Non-painful Tactile Stimuli Research Articles

Simultaneous cortical, subcortical, and brainstem mapping of sensory activation.

Nonpainful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging studies have highlighted the value of whole-brain, systems-level investigation for examining sensory processing. However, whole-brain functional magnetic resonance imaging studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high-resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo functional magnetic resonance imaging acquisition at 3T with multi-echo independent component analysis denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to nonpainful brushing of the right hand, left hand, and right foot (n= 10 per location), and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we differentiated the adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

Processing in the non-dominant hand during sleep: in terms of early, middle-early and late brain responses.

The aim was to investigate brain responses to non-painful tactile stimuli applied to the non-dominant hand during sleep. 21 healthy subjects participated in the study (11 female, mean age ± SD: 20.67 ± 1.91years). A 40-channel polysomnography system and a pneumatic tactile stimulator unit were used. Stimuli were applied to the participants' non-dominant hand. Evoked potential components of the CZ electrode were examined in four sleep stages (N1, N2, N3, and REM). Repeated measures ANOVA was used in statistical analyses. Brain responses, categorized as early (P50, N100, and P200), mid-early (N300, P450, and N550), and late (P900 and Nlate), were detected all sleep stages. No notable variances were found in the amplitude and latency of early brain responses when analyzed across different sleep stages. Differences in both amplitude and latency were observed across different sleep stages for the N300, P450, P900, and Nlate response components. This study presents a pioneering exploration into the responses of the non-dominant hand throughout all sleep stages, encompassing eight distinct response components. This novel investigation contributes to the existing literature by shedding light on previously unexplored aspects. The observed early responses are identified as sensory, while middle to late responses align with cognitive processes within the realm of sleep research. Notably, N300, P450, P900, and Nlate components display variations across diverse sleep stages, marked by alterations in both amplitude and latency. These findings offer valuable insights into the dynamic nature of hand responses throughout the sleep continuum.

Primed Tactile Stimulus Processing during Sleep.

The aim was to investigate how the primed and unprimed non-painful tactile stimuli during sleep would be processed. A total of 22 healthy subjects (19.55 ± 1.10 years) were randomly divided into two groups. The same stimuli were applied to both groups, but the study group (SG) received them twice (daytime and sleep), whereas the control group (CG) received them only during sleep. A 40-channel PSG and a pneumatic tactile stimulator unit were used. Evoked potential components of the CZ electrode were examined in four sleep stages (N1, N2, N3, and REM). The Mann-Whitney U test was used for group comparison, and the Wilcoxon test was used for in-group evaluations. The P50 and N300 response components were observed in all sleep stages in both groups. P50 decreased as sleep deepened in the SG. The N300 increased as sleep deepened and started to decrease again in the REM stage. Moreover, in N1, the amplitudes of P200-N300 and N300-P450 in the SG were significantly greater than those in the CG. The fact that P50 was observed even in N3 indicates that bottom-up sensory processing continues during sleep. Moreover, the central processing of primed and unprimed stimuli exhibited dynamic differences. Furthermore, an increase in N300 amplitude suggests suppressive processes to facilitate and maintain sleep.

Sensory Brain Responses and Lateralization in Nonpainful Tactile Stimuli during Sleep

Aims and Objectives: The aim of this study was to investigate the difference between sensory brain responses of nonpainful tactile stimuli applied to the fingers of the right-hand dominant individuals between the hemispheres. Materials and Methods: Nineteen healthy volunteers (9 women, mean age ± standard deviation: 23.00 ± 2.24 years) participated in the study. Electroencephalogram (EEG) recordings were taken from 40 channels polysomnography system. A uniform nonpainful stimulus was applied to two fingers (index and middle fingers) of the right and left hand with a pneumatic stimulator unit. Results: Non-rapid eye movement sleep (NREM) whole night sleep-related potentials were evaluated. When the stimulus was applied to the right hand, central and parietal regions of the P50 response component appeared significantly earlier in the left hemisphere. When the left-hand stimulus was applied, the P50 and N100 response components appeared significantly early in central, parietal, and temporal regions in the left hemisphere. Hence, amplitudes of the right-hand response components (P50 and N100) were found to be greater in the central, parietal, and temporal regions in the left hemisphere. When the stimulus is applied to the left hand, the amplitude of the P50 component was greater in the central and temporal regions in the left hemisphere. Conclusion: P50 and N100 are components related to sensory processing. The difference in latency and amplitude observed in these components between hemispheres indicates the presence of lateralization in sensory processing during sleep.

