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1.  Comparison of anterior cingulate vs. insular cortex as targets for real-time fMRI regulation during pain stimulation 
Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback allows learning voluntary control over specific brain areas by means of operant conditioning and has been shown to decrease pain perception. To further increase the effect of rt-fMRI neurofeedback on pain, we directly compared two different target regions of the pain network, notably the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC). Participants for this prospective study were randomly assigned to two age-matched groups of 14 participants each (7 females per group) for AIC and ACC feedback. First, a functional localizer using block-design heat pain stimulation was performed to define the pain-sensitive target region within the AIC or ACC. Second, subjects were asked to down-regulate the BOLD activation in four neurofeedback runs during identical pain stimulation. Data analysis included task-related and functional connectivity analysis. At the behavioral level, pain ratings significantly decreased during feedback vs. localizer runs, but there was no difference between AIC and ACC groups. Concerning neuroimaging, ACC and AIC showed consistent involvement of the caudate nucleus for subjects that learned down-regulation (17/28) in both task-related and functional connectivity analysis. The functional connectivity toward the caudate nucleus is stronger for the ACC while the AIC is more heavily connected to the ventrolateral prefrontal cortex. Consequently, the ACC and AIC are suitable targets for real-time fMRI neurofeedback during pain perception as they both affect the caudate nucleus, although functional connectivity indicates that the direct connection seems to be stronger with the ACC. Additionally, the caudate, an important area involved in pain perception and suppression, could be a good rt-fMRI target itself. Future studies are needed to identify parameters characterizing successful regulators and to assess the effect of repeated rt-fMRI neurofeedback on pain perception.
PMCID: PMC4191436  PMID: 25346666
real-time fMRI neurofeedback; realtime fMRI; pain; anterior cingulate cortex (ACC); anterior insular cortex; insular cortex
2.  Altered cognition-related brain activity and interactions with acute pain in migraine 
NeuroImage : Clinical  2015;7:347-358.
Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain–cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain–task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.
•Migraine patients had blunted task-related deactivations in DLPFC, aMCC, and cerebellum in the absence of pain, vs. controls.•Unlike in healthy controls, these task-related deactivations were not modulated by the presence of an acute pain stimulus.•Migraine patients had less task-related activity during pain, compared to controls.•Acute pain disturbs cognitive processing more in patients than controls.
PMCID: PMC4297882  PMID: 25610798
fMRI; Pain–cognition interaction; Chronic pain; Cognitive networks; Posterior insula; Dorsolateral prefrontal cortex
3.  An fMRI study of unconditioned responses in post-traumatic stress disorder 
Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response.
Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD.
Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased.
PMCID: PMC3384234  PMID: 22738227
Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in AN individuals, such as the insula.
Functional Magnetic Resonance Imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in ten healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli.
REC AN compared to CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN subjects.
REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from anorexia nervosa.
PMCID: PMC3507323  PMID: 22836447
Anorexia; insula; pain; anticipation; homeostasis; fmri; interoception; alexithymia; eating disorders; dorsolateral prefrontal
5.  Does pain necessarily have an affective component? Negative evidence from blink reflex experiments 
The experience of pain can be described using two dimensions – sensory and affective-motivational – of which the affective-motivational component is strongly modulated by context and the cognitive appraisal of pain. In pain research, the sensory component is commonly represented by ratings of pain intensity, while the affective component is represented by ratings of pain unpleasantness. However, there is evidence to suggest that test subjects tend to judge pain intensity different from unpleasantness whenever separate scales for both dimensions are presented concurrently. This study used a startle reflex as an objective measure of affective response to stimuli of varying intensities to determine whether the affective component can be abolished when predictable stimulation paradigms are applied.
Experimental pain research has shown that the affective component of pain is influenced strongly by situational characteristics; affective pain processing appears to be particularly pronounced in situations that provoke a feeling of uncertainty and uncontrollability.
To determine whether the affective component of pain can be completely abolished if a ‘safe’, particularly predictable stimulation paradigm is applied.
Forty healthy volunteers recruited at the University of Bamberg (Bamberg, Germany) were assessed in two experiments. Tonic contact heat stimuli staged in three intensities (warmth, heat and pain) relative to the individual pain threshold was applied; these were predictable with regard to intensity and course, and the subjects had easy access to control. The startle reflex was assessed as an objective measure of affective response. In addition, the subjects provided unpleasantness ratings. To compare these results to a gold standard for affective response, affective pictures taken from the International Affective Picture System were presented during temperature stimulation in the second experiment.
Both experiments showed no potentiation of the startle reflex under painful heat stimulation compared with the two nonpainful stimulus intensities (heat and warmth), although the painful stimulation was clearly rated as more unpleasant.
Results suggest that it is possible to develop a ‘safe’ noxious stimulus, which is rated as clearly unpleasant, but lacks physiological