N-P amplitude N-Latency P-Latency name Mean (SD) ICC Mean (SD) ICC Mean (SD) ICC Mean (SD) ICC Mean (SD) ICC Mean (SD) ICC (µV) (95% CI) (ms) (95% CI) (ms) (95% CI) (µV) (95% CI) (ms) (95% CI) (ms) (95% CI) Cz 2.89 (2.14) 0.573 68.95 0.723 147.54 0.793 2.95 0.624 63.43 0.487 196.28 0.436 (0.151, (38.80) (0.110, (74.13) (0.539, (1.36) (0.262, (40.16) (0.069, (64.60) (0.038, 0.897) 0.938) 0.915) 0.832) 0.769) 0.714) C3/C4 2.66 (1.23) 0.763 74.84 –0.122 171.77 0.428 2.77 0.601 51.50 0.159 169.04 0.272 (0.494, (38.85) (–0.527, (73.81) (0.208, (1.44) (0.228, (39.20) (–0.294, (77.01) (0.182, 0.899) 0.328) 0.709) 0.821) 0.554) 0.631) Fz 2.71 (1.90) 0.312 80.46 –0.114 176.55 0.334 2.34 0.537 93.60 0.327 157.06 0.265 (–0.106, (73.76) (–0.485, (98.61) (–0.082, (1.76) (0.160, (74.06) (–0.100, (71.79) (–0.166, 0.636) 0.305) 0.650) 0.778) 0.652) 0.611) Pz 2.69 µV 0.198 186.42 0.141 122.05 0.397 2.09 0.489 148.82 0.087 119.10 0.482 (1.47) (–0.284, (66.61), (–0.336, (88.86) (–0.019, (1.36) (0.027, (76.94) (–0.397, (87.04) (0.086, 0.599) 0.561) 0.696) 0.779) 0.534) 0.747) 2.66 to 2.89 µV, with N-Latency ranged from 68.95 to 80.46 ms Time-Frequency Analysis and P-Latency 147.54–176.55 ms (Table 1). For session 1, left and right pinprick stimulus elicited an early For the left hand, NP mean amplitude for Cz, C4 and Fz marked increase of low-frequency activities (< 5 Hz) (Figure 3) ranged from 2.09 to 2.95 µV, N-Latency ranged from 51.50 extending at mean peak latency of 0.262 s (SD: 0.159) at the to 93.60 ms and the P-Latency ranged from 157.06 to 196.28 right hand and 0.251 s (SD: 0.169) at the left hand at the ms (Table 1). For both hands, a negative peak was seen after Cz channel. Changes in the 6–10 Hz occurred earlier at 0.160 a positive peak at Pz channel. The N-P or P-N complex was ms (SD: 0.070) at the right hand and 0.146 (0.076) at the left followed by a second late positive smaller peak [1.04 µV, 445.89 hand. Similar results were found at C3 or C4 channel (Table 2). ms (C3 channel); 1.55 µV, 449.52 ms (Cz channel); 1.35 µV, From ERS/ERS analysis, activity in the alpha (8–3 Hz) and 452.18 ms (Fz channel); 1.22 µV, 501.66 ms (Pz channel) right beta bands (13–30 Hz) were also visualized extending at mean hand; 1.04 µV, 445.89 ms (C3 channel); 1.55 µV, 449.52 ms peak latencies from 0.060 to 0.160 s (Table 2 and Figure 4). (Cz channel); 1.35 µV, 452.18 ms (Fz channel); 1.22 µV, 501.66 However, the latter analysis was not consistent as seen in the ms (Pz channel) left hand]. low-frequency analysis. Frontiers in Human Neuroscience | www.frontiersin.org 5 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation (95% CI) (0.226, (0.648, 0.878) 0.949) TABLE 2 | Showing the mean (SD) peak times at 0–5, 6–10, 8–12.5, and 13–30 Hz and respective intraclass correlation coefficients (95% CI) at both hands at Cz channel and C3 channels for right hand stimulation 0.663 0.861 ICC Mean (SD) 13–30 Hz time (s) Actual (0.050) (0.089) 0.078 0.105 peak (95% CI) (0.239, (0.421, 0.816) 0.905) 0.601 0.751 ICC Mean (SD) 8–12.5 Hz time (s) Actual (0.064) (0.060) 0.141 0.099 peak Left hand (95% CI) (0.726, (0.517, 0.945) 0.918) 0.874 0.805 ICC FIGURE 3 | Averaged spectra for all participants during right and left hand Mean (SD) 6–10 Hz time (s) pin-prick stimulation at the Cz channel. Actual (0.076) (0.074) 0.146 0.124 peak Source Estimation Analysis (95% CI) (0.945, (0.705, 0.991) 0.942) 0.978 0.866 ICC For the displaying what is happening in time during P-Peak, sLORETA identified similar peak activity at the contralateral post-central gyrus (Brodmann areas 3b and 1) especially for Mean (SD) time (s) 0–5 Hz Actual (0.169) (0.076) 0.251 0.189 right hand stimulation, indicating contralateral S1 sources. There peak seemed to be increased activity in the superior frontal area for the right hand stimulation for session 2 however, this was not (95% CI) consistent for the other sessions. Additional pre-central gyri (0.447, (0.108, 0.946) 0.905) 0.813 0.666 ICC activation was noted in left hand stimulation (Figure 5). No distinctive activity was identified during the N-peak of the PPEP. Mean (SD) 13–30 Hz time (s) Actual (0.488) (0.553) 0.075 0.064 peak Reliability Analysis For the evoked potentials, at Cz and C4 channels, substantial reliability for P-Latency [ICC: 0.793 (0.539, 0.915) right hand] (95% CI) (0.693, (0.204, 0.848) 0.812) 0.869 0.585 and