Inter-stimulus Interval Effect on Tactile Habituation: An Electrophysiological Approach

Objective: The current study aims to investigate different inter-stimulus interval effect on habituation process by using non-painful tactile stimuli. Methods: Twelve right-handed healthy volunteers (6 female; mean age: 22.9 ± 1.93 years) participated to the study. The electroencephalography (EEG) was recorded from 64 channels. Non-painful tactile stimuli (~140 kPa) were delivered to the right index finger via using a pneumatic stimulator. Somatosensory evoked potentials (SEP) paradigm was used in all session. Inter-stimulus interval (ISI) was selected as 2s, 4s, and 8s and applied in separate sessions (as ISI2, ISI4 and ISI8). Results: Peak-to-peak maximum amplitudes of N2, P3 and N4 components were measured for three different ISI and for three different electrode sites (Fz, Cz, Pz). The 3x3 repeated measures ANOVA test was employed for statistical analysis. According to the analysis, a significant inter-stimulus interval (ISI) effect was found on both PPmaxN2P3 and PPmaxP3N4 (p=0.004 and p=0.001 respectively). The amplitudes of ISI8 session in all electrode sites higher than ISI2 session for both PPmaxN2P3 (p=0.024) and PPmaxP3N4 (p=0.012). Also, ISI4 session has higher amplitudes than ISI2 session (p=0.05) for the PPmaxP3N4. Conclusion: This study revealed that the late components of SEPs are affected by the ISI change. The amplitudes of SEP components are increased as ISI increased.

Deaf adolescents have bigger responses for somatosensory and visual stimulations

The functions of the sensory systems on disabled people have been one of the most investigated topics in brain research. In these studies, mostly visual stimuli had been employed while investigating the deaf participants. Limited number of electrophysiological studies revealed better visual sensory processing in deaf participants. On the other hand, studies deploying tactile stimuli especially used either electrical or painful stimulus or they focused the psychophysical assessments of thresholds associated with tactile stimuli. The present study tried to evaluate electrophysiological brain responses in deaf and control group with a unimodal study design including both the visual and non-painful tactile stimuli, and to reveal the possible changes in brain plasticity within modality basis.Thirteen congenitally deaf adolescents (mean: 14.61 ± 1.06 years; 7 girls) and 10 adolescents with normal hearing (16.6 ± 2.72 years; 4 girls) were recruited for the study. Somatosensory evoked potentials (SEP) and visual evoked potentials (VEP) were separately delivered to the participants and in order to maintain neutrality among sessions they were presented in random order while the electroencephalography (EEG) recordings were taken.Brain responses to non-painful tactile and visual stimuli were measured for N1, P2, and N2 components. All amplitudes of deaf group were significantly larger than all amplitudes of control group in SEP session whereas in VEP session only P2 and N2 amplitudes of deaf group were statistically larger. In addition, the latency of N1 component in VEP session was significantly earlier in deaf group.These findings suggest early cortical excitability, less neuronal capacity usage and also more efficient sensory processing in deaf group.

Dopaminergic and serotonergic mechanisms in the modulation of pain: In vivo studies in human brain

Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D2/D3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D2/D3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D2/D3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D2/D3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D2/D3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D2/D3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D2/D3 receptors. These findings suggest that dopamine acting on striatal dopamine D2/D3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.

Investigation of non-painful tactile stimuli via bispectral index system during sleep

Investigation of non-painful tactile stimuli via bispectral index system during sleep

Brain responsiveness to non-painful tactile stimuli prior and during sleep

The purpose of this study is analyzing the responses to non-painful tactile stimuli prior-to-sleep (PS) and during the sleep. A total of 21 healthy participants (10 male, mean age ± SD 22.82 ± 1.12 years) were recruited and tested in this study. EEG recordings were taken from 40 channels. Single type of non-painful tactile stimuli was applied to the two fingers of the right hand by means of pneumatic stimulator. Sleep stages were scored according to American Academy of Sleep Medicine sleep scoring systems. Somatosensory-evoked potentials (SEPs) were analyzed for PS and each of sleep stages. While P50, N100, P200, N300, P900 and N_late components were recorded both PS and during the sleep, P300 and N450 were observed only in PS. Likewise, P450 and N550 components were observed only during the sleep cycle (light, deep and REM). P50, N100 and P200 components related to sensorial processing had relatively higher amplitudes in PS than in the sleep cycle. On the other hand, N300, P450, P900 and N_late responses had the highest amplitudes during sleep. The changes in brain responses to non-painful tactile stimuli PS and during the sleep were presented in this study. To our knowledge, it is the first study to demonstrate the eight SEP components all at once. Early components have been related to sensory processing and thus hint at the limitation of the brain towards external world for sleep, whereas later components show the network activity for sustaining the sleep environment.

