Gender differences in brain activity evoked by muscle and cutaneous pain: a retrospective study of single-trial fMRI data

Gender greatly influences pain processing. Not only do females display greater pain sensitivity, many chronic pain conditions affect females more than males. Although gender-based differences in pain sensitivity may be related to cultural and social factors, animal studies also reveal gender differences in pain sensitivity, suggesting that physiological factors may contribute to differences in the processing of pain in males and females. It has been recently reported that noxious cutaneous heat stimuli evoke gender-based differences in activity in some brain regions. Given that most chronic pain conditions, including those with gender bias are of "deep" origin (e.g. arising in muscle, joints or viscera), we investigated whether gender differences also exist in the central processing of muscle pain. In 24 healthy adults we used functional magnetic resonance imaging (fMRI) to measure signal intensity changes during muscle and cutaneous pain induced by intramuscular and subcutaneous injections of hypertonic saline, respectively. In addition to activating the "pain neuromatrix", i.e. cingulate, insular, somatosensory and cerebellar cortices, both muscle pain and cutaneous pain evoked gender-based differences in the mid-cingulate cortex, dorsolateral prefrontal cortex, hippocampus and cerebellar cortex. These differences may reflect differences in emotional processing of noxious information in men and women and may underlie the gender bias that exists in many chronic pain conditions.     

Somatotopic organization of human somatosensory cortices for pain: a single trial fMRI study

The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. To investigate the somatotopic organization of the nociceptive system, we applied Thulium-YAG-laser evoked pain stimuli, which have no concomitant tactile component, to the dorsum of the left hand and foot in randomized order. We used single-trial functional magnetic resonance imaging (fMRI) to assess differential hemodynamic responses to hand and foot stimulation for the group and in a single subject approach. The primary somatosensory cortex (SI) shows a clear somatotopic organization ipsi- and contralaterally to painful stimulation. Furthermore, a differential representation of hand and foot stimulation appeared within the contralateral opercular--insular region of the secondary somatosensory cortex (SII). This result provides evidence that both SI and SII encode spatial information of nociceptive stimuli without additional information from the tactile system and highlights the concept of a redundant representation of basic discriminative stimulus features in human somatosensory cortices, which seems adequate in view of the evolutionary importance of pain perception.     

Subcortical structures involved in pain processing: evidence from single-trial fMRI

Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single-trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium-YAG (yttrium-aluminum-granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right- and left-sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.     

基于右侧脑岛功能连接性的哮喘针刺fMRI研究

目的 观察哮喘患者与健康人群右侧脑岛各亚区与全脑的功能连接性(functional connectivity,FC)差异,以及电针干预前后,哮喘患者右侧脑岛FC值的变化.材料与方法 招募符合标准的健康对照组受试者与哮喘组患者各18名,采集两组受试者基线期静息态功能磁共振数据.哮喘组患者电针大椎、风门、肺俞30 min后...     

Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex

The question whether pain encoding in the human insula shows some somatotopic organization is still pending. We studied 142 patients undergoing depth stereotactic EEG (SEEG) exploration of the insular cortex for pre-surgical evaluation of epilepsy. 472 insular electrical stimulations were delivered, of which only 49 (10.5%) elicited a painful sensation in 38 patients (27%). Most sites where low intensity electric stimulation produced pain, without after-discharge or concomitant visually detectable change in EEG activity outside the insula, were located in the posterior two thirds of the insula. Pain was located in a body area restricted to face, upper limb or lower limb for 27 stimulations (55%) and affected more than one of these regions for all others. The insular cortex being oriented parallel to the medial sagittal plane we found no significant difference between body segment representations in the medio-lateral axis. Conversely a somatotopic organization of sites where stimulation produced pain was observed along the rostro-caudal and vertical axis of the insula, showing a face representation rostral to those of upper and lower limbs, with an upper limb representation located above that of the lower limb. These data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.     

Time-dependent changes in learning audiovisual associations: a single-trial fMRI study