N-P amplitude [ICC: 0.763 (0.494, 0.899) left hand] ICC respectively, were found (Table 1 and Figure 6). The results for frequency analysis are focused on the electrodes in the central Mean (SD) 8–12.5 Hz time (s) region (Cz/C3/C4) since substantial reliability were identified in Actual (0.832) (0.676) 0.165 0.106 peak these regions. Almost perfect reliability values were found for time-frequency analysis between peak times at 0–5 and 6–10 Hz Right hand at sessions 1 and 2 showing ICC scores ranging from 0.977 to (95% CI) (0.783, (0.629, 0.957) 0.921) 0.902 0.824 ICC 0.824 for the right hand and 0.978–0.805 for the left hand (Table 2 and Figure 6). Substantial reliability values were also found for 8–12.5 and 13–30 Hz analysis (ICC: 0.813–0.869) at Cz channel Mean (SD) 6–10 Hz time (s) Actual (0.070) (0.048) 0.160 0.116 for the right hand. For the left hand, higher reliability values were peak found at the C4 channel compared to the Cz channel for the latter analysis (ICC: 0.751–0.861). (95% CI) (0.947, (0.826, 0.990) 0.969) 0.977 0.926 ICC and C4 for left hand stimulation. DISCUSSION Mean (SD) time (s) 0–5 Hz Actual (0.103) (0.111) 0.222 0.238 peak To our knowledge, this is the first study exploring the sources of the N-P complex from pin-prick stimulation. Reliable sources were identified in the contralateral post and pre-central gyri especially for right hand stimulation Channel C3/C4 name indicating primary somatosensory and motor cortices Cz activation. The presented research was also novel to explore Frontiers in Human Neuroscience | www.frontiersin.org 6 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation FIGURE 4 | Averaged ERS/ERD plots for all participants during right and left hand pin-prick stimulation at the respective C3 and C4 channels. FIGURE 5 | Top images displaying the topography at sensor level during the positive peak activity of the pin-prick evoked potential for the right and left hand. Bottom figures displaying the averaged peak activity at the precentral and postcentral gyri for sessions 1 and 2 at both hands. the reliability of time-frequency analysis from pin-prick could be explained by the age of participants since our population stimulation providing insight into the functional state was older compared to the young participants between 23 of the sensorimotor cortex. Almost perfect reliability was and 30 years in similar research. Further investigation of the identified for this type of analysis. Therefore, we recommend impact of age on evoked potential amplitude is warranted. that both frequency and source analysis using sLORETA Implementing a reliable neurophysiological assessment for could be valuable source of exploring somatosensory assessing somatosensory impairments is important for future impairments in neurological conditions. However, inconsistent stroke research, since exteroceptive impairments can be present reliability values were identified for latency and amplitude in 41–50% of patients with acute stroke (Meyer et al., 2016). of the PPEPs at the left and right hand from the time- We identified substantial reliability for P-Latency at the right domain analysis. Using the latter measure to evaluate hand and N-P amplitude for the left hand but moderate efficacy of upper limb sensorimotor rehabilitation programs reliability for P-Latency for the left hand and N-P amplitude cannot be considered. for the right hand. This result was not expected. One possible From the time-domain analysis, the latency of the evoked reason for this is the thickness of pin-prick filament. Recently, potentials of this study matched well with similar studies (Iannetti Rosner et al. (2020), identified that 256 mN stimulation et al., 2013; van den Broeke et al., 2015, 2016), although the intensity led to higher reliable values than the 128 mN identified peak amplitudes were relatively smaller. This difference which was used in our study (Rosner et al., 2020). The Frontiers in Human Neuroscience | www.frontiersin.org 7 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation FIGURE 6 | Bland-Altman plots demonstrating the 95% limits of agreement between 1st and 2nd sessions for variables with ICC = 0.75. The middle line represents the mean. The upper and lower line represent the upper and lower limits of agreement (mean ± 1.96 SD), respectively. The Bland-Altman analysis could not be performed