Effects of repetitive noxious stimuli during neonatal period on pain sensitivity during adulthood in rats

Objective To evaluate the effects of repetitive noxious stimuli during the neonatal period on the pain sensitivity during adulthood in rats. Methods Twenty pathogen-free male neonatal Sprague-Dawley rats, weighing 6.2-6.8 g, were randomly divided into 2 groups (n=10 each) using a random number table: control group (group C) and repetitive noxious stimuli group (group RNS). In RNS group, neonatal rats sequentially received needle pricks into the dorsal surface of 4 paws at 6 h intervals with a 28 G needle per day during the first postnatal week. In group C, the animals received non-painful tactile stimuli with cotton tip rub. At the age of 10 weeks, complete Freund's adjuvant was injected into the plantar surface of the right hind paw to induce inflammatory pain. Before injection, and at 24 h and 7 days after injection (T0-2), the mechanical and thermal thresholds were measured, and alcohol preference test was performed for assessment of the behavior at T2. Results The mechanical threshold of the right paws was significantly lower at T1, 2 than that of the left paws in the two groups. Compared to group C, the mechanical threshold of the left and right paws at T0-2 and thermal threshold of the right paws at T1 were significantly decreased, and alcohol intake was increased in group RNS. Conclusion Repetitive noxious stimuli during the neonatal period can lead to increase in the pain sensitivity during adulthood in rats. Key words: Infant, newborn; Hyperalgesia; Pain; Adult

The nocebo effect: should we be worried?

Lack of adherence to therapeutic regimes and side effects observed in placebo arms are common problems in randomized clinical trials and practice [1]. These effects can be partially due to the occurrence of negative placebo effects, the so-called ‘nocebo effects’. Nocebo effects rely on a phenomenon that is opposite to placebo, in which expectations of worsening play a crucial role. Recent neuroanatomical and neurochemical advances support the notion that specific modulators and brain areas are involved in the formation of nocebo effects. Negative expectations can produce increases in pain experienced and can interfere with the therapeutic action of active drugs. It has been reported that the negative and positive disclosures interfere with the analgesic efficacy of the μ-opioid agonist, remifentanil [2]. A positive communication such as, “you are going to receive a potent analgesic medication,” substantially enhanced (doubled) the analgesic effect of remifentanil. Conversely, a negative disclosure such as informing a health volunteer that the painkiller is going to be stopped when in actuality, was continuously administrated, abolished the remifentanil-induced pain relief. The subjective pain reports correlated significantly with modifications in specific brain regions that are known to be involved in pain processing [2]. Studies in human models have also indicated that the CCK system is linked to nocebo effects, at least in the field of pain. Verbal cues of increased pain produce the anticipated effects and these effects can be reversed by administering the nonspecific CCK-antagonist proglumide, suggesting that blocking CCK-A and -B receptors antagonizes verbally induced increases in pain. Furthermore, sensorial stimulations that would never normally produce pain began to do so under verbal suggestions of hyperalgesia [3]. Nocebos can produce deleterious effects as nonpainful tactile stimuli can become painful and hyperalgesic responses in which low-intensity painful stimuli are perceived as highintensity stimuli [4]. Apparently, direct experience matters in nocebo responses, but less than the placebo counterpart in which learning from previous positive experience is fundamental for consolidating positive outcomes. We can speculate that nocebos induce short-term innate responses that are aimed at enhancing the perceptual processing and at anticipating negative outcomes, which in turn help initiate potentially defensive behavioral reactions. On the other hand, perpetuation of unsuccessful experiences may promote the consolidation of negative outcomes and the severity of symptoms. From a clinical point of view, it is plausible to think that if nocebos and negative verbal cues are powerful in eliciting negative outcomes in laboratory settings, it is licit to postulate that the doctor’s words and attitudes can induce immediate worsening of symptoms [5]. For example, communication about the interruption of a therapy (pharmacological or non-pharmacological) results in the occurrence “Research on nocebo effects affirms the need for rethinking the ethics of patient–clinician communication, informed consent and, perhaps more importantly, the decision-making processes.”

Fine-Grained Nociceptive Maps in Primary Somatosensory Cortex

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded functional magnetic resonance imaging analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the time course and the spatial pattern of plastic changes in cortical organization involved in chronic pain.