Functional imaging studies of learning and memory have primarily focused on stimulus material presented within a single modality (see review by Gabrieli, 1998, Annu. Rev. Psychol. 49: 87-115). In the present study we investigated mechanisms for learning material presented in visual and auditory modalities, using single-trial functional magnetic resonance imaging. We evaluated time-dependent learning effects under two conditions involving presentation of consistent (repeatedly paired in the same combination) or inconsistent (items presented randomly paired) pairs. We also evaluated time-dependent changes for bimodal (auditory and visual) presentations relative to a condition in which auditory stimuli were repeatedly presented alone. Using a time by condition analysis to compare neural responses to consistent versus inconsistent audiovisual pairs, we found significant time-dependent learning effects in medial parietal and right dorsolateral prefrontal cortices. In contrast, time-dependent effects were seen in left angular gyrus, bilateral anterior cingulate gyrus, and occipital areas bilaterally. A comparison of paired (bimodal) versus unpaired (unimodal) conditions was associated with time-dependent changes in posterior hippocampal and superior frontal regions for both consistent and inconsistent pairs. The results provide evidence that associative learning for stimuli presented in different sensory modalities is supported by neural mechanisms similar to those described for other kinds of memory processes. The involvement of posterior hippocampus and superior frontal gyrus in bimodal learning for both consistent and inconsistent pairs supports a putative function for these regions in associative learning independent of sensory modality.     

Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula

Psychological factors play a major role in exacerbating chronic pain. Effective self-management of pain is often hindered by inaccurate beliefs about the nature of pain which lead to a high degree of emotional reactivity. Probabilistic models of perception state that greater confidence (certainty) in beliefs increases their influence on perception and behavior. In this study, we treat confidence as a metacognitive process dissociable from the content of belief. We hypothesized that confidence is associated with anticipatory activation of areas of the pain matrix involved with top-down modulation of pain. Healthy volunteers rated their beliefs about the emotional distress that experimental pain would cause, and separately rated their level of confidence in this belief. Confidence predicted the influence of anticipation cues on experienced pain. We measured brain activity during anticipation of pain using high-density EEG and used electromagnetic tomography to determine neural substrates of this effect. Confidence correlated with activity in right anterior insula, posterior midcingulate and inferior parietal cortices during the anticipation of pain. Activity in the right anterior insula predicted a greater influence of anticipation cues on pain perception, whereas activity in right inferior parietal cortex predicted a decreased influence of anticipatory cues. The results support probabilistic models of pain perception and suggest that confidence in beliefs is an important determinant of expectancy effects on pain perception.     

Attention to aversive emotion and specific activation of the right insula and right somatosensory cortex

The evaluation of emotional stimuli is based on different levels of information processing, ranging from rather automatic processes to focused attention to the emotional relevance of stimuli. The role of specific brain areas for these processes is a matter of debate. In this event-related fMRI study, we varied the information processing mode of participants exposed to aversive and neutral pictures. Based on four different tasks, participants' attentional focus onto the emotional quality of the stimuli and the own emotional involvement was increased systematically across tasks. Regardless of task, stronger activation to threatening vs. neutral pictures was found in several regions such as the amygdala, anterior insula, anterior cingulate cortex, primary somatosensory cortex and medial prefrontal cortex. However, there was a parametric increase of activation with increasing attention to one's own emotion specifically in the right posterior insula and right primary and secondary somatosensory cortex, i.e. in areas implicated in self-awareness of a person's own body. These findings are in accordance with theories suggesting a crucial role of the perception of bodily states for emotional experiences.     

Middle short gyrus of the insula implicated in pain processing

Different lines of evidence have suggested an involvement of the insular cortex in pain processing. Direct electrical stimulation (ES) of the human insular cortex during surgical procedure sometimes induces painful sensations and painful stimuli induce activation of the insular cortex as shown by functional neuroimaging. Invasive evaluation of epileptic patients by deep brain stereotactically implanted electrodes provides an opportunity to analyze responses induced by ES of the insular cortex in awake and fully conscious patients. For this study, we included 25 patients suffering from drug refractory focal epilepsy with at least one electrode stereotactically implanted in the insular cortex using an oblique approach (transfrontal or transparietal). Out of the 83 responses induced by insular ES, eight (9.6%) were reported by five patients as painful sensations. Four were restricted to the cephalic region and four were felt on the ipsilateral or bilateral upper limbs, the shoulders and the trunk (pinprick sensations). The eight stimulation sites were anatomically localized via image fusion between pre-implantation 3D MRI and post-implantation 3D CT scans revealing the electrode contacts. All sites inducing painful sensations were restricted to the upper portion of the middle short gyrus of the insula. The findings of this study suggest that middle short gyrus is involved in the processing of pain-producing stimuli.     

Unpleasant odors increase pain processing in a patient with neuropathic pain: psychophysical and fMRI investigation

A 49-year old man with neuropathic pain in his right elbow, wrist and digits III-V of his hand reported that certain odors increased his pain by superimposing an electric shock-like pain to his already existing pain. Psychophysical testing revealed that the best predictor of pain exacerbation was odor unpleasantness. Functional magnetic resonance imaging (fMRI) showed increased activation following an unpleasant odor in pain related areas, including the thalamus, amygdala, insular and anterior cingulate cortices, with similar trends in primary somatosensory cortex hand/arm area. The increased pain and associated neural activations in response to unpleasant odors may be related to the phenomenon of synesthesia, to a rewiring of olfactory pathways onto pain pathways mimicking synesthesia or, to activation of the sympathetic nervous system.     