for actual_peak_time analysis 0_5 Hz for C3 channel because the difference was found significant (p = 0.017). main reason for choosing a smaller force was to minimize A 20 Hz rhythm has also been modulated from proprioception pain through the lateral spinothalamic tract but also to and tactile stimulation in people with stroke; However, the explore the response to crude touch and pressure from pin- reliability of the latter assessment has never been explored prick stimulation through the anterior spinothalamic tract. (Illman et al., 2020). The presence or absence of alpha and beta Incidentally, pin-prick stimulation could be painful however, band frequency response in people with pin-prick impairment from our experiment participants reported pain levels with mean could give an indication of the level of recovery of upper scores of 30%, which is low. limb somatosensory and even motor impairments in the acute As presented in similar research, pin-prick stimulation stage of stroke. resulted in a low frequency response (< 5 Hz) in both As for previous research involving laser-evoked potentials sessions (van den Broeke et al., 2017). As identified in a and median nerve stimulation (Bak et al., 2011; Valentini et al., recent magnetoencephalography (MEG) study, stimuli which 2012), we can accept our hypothesis that pin-prick stimulation were repeated and expectations that were established, resulted in results in sources within the contralateral S1. This was more associated activity in the theta and beta bands (Andersen and pronounced during right hand stimulation. In addition, sources Lundqvist, 2019). We also found reliable peak activity in the within the contralateral M1 were also identified which is similar alpha band between 6–10 and 8–13 Hz but we identified this to what was identified in fMRI data involving median nerve change between 0.146 and 0.160 ms which is earlier compared stimulation (Spiegel et al., 1999). This is as expected since to previous research (van den Broeke et al., 2017). A reduction S1 is the primary area for sensorimotor integration (Borich in alpha band has been linked with somatosensory information et al., 2015a). For the negative peak response, inconsistent processing (Pfurtscheller et al., 1996; Jensen and Mazaheri, sources were identified. The negative peaks found in our 2010). In similar studies, EEG and MEG assessment with other participants were and earlier compared those found in laser sensory modalities such as proprioception or vibrotactile stimuli evoked potentials which relate to activity in this area as a also resulted in rhythmic oscillatory activity at the alpha (8– response to pain (Strigo et al., 2005). Compared to median 12 Hz) and also the beta band (13–30 Hz) (Kim et al., 2020). nerve stimulation, negative responses have been shown to be Our ERS/ERD plots also showed activity at the beta band generated within the temporal lobe at 72–96 ms (Tesche, 2000). which had substantial reliability between sessions. During tactile This could be referred to as source location of SII in the stimuli, suppression of beta band has been identified in the upper bank of the Sylvian fissure, i.e., temporal region (Vogel contralateral hemisphere using MEG (Gaetz and Cheyne, 2006). et al., 2003). From MEG and fMRI studies, it was shown that Frontiers in Human Neuroscience | www.frontiersin.org 8 July 2022 | Volume 16 | Article 881291 Tedesco Triccas et al. Electroencephalography and Pin-Prick Stimulation tactile topographic representation was identified in the supra- DATA AVAILABILITY STATEMENT sylvian cortex [including the secondary somatosensory area (S2)], indicating that this area may contribute to touch localization The raw data supporting the conclusions of this article will be (Maeda et al., 1999; Del Gratta et al., 2002). However, we used made available by the authors, without undue reservation. a small amount of channels compared to previous research using MEG which could have contributed to the lack of consistency in identifying sources. ETHICS STATEMENT Apart from identifying novel findings, some limitations from this research need to be recognized. The experiments were All study procedures were approved by the University of Malta conducted in two centers with two different EEG systems and Research Ethics Committee (Registration number: 002/2016) raters. The preliminary data was always