Neonatal repetitive needle pricking: Plasticity of the spinal nociceptive circuit and extended postoperative pain in later life

Repetitive exposure of neonates to noxious events is inherent to their health status monitoring in neonatal intensive care units (NICU). Altered basal nociception in the absence of an injury in later life has been demonstrated in ex-NICU children, but the impact on pain hypersensitivity following an injury in later life is unknown. Also, underlying mechanisms for such long-term changes are relatively unknown. The objective of this study is to investigate acute and long-term effects of neonatal repetitive painful skin-breaking procedures on nociception and to investigate plasticity of the nociceptive circuit. The repetitive needle prick animal model was used in which neonatal rats received four needle pricks into the left hind paw per day during the first postnatal week and control animals received nonpainful tactile stimuli. Repetitive needle pricking during the first week of life induced acute hypersensitivity to mechanical stimuli. At the age of 8 weeks, increased duration of postoperative hypersensitivity to mechanical stimuli after ipsilateral hind paw incision was shown in needle prick animals. Basal nociception from 3 to 8 weeks of age was unaffected by neonatal repetitive needle pricking. Increased calcitonin gene-related peptide expression was observed in the ipsilateral and contralateral lumbar spinal cord but not in the hind paw of needle prick animals at the age of 8 weeks. Innervation of tactile Aβ-fibers in the spinal cord was not affected. Our results indicate both acute and long-term effects of repetitive neonatal skin breaking procedures on nociception and long-term plasticity of spinal but not peripheral innervation of nociceptive afferents.

Sex differences in inflammatory mechanical hypersensitivity in later life of rats exposed to repetitive needle pricking as neonates

Repetitive pain exposure of neonates in the neonatal intensive care unit (NICU) might affect proper fine-tuning of the nociceptive network, a process which continues in the postnatal period. In ex-NICU children altered basal nociception in the absence of an injury has been shown. However, the impact on nociception after an injury, e.g. surgery, is unknown. In this study we aimed to determine the effect of neonatal repetitive small painful skin-breaking procedures in both sexes on nociception in the absence and in the presence of an ongoing injury in later life. To this end the repetitive needle prick animal model was used in which neonatal Sprague–Dawley male and female rat pups received four needle pricks per day into one hind paw during the first week of life and control animals received non-painful tactile stimuli. Nociceptive thresholds to mechanical stimuli in the absence of injury, i.e. basal nociception, were not affected by neonatal repetitive needle pricking. Only male animals which received neonatal needle pricks showed increased hypersensitivity to mechanical stimuli at 24h after ipsilateral CFA-injection. Our study shows that repetitive small needle pricks during the first week of life result in increased hypersensitivity to mechanical stimuli at 24h after ipsilateral CFA-injection in later life in male animals and not in females.

Cortical activation by tactile stimulation to face and anterior neck areas: An fMRI study with three analytic methods

The main purpose of this study was to investigate the sensory cortical activation of the anterior neck region and the relationship between the neck and face representation areas. Functional MRI by blood oxygenation level dependent measurements was performed while tactile stimulation was applied to the face or neck area. Nonpainful tactile stimuli were manually delivered by an experimenter at a frequency of ∼1 Hz. Block (epoch) design was adopted with a block duration of 30 s and a whole run duration of 6 min. For each location, two runs were performed. After the image data were preprocessed, both parameteric and nonparametric methods were performed to test the group results. The results showed that (1) unilateral face or neck stimulation could elicit bilateral cortical activation, (2) mainly the face representation and face-hand junction areas, but not the conventional neck representation area, were activated by face or neck stimulation, and (3) the activation areas were larger when right face or neck was stimulated. In conclusion, the sensory cortical representation area of the anterior neck region was mainly at the junction of hand and face representation area and the activated area was larger when the right face or neck was stimulated.

Somatosensory processing of non-painful tactile stimuli in patients with idiopathic trigeminal neuralgia

Somatosensory processing of non-painful tactile stimuli in patients with idiopathic trigeminal neuralgia

Laterality and modality-specific effects of chronic pain.

Previous investigations indicated that thresholds to nonpainful tactile stimuli were elevated in chronic-pain patients when compared with pain-free individuals (Seltzer & Seltzer, 1986; Seltzer et al., 1988). The present study attempted to determine whether thresholds to tactual and visual stimuli also were elevated by chronic pain. Furthermore, lateralization of the pain effect on tactile thresholds was assessed by obtaining thresholds from both left and right arms. A decrease in tactile sensitivity to nonpainful stimuli in chronic-pain patients was confirmed, but laterality of the effect was not demonstrated. Visual thresholds were not significantly affected by chronic pain. The data in the present study, taken together with other data, support the proposition that pain does not affect right hemispheric processes more than left hemispheric processes.