Human secondary somatosensory cortex is involved in the processing of somatosensory rare stimuli: an fMRI study

In the human somatosensory system, the contralateral primary somatosensory cortex (SI) is presumed to process and encode type and intensity of the sensory inputs, whereas the bilateral secondary somatosensory cortex (SII) is believed to perform higher order functions including sensorimotor integration, integration of information from the two body halves, attention, learning and memory. In this fMRI study we investigated the effect of attention on the activation of SI and SII, as induced by nonpainful and painful rare deviant electric stimuli during somatosensory oddball tasks. The working hypothesis is of stronger effects of attention on SII with respect to SI. Four runs were acquired according to an oddball scheme. Frequent nonpainful electrical stimuli were delivered to the ulnar nerve at motor threshold, whereas rare/deviant stimuli were delivered to median nerve in four conditions (one condition per run): nonpainful, painful, counting nonpainful, and counting painful. Results showed a statistically significant fMRI activation in bilateral SII but not in contralateral SI when the rare/deviant median nerve stimuli were delivered at nonpainful and painful levels as well as at the two levels of attention considered (i.e., associated with counting and non-counting tasks). Furthermore, fMRI activation in SII did not differ across the different levels of stimulus intensity (nonpainful, painful) and attention (non-counting, counting). These results corroborate the notion that SII is the target of independent pathways for the processing and integration of nonpainful and painful somatosensory stimuli salient for further high-order elaborations.     

An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients

Previous human imaging studies have revealed a network of brain regions involved in the processing of allodynic pain; this includes prefrontal areas, insula, cingulate cortex, primary and secondary somatosensory cortices and parietal association areas. In this study, the neural correlates of the perceived intensity of allodynic pain in neuropathic pain patients were investigated. In eight patients, dynamic mechanical allodynia was provoked and brain responses recorded using functional magnetic resonance imaging (fMRI). Voxels in which the magnitude of fMRI signal correlated linearly with the ratings of allodynic pain across the group were determined in a whole brain analysis using a general linear model. To ensure that activation reflected only allodynic pain ratings, a nuisance variable containing ratings of ongoing pain was included in the analysis. We found that the magnitude of activation in the caudal anterior insula (cAI) correlates with the perceived intensity of allodynic pain across subjects, independent of the level of ongoing pain. However, the peak of activation in the allodynic condition was located in the rostral portion (rAI). This matches the representation of other clinical pain syndromes, confirmed by a literature review. In contrast, experimental pain in healthy volunteers resides predominantly in the cAI, as shown by the same literature review. Taken together, our data and the literature review suggest a functional segregation of anterior insular cortex.     

The human parietal cortex is involved in spatial processing of tongue movement-an fMRI study

The human tongue is so sensitive and dexterous that spatial representations of the inside of the oral cavity for the tongue movement are naturally expected to exist. In the present study, we examined the brain activity associated with spatial processing during tongue movements using a functional magnetic resonance imaging technique. Twenty-four normal subjects participated in the study, which consisted of a periodic series of three blocks; resting of the tongue, tongue movement (pressing the inside of a tooth with the tip of the tongue), and tongue retraction. The cerebral fields of activation during the tongue movement to the left and right side relative to those during rest were found in the primary sensorimotor area and supplementary motor area bilaterally, and in the left inferior parietal lobule (IPL). The activation areas during the tongue retraction relative to those during rest were almost the same, except that activation in the left IPL was not observed. The fields of activation during tongue movement to the left and right side relative to those during tongue retraction were found bilaterally in the dorsal premotor area, superior parietal lobule (SPL), and the IPL. The results indicate that the bilateral SPL and IPL were specifically involved in the processing for human tongue movement. Although no significant laterality was observed, the left parietal area tended to show greater activation in statistical values and area than the right parietal area, thus indicating the possibility that this processing for human tongue movement is related to that for language.     