checked before data and the UZ/KU Leuven Ethics Committee (Registration number: collection on the present sample and also training was provided S61174). The patients/participants provided their written for each rater; However, the environmental differences could informed consent to participate in this study. have impacted the level of reliability results. In order to obtain sufficient data, the experimental procedure was quite long which lasted around 45 min in addition to the EEG setup. At the end of the second session, participants were often tired and sometimes AUTHOR CONTRIBUTIONS disinterested in the experiment. Averaged referencing could have LTT: development of protocol, data collection and analyses, and also contributed to the variability in the PPEP responses between writing of the manuscript. KC, CT, MD, and VG: development of sessions (Yao et al., 2019). Since we did not have a MRI of protocol, data analyses, and review of the manuscript. FM: data the healthy participants, source localization was conducted on a analyses and review of the manuscript. WB: data analysis. BL and standard MRI implemented in Brainstorm. Therefore, identifying MF: data collection. All authors contributed to the article and the exact coordinates in relation to the cortical activation might approved the submitted version. have not been identical. We used 32 electrodes in 10 of the recruited participants. Mislocalizations could occur with a low number of channels (Srinivasan et al., 1998). However, well- defined focal activity was expected from pin-prick stimulation FUNDING and therefore, having 32 electrodes could give valuable insight of the underlying sources (Michel and Brunet, 2019). This work was supported by Promobilia Foundation (grant no. 17064). The research work disclosed in this publication is partially funded by the Reach High Scholars Programme—Post- CONCLUSION doctoral Grants awarded to LTT. The project was part financed by the European Union, Operational Programme II—Cohesion The main aim of this research was to explore the variability of Policy 2014–2020 Investing in human capital to create more pin-prick measurement with EEG. Almost perfect reliability was opportunities and promote the wellbeing of society – European identified for response at low frequency and theta bands from Social Fund. upper limb pin-prick stimulation was identified. Additionally, measurement of evoked potential latency of the positive peak has also substantial reliability. 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The primary somatosensory cortex largely contributes to the early and do not necessarily represent those of their affiliated organizations, or those of part of the cortical response elicited by nociceptive stimuli. Neuroimage 59, the publisher, the editors and the reviewers. Any product that may be evaluated in 1571–1581. doi: 10.1016/j.neuroimage.2011.08.069 this article, or claim that may be made by its manufacturer, is not guaranteed or van den Broeke, E. N., De Vries, B., Lambert, J., Torta, D. M., and Mouraux, endorsed by the publisher. A. (2017). Phase-locked and non-phase-locked EEG responses to pinprick stimulation before and after experimentally-induced secondary hyperalgesia. Copyright © 2022 Tedesco Triccas, Camilleri, Tracey, Mansoureh, Benjamin, Clin. Neurophysiol. 128, 1445–1456. doi: 10.1016/j.clinph.2017.05.006 Francesca, Leonardo, Dante and Geert. This is an open-access article distributed van den Broeke, E. N., Lambert, J., Huang, G., and Mouraux, A. (2016). Central under the terms of the Creative Commons Attribution License (CC BY). The sensitization of mechanical nociceptive pathways is associated with a long- use, distribution or reproduction in other forums is permitted, provided the lasting increase of pinprick-evoked brain potentials. Front. Hum. Neurosci. original author(s) and the copyright owner(s) are credited and that the original 10:531. doi: 10.3389/fnhum.2016.00531 publication in this journal is cited, in accordance with accepted academic practice. van den Broeke, E. N., Mouraux, A., Groneberg, A. H., Pfau, D. B., Treede, R.-D., No use, distribution or reproduction is permitted which does not comply with and Klein, T. (2015). Characterizing pinprick-evoked brain potentials before these terms. Frontiers in Human Neuroscience | www.frontiersin.org 11 July 2022 | Volume 16 | Article 881291