Sustained Spatial Attention to Vibrotactile Stimulation in the Flutter Range: Relevant Brain Regions and Their Interaction

The present functional magnetic resonance imaging (fMRI) study was designed to get a better understanding of the brain regions involved in sustained spatial attention to tactile events and to ascertain to what extent their activation was correlated. We presented continuous 20 Hz vibrotactile stimuli (range of flutter) concurrently to the left and right index fingers of healthy human volunteers. An arrow cue instructed subjects in a trial-by-trial fashion to attend to the left or right index finger and to detect rare target events that were embedded in the vibrotactile stimulation streams. We found blood oxygen level-dependent (BOLD) attentional modulation in primary somatosensory cortex (SI), mainly covering Brodmann area 1, 2, and 3b, as well as in secondary somatosensory cortex (SII), contralateral to the to-be-attended hand. Furthermore, attention to the right (dominant) hand resulted in additional BOLD modulation in left posterior insula. All of the effects were caused by an increased activation when attention was paid to the contralateral hand, except for the effects in left SI and insula. In left SI, the effect was related to a mixture of both a slight increase in activation when attention was paid to the contralateral hand as well as a slight decrease in activation when attention was paid to the ipsilateral hand (i.e., the tactile distraction condition). In contrast, the effect in left posterior insula was exclusively driven by a relative decrease in activation in the tactile distraction condition, which points to an active inhibition when tactile information is irrelevant. Finally, correlation analyses indicate a linear relationship between attention effects in intrahemispheric somatosensory cortices, since attentional modulation in SI and SII were interrelated within one hemisphere but not across hemispheres. All in all, our results provide a basis for future research on sustained attention to continuous vibrotactile stimulation in the range of flutter.     

Functional brain mapping of pain perception

In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes were almost exclusively the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been confirmed with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area which amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only--and not in other brain areas--was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief is taken into account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the PAG, and, at least in some instances, with the involvement of endogenous opioids.     

Pain perception and its genesis in the human brain

In the past two decades, pain perception in the human brain has been studied with EEG/MEG brain topography and PET/ fMRI neuroimaging techniques. A host of cortical and subeortical loci can be activated by various nociceptive conditions. The activation in pain perception can be induced by physical (electrical, thermal, mechanical), chemical (capsacin, ascoric acid), psychological (anxiety, stress, nocebo) means, and pathological (e.g. migraine, neuropathic) diseases. This article deals mainly on the activation, but not modulation, of human pain in the brain. The brain areas identified are named pain representation, matrix, neuraxis, or signature. The sites are not uniformly isolated across various studies, but largely include a set of cores sites: thalamus and primary somatic area (SI), second somatic area (SII), insular cortex (IC), prefrontal cortex (PFC), cingnlate, and parietal cortices. Other areas less reported and considered important in pain perception include brainstem, hippocampus, amygdala and supplementary motor area (SMA). The issues of pain perception basically encompass both the site and the mode of brain function. Although the site issue is delineared to a large degree, the mode issue has been much less explored. From the temporal dynamics, IC can be considered as the initial stage in genesis of pain perception as conscious suffering, the unique aversion in the human brain.     

Readiness potentials recorded from the scalp and depth leads.

Readiness potentials on voluntary hand movements were recorded from the scalp (C3, C4), premotor cortex, subcortical white matter and VL nucleus of the thalamus. Subjects were healthy right-handed men and patients with involuntary movement disorders. We obtained a slow negative shift of brain electrical potentials from the scalp and cortex preceding voluntary hand movements. The mean time interval between the onset of the readiness potential and the onset of motor activity (mean T) was 0.8 sec on right hand movements and 1.0 sec on left hand movements in healthy men. In cases with parkinsonism, the mean T value was 1.4 sec in patients with akinesia, 1.1 sec in those without akinesia. The amplitude of readiness potentials was higher in the scalp contralateral to the hand movement. The readiness potentials recorded from the VL nucleus and white matter were reversed in polarity from those of scalp and cortex. Simultaneous recordings from cortex and VL nucleus showed early onset of readiness potentials from the cortex by approximately 0.1 sec compared with the VL nucleus.     

Dynamic Changes in Brain Activations and Functional Connectivity during Affectively Different Tactile Stimuli

In the present study, we compared brain activations produced by pleasant, neutral and unpleasant touch, to the anterior lateral surface of lower leg of human subjects. It was found that several brain regions, including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII), as well as contralateral middle and posterior insula cortex were commonly activated under the three touch conditions. In addition, pleasant and unpleasant touch conditions shared a few brain regions including the contralateral posterior parietal cortex (PPC) and bilateral premotor cortex (PMC). Unpleasant touch specifically activated a set of pain-related brain regions such as contralateral supplementary motor area (SMA) and dorsal parts of bilateral anterior cingulated cortex, etc. Brain regions specifically activated by pleasant touch comprised bilateral lateral orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), intraparietal cortex and left dorsal lateral prefrontal cortex (DLPFC). Using a novel functional connectivity model based on graph theory, we showed that a series of brain regions related to affectively different touch had significant functional connectivity during the resting state. Furthermore, it was found that such a network can be modulated between affectively different touch conditions.     