An fMRI study on the acute effects of exercise on pain processing in trained athletes

Endurance exercise is known to promote sustained antinociceptive effects, and there is evidence that the reduction of pain perception mediated by exercise is driven by central opioidergic neurotransmission. To directly investigate the involved brain areas and the underlying neural mechanisms in humans, thermal heat-pain challenges were applied to 20 athletes during 4 separate functional magnetic resonance imaging (fMRI) scans, i.e., before and after 2 hours of running (exercise condition) and walking (control condition), respectively. Imaging revealed a reproducible pattern of distributed pain-related activation in all 4 conditions, including the mesial and lateral pain systems, and the periaqueductal gray (PAG) as a key region of the descending antinociceptive pathway. At the behavioral level, running as compared with walking decreased affective pain ratings. The influence of exercise on pain-related activation was reflected in a significant time × treatment interaction in the PAG, along with similar trends in the pregenual anterior cingulate cortex and the middle insular cortex, where pain-induced activation levels were elevated after walking, but decreased or unchanged after running. Our findings indicate that enhanced reactive recruitment of endogenous antinociceptive mechanisms after aversive repeated pain exposure is attenuated by exercise. The fact that running, but not walking, reproducibly elevated β-endorphin levels in plasma indicates involvement of the opioidergic system in exercise. This may argue for an elevated opioidergic tone in the brain of athletes, mediating antinociceptive mechanisms. Our findings provide the first evidence using functional imaging to support the role of endurance exercise in pain modulation.     

Cerebral processing of pain in school-aged children with neonatal nociceptive input: An exploratory fMRI study

Due to maturation-related plasticity of the developing nociceptive system, neonatal nociceptive input, as induced by medical procedures in the neonatal intensive care unit (NICU), may cause long-term alterations in pain processing. Using functional magnetic resonance imaging, this study investigated the cerebral pain response in school-aged children and adolescents (11–16 yr) with experience in a NICU after preterm (?31 weeks gestational age, N = 9) or fullterm birth (?37 weeks gestational age, N = 9) as compared to fullterm control children without early hospitalization (N = 9). NICU children had been recruited retrospectively among former patients of the Children’s University Hospital Mannheim. All children had participated in our previous studies 46 and 49 entailing psychophysical measurements. In response to tonic (30 s) heat stimuli of individually adjusted moderate pain intensity, which were of comparable temperature across groups, the preterm but not the fullterm NICU children exhibited significant activations in a number of brain regions (thalamus, anterior cingulate cortex, cerebellum, basal ganglia, and periaquaeductal gray) that were not significantly activated in controls. The preterms showed significantly higher activations than controls in primary somatosensory cortex, anterior cingulate cortex, and insula. This exaggerated brain response was pain-specific and was not observed during non-painful warmth stimulation. Preterms’ continuous pain ratings revealed a tendency for increased sensitization within and a lack of habituation across trials. In highly vulnerable children such as preterms, neonatal nociceptive input may, aside from other neurodevelopmental consequences, persistently increase the gain within pain pathways.     

Altered functional connectivity between the insula and the cingulate cortex in patients with temporomandibular disorder: a pilot study

Background.— Among the most common chronic pain conditions, yet poorly understood, are temporomandibular disorders (TMDs), with a prevalence estimate of 3‐15% for Western populations. Although it is increasingly acknowledged that central nervous system mechanisms contribute to pain amplification and chronicity in TMDs, further research is needed to unravel neural correlates that might abet the development of chronic pain. Objective.— The insular cortex (IC) and cingulate cortex (CC) are both critically involved in the experience of pain. The current study sought specifically to investigate IC–CC functional connectivity in TMD patients and healthy controls (HCs), both during resting state and during the application of a painful stimulus. Methods.— Eight patients with TMD, and 8 age‐ and sex‐matched HCs were enrolled in the present study. Functional magnetic resonance imaging data during resting state and during the performance of a pressure pain stimulus to the temple were acquired. Predefined seed regions were placed in the IC (anterior and posterior insular cortices) and the extracted signal was correlated with brain activity throughout the whole brain. Specifically, we were interested whether TMD patients and HCs would show differences in IC–CC connectivity, both during resting state and during the application of a painful stimulus to the face. Results.— As a main finding, functional connectivity analyses revealed an increased functional connectivity between the left anterior IC and pregenual anterior cingulate cortex (ACC) in TMD patients, during both resting state and applied pressure pain. Within the patient group, there was a negative correlation between the anterior IC–ACC connectivity and clinical pain intensity as measured by a visual analog scale. Conclusions.— Since the pregenual region of the ACC is critically involved in antinociception, we hypothesize that an increase in anterior IC–ACC connectivity is indicative of an adaptation of the pain modulatory system early in the chronification process. (Headache 2012;52:441‐454)     

Amplitopicity of the human auditory cortex: an fMRI study

Whereas specialized frequency-encoding patterns in the human auditory cortex are generally accepted, termed tonotopicity, a similar principle of intensity encoding--amplitopicity--is debated controversially. This functional magnetic resonance imaging study describes the relationship of the activation volume and the spatial distribution of activated clusters under different sound pressure levels (SPL) across the temporal plane including the transverse temporal gyrus (TTG). Nine healthy subjects with no hearing deficiencies were investigated using an echo-planar imaging technique at 1.5 T. A boxcar stimulation paradigm was applied with a 5-Hz pulsed sine tone of 1000 Hz frequency at three SPLs of 70, 82, and 90 dB. Linear cross-correlation analysis (correlation coefficient > 0.3 corresponding to P < 0.08) of the functional data set revealed bilateral BOLD response within the auditory cortex of the nine subjects with moderate increase of activation volume for higher sound pressure levels. With increasing sound pressure a two-dimensional drift of cortical activation was observed (a) from the ventral to the dorsal edge and (b) from lateral to medial parts of TTG. This latero-medial drift therefore mimics the well-accepted principle of tonotopy for frequency-encoding neurons. This study demonstrates the existence of an amplitopic pattern of intensity-encoding neuronal clusters that in part resembles the tonotopic distribution of frequency-encoding neurons. This finding has to be integrated into the understanding of the auditory organization for the interpretation of higher auditory functions such as sound perception or speech.     

Somatotopic organization of the ventral and dorsal finger surface representations in human primary sensory cortex evaluated by magnetoencephalography.

Cortical reorganization of the subtly differentiated hand map after peripheral nerve injury might be better understood if there was a topographic conception of the homuncular representation of the dorsal finger surfaces in humans, in addition to the well-established sequential rostrocaudal array of the ventral finger aspects in cortical area 3b. In the present magnetoencephalographic study, tactile pneumatic stimulation was delivered to the fingertip and to the ventral and dorsal proximal phalanx of each digit of the dominant hand in 20 right-handed volunteers. Source localization of equivalent current dipoles underlying the recorded somatosensory evoked magnetic field was performed using a Cartesian coordinate system established by the anatomical landmarks nasion and preauricular points. Of the first major peak of each somatosensory evoked field, the region with the maximum field power (root-mean-square across channels) was selected for source reconstruction. Analysis of variance for repeated measures yielded significant results with respect to the arrangement of digits along the vertical coordinate axis, demonstrating a sequential array from the most inferiorly located D1 to the most superiorly located D5 for all different stimulus positions. This is the first study providing evidence for a sequential topographical arrangement of not only the ventral but also the dorsal surface representations of the individual digits in the human somatosensory cortex. The study contributes to a better understanding of the somatosensory hand representation in human primary cortex and provides useful information with regard to cortical plasticity studies in patients with peripheral nerve injuries at the upper extremity.     

Adults and children processing music: an fMRI study

The present study investigates the functional neuroanatomy of music perception with functional magnetic resonance imaging (fMRI). Three different subject groups were investigated to examine developmental aspects and effects of musical training: 10-year-old children with varying degrees of musical training, adults without formal musical training (nonmusicians), and adult musicians. Subjects made judgements on sequences that ended on chords that were music-syntactically either regular or irregular. In adults, irregular chords activated the inferior frontal gyrus, orbital frontolateral cortex, the anterior insula, ventrolateral premotor cortex, anterior and posterior areas of the superior temporal gyrus, the superior temporal sulcus, and the supramarginal gyrus. These structures presumably form different networks mediating cognitive aspects of music processing (such as processing of musical syntax and musical meaning, as well as auditory working memory), and possibly emotional aspects of music processing. In the right hemisphere, the activation pattern of children was similar to that of adults. In the left hemisphere, adults showed larger activations than children in prefrontal areas, in the supramarginal gyrus, and in temporal areas. In both adults and children, musical training was correlated with stronger activations in the frontal operculum and the anterior portion of the superior temporal gyrus.     

Engagement of the prefrontal cortex in representational momentum: an fMRI study

Behavioral studies have identified a robust phenomenon that an observer's memory of the final position of a moving target is shifted a little further in its motion direction, which is usually called representational momentum (RM). However, the neural substrates underlying RM are poorly understood. The current study measured hemodynamic responses in association with RM using functional magnetic resonance imaging (fMRI). Two experiments using block and event-related designs, respectively, were conducted in which subjects compared the orientation of a probe rectangle with the remembered orientation of the final inducing figures in a set of rotating rectangles. Both experiments showed that, relative to the control task in which behavioral data did not show RM effects, RM task induced stronger activation in the prefrontal cortex. However, no activation was found in MT/MST complex in association with RM. The fMRI results suggest that RM may not simply reflect implicit motion perception and high level cognitive mechanisms underpinned by the prefrontal cortex may be involved in the RM effect.