Postnatal changes in functional activities of the pig's brain: a combined functional magnetic resonance imaging and immunohistochemical study

Developmental changes in brain activation after pain stimulation and after passive movement of the hind paw were assessed by functional magnetic resonance imaging (fMRI) in pigs of postnatal ages 2, 4 and 6 months. Response patterns were correlated with histological maturation parameters. At 2 months, fMRI failed to detect brain activation after pain stimulation and revealed weak, but widespread activation after passive movement. At 4 months, strong reaction of numerous cortical areas on the contralateral side was seen after pain stimulation. Following passive movement, activation was weaker but more widespread, and the brainstem was also involved. By 6 months, cortical activation became more restricted to the contralateral sensory cortex and brainstem after pain stimulation and to the contralateral sensory and ipsilateral premotor and motor cortices after passive movement. Neocortical synaptophysin immunoreaction increased significantly between 2 and 4 months and slightly decreased by 6 months. The density of GABA-immunoreactive neurons and fibers significantly increased, reaching a maximum at 6 months. Our studies indicate that remodeling of synapses and development of inhibitory GABA neurons last until 6 months postnatally, when the fMRI response of the pig's brain also attains its mature adult pattern.     

Optical imaging of nociception in primary somatosensory cortex of non-human primates

While the activation of primary somatosensory (SI) cortex during pain perception is consistently reported in functional imaging studies on normal subjects and chronic pain patients, the specific roles of SI, particularly the subregions within SI, in the processing of sensory aspects of pain are still largely unknown. Using optical imaging of intrinsic signal (OIS) and single unit electrophysiology, we studied cortical activation patterns within SI cortex (among Brodmann areas 3a, 3b and 1) and signal amplitude changes to various intensities of non-nociceptive, thermal nociceptive and mechanical nociceptive stimulation of individual distal finerpads in anesthetized squirrel monkeys. We have demonstrated that areas 3a and 1 are preferentially involved in the processing of nociceptive information while areas 3b and 1 are preferentially activated in the processing of non-nociceptive (touch) information. Nociceptive activations of individual fingerpad were organized topographically suggesting that nociceptive topographic map exits in areas 3a and 1. Signal amplitude was enhanced to increasing intensity of mechanical nociceptive stimuli in areas 3a, 3b and 1. Within area 1, nociceptive response co-localizes with the non-nociceptive response. Therefore, we hypothesize that nocicepitve information is area-specifically represented within SI cortex, in which nociceptive inputs are preferentially represented in areas 3a and 1 while non-nociceptive inputs are preferentially represented in areas 3b and 1.     

Mirroring Pain in the Brain: Emotional Expression versus Motor Imitation

Perception of pain in others via facial expressions has been shown to involve brain areas responsive to self-pain, biological motion, as well as both performed and observed motor actions. Here, we investigated the involvement of these different regions during emotional and motor mirroring of pain expressions using a two-task paradigm, and including both observation and execution of the expressions. BOLD responses were measured as subjects watched video clips showing different intensities of pain expression and, after a variable delay, either expressed the amount of pain they perceived in the clips (pain task), or imitated the facial movements (movement task). In the pain task condition, pain coding involved overlapping activation across observation and execution in the anterior cingulate cortex, supplementary motor area, inferior frontal gyrus/anterior insula, and the inferior parietal lobule, and a pain-related increase (pain vs. neutral) in the anterior cingulate cortex/supplementary motor area, the right inferior frontal gyrus, and the postcentral gyrus. The ‘mirroring’ response was stronger in the inferior frontal gyrus and middle temporal gyrus/superior temporal sulcus during the pain task, and stronger in the inferior parietal lobule in the movement task. These results strongly suggest that while motor mirroring may contribute to the perception of pain expressions in others, interpreting these expressions in terms of pain content draws more heavily on networks involved in the perception of affective meaning.     

Peripheral Nerve Injury Is Associated with Chronic,Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.     

Somatotopic representation of action words in human motor and premotor cortex

Since the early days of research into language and the brain, word meaning was assumed to be processed in specific brain regions, which most modern neuroscientists localize to the left temporal lobe. Here we use event-related fMRI to show that action words referring to face, arm, or leg actions (e.g., to lick, pick, or kick), when presented in a passive reading task, differentially activated areas along the motor strip that either were directly adjacent to or overlapped with areas activated by actual movement of the tongue, fingers, or feet. These results demonstrate that the referential meaning of action words has a correlate in the somatotopic activation of motor and premotor cortex. This rules out a unified "meaning center" in the human brain and supports a dynamic view according to which words are processed by distributed neuronal assemblies with cortical topographies that reflect word semantics.     

Dissociation of motor task-induced cortical excitability and pain perception changes in healthy volunteers

Background

There is evidence that interventions aiming at modulation of the motor cortex activity lead to pain reduction. In order to understand further the role of the motor cortex on pain modulation, we aimed to compare the behavioral (pressure pain threshold) and neurophysiological effects (transcranial magnetic stimulation (TMS) induced cortical excitability) across three different motor tasks.

Methodology/Principal Findings

Fifteen healthy male subjects were enrolled in this randomized, controlled, blinded, cross-over designed study. Three different tasks were tested including motor learning with and without visual feedback, and simple hand movements. Cortical excitability was assessed using single and paired-pulse TMS measures such as resting motor threshold (RMT), motor-evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP). All tasks showed significant reduction in pain perception represented by an increase in pressure pain threshold compared to the control condition (untrained hand). ANOVA indicated a difference among the three tasks regarding motor cortex excitability change. There was a significant increase in motor cortex excitability (as indexed by MEP increase and CSP shortening) for the simple hand movements.

Conclusions/Significance

Although different motor tasks involving motor learning with and without visual feedback and simple hand movements appear to change pain perception similarly, it is likely that the neural mechanisms might not be the same as evidenced by differential effects in motor cortex excitability induced by these tasks. In addition, TMS-indexed motor excitability measures are not likely good markers to index the effects of motor-based tasks on pain perception in healthy subjects as other neural networks besides primary motor cortex might be involved with pain modulation during motor training.     

Alteration of neural activity and neuroinflammatory factors in the insular cortex of mice with corneal neuropathic pain

Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs-fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low-frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real-time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c-Fos (p < 0.001), brain-derived neurotrophic factor (p < 0.01), TNF-α, IL-6, and IL-1β (p < 0.05). In contrast, IL-10 levels (p < 0.05) decreased in the dry eye group. DED-induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin-B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye-related corneal neuropathic pain.     

Functional Cortical Hubs in the Eyes-Closed Resting Human Brain from an Electrophysiological Perspective Using Magnetoencephalography

It is not clear whether specific brain areas act as hubs in the eyes-closed (EC) resting state, which is an unconstrained state free from any passive or active tasks. Here, we used electrophysiological magnetoencephalography (MEG) signals to study functional cortical hubs in 88 participants. We identified several multispectral cortical hubs. Although cortical hubs vary slightly with different applied measures and frequency bands, the most consistent hubs were observed in the medial and posterior cingulate cortex, the left dorsolateral superior frontal cortex, and the left pole of the middle temporal cortex. Hubs were characterized as connector nodes integrating EC resting state functional networks. Hubs in the gamma band were more likely to include midline structures. Our results confirm the existence of multispectral cortical cores in EC resting state functional networks based on MEG and imply the existence of optimized functional networks in the resting brain.     

Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline on the incidence of delayed postherpetic pain in mice

The inoculation of mice with herpes simplex virus type-1 (HSV-1) causes herpes zoster-like skin lesions and pain-related responses (tactile allodynia and mechanical hyperalgesia) from day 5 after inoculation. Skin lesions completely heal by day 15 after inoculation, but about half of mice with acute herpetic pain show pain-related responses long after the lesions heal. Using this mouse model, we examined the effects of repeated administration of gabapentin and amitriptyline on the acute herpetic pain and the incidence of postherpetic pain. Gabapentin and amitriptyline were administered three times daily from day 5 to 11 after inoculation. Postherpetic pain-related responses were assessed on day 30 after inoculation. Gabapentin (10-100 mg/kg) produced the dose-dependent inhibition of acute herpetic pain-related responses. This medication produced marked reduction in the incidence of delayed postherpetic pain and the dose of 100 mg/kg produced the complete inhibition. Amitriptyline (10 mg/kg) did not affect the acute pain-related responses in the initial 3- and 2-day periods and then gradually inhibited them. This dosage produced a substantial but non-significant decrease in the incidence of postherpetic pain-related responses. Amitriptyline (1 and 3 mg/kg) was without effects on acute herpetic and postherpetic pain-related responses. The results strongly support the idea that the severity of the acute herpetic pain is a risk factor of postherpetic neuralgia. It may be worth testing the effects of gabapentin on acute herpetic pain and the incidence of postherpetic neuralgia in human subjects.     

Cerebral control of face,jaw, and tongue movements in awake cats: Changes in regional cerebral blood flow during lateral feeding

Mastication is achieved by cooperation among facial, masticatory, and lingual muscles. However, cortical control in cats for the masticatory performance is processed by two systems: facial movement processed by facial SI (the first somatosensory cortex), area C, and area M (motor areas), and jaw and tongue movements performed by intraoral SI, masticatory area, and area P (motor area). In particular, outputs from area P organized in the corticobulbar tract are projected bilaterally in the brainstem. In this present study, the aim is to explore changes in the regional cerebral blood flow (rCBF) in the facial SI, area M, and area P during trained lateral feeding (licking or chewing from the right or left side) of milk, fish paste, and small dry fish. The rCBF in area M showed contralateral dominance, and rCBF in area P during chewing or licking from the right or left side was almost the same value. Furthermore, activities of genioglossus and masseter muscles in the left side showed almost the same values during licking of milk and of fish paste, and chewing of small dry fish during lateral feeding. These findings suggest that the cortical process for facial, jaw, and tongue movements may be regulated by the contralateral dominance of area M and the bilateral one of area P.     

Cerebral control of face, jaw, and tongue movements in awake cats: changes in regional cerebral blood flow during lateral feeding

Mastication is achieved by cooperation among facial, masticatory, and lingual muscles. However, cortical control in cats for the masticatory performance is processed by two systems: facial movement processed by facial SI (the first somatosensory cortex), area C, and area M (motor areas), and jaw and tongue movements performed by intraoral SI, masticatory area, and area P (motor area). In particular, outputs from area P organized in the corticobulbar tract are projected bilaterally in the brainstem. In this present study, the aim is to explore changes in the regional cerebral blood flow (rCBF) in the facial SI, area M, and area P during trained lateral feeding (licking or chewing from the right or left side) of milk, fish paste, and small dry fish. The rCBF in area M showed contralateral dominance, and rCBF in area P during chewing or licking from the right or left side was almost the same value. Furthermore, activities of genioglossus and masseter muscles in the left side showed almost the same values during licking of milk and of fish paste, and chewing of small dry fish during lateral feeding. These findings suggest that the cortical process for facial, jaw, and tongue movements may be regulated by the contralateral dominance of area M and the bilateral one of area P.     

Levodopa Effects on Hand and Speech Movements in Patients with Parkinson’s Disease: A fMRI Study

Levodopa (L-dopa) effects on the cardinal and axial symptoms of Parkinson’s disease (PD) differ greatly, leading to therapeutic challenges for managing the disabilities in this patient’s population. In this context, we studied the cerebral networks associated with the production of a unilateral hand movement, speech production, and a task combining both tasks in 12 individuals with PD, both off and on levodopa (L-dopa). Unilateral hand movements in the off medication state elicited brain activations in motor regions (primary motor cortex, supplementary motor area, premotor cortex, cerebellum), as well as additional areas (anterior cingulate, putamen, associative parietal areas); following L-dopa administration, the brain activation profile was globally reduced, highlighting activations in the parietal and posterior cingulate cortices. For the speech production task, brain activation patterns were similar with and without medication, including the orofacial primary motor cortex (M1), the primary somatosensory cortex and the cerebellar hemispheres bilaterally, as well as the left- premotor, anterior cingulate and supramarginal cortices. For the combined task off L-dopa, the cerebral activation profile was restricted to the right cerebellum (hand movement), reflecting the difficulty in performing two movements simultaneously in PD. Under L-dopa, the brain activation profile of the combined task involved a larger pattern, including additional fronto-parietal activations, without reaching the sum of the areas activated during the simple hand and speech tasks separately. Our results question both the role of the basal ganglia system in speech production and the modulation of task-dependent cerebral networks by dopaminergic treatment.     

Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber)

In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes “normal” mammalian nociception.     

Cortical correlates of perception and suppression of electrically induced pain

Two neuroimaging studies using fMRI were conducted in order to assess the cortical processes involved in the perception and suppression of pain. In the first study, 15 healthy subjects were stimulated with variable intensities of electrical pulses during a discrimination task. In the second study, the same subjects had to try to suppress the feeling of pain during tonic stimulation. The discrimination task resulted in cortical activation of contralateral SI, corresponding in extent to the intensity of the stimulus. Activation of contralateral operculum/posterior insula (SII) and non-dominant dorsolateral prefrontal cortex (DLPFC) with non-painful stimuli changed to activations of non-dominant anterior insula upon painful stimulation. In the second study, all subjects succeeded in suppressing the feeling of pain during previously painful levels of stimulation. During this suppression task, activations changed from anterior to posterior insula; also there was a suppression of activity in the anterior cingulated cortex (ACC) and caudate nucleus. Subjects seem to be able to suppress to a certain degree the feeling of pain under constant (and previously painful) stimulation. The cortical correlate seems to be a shift of cerebral activation from anterior to posterior right insula and a suppression of activity in the ACC and caudate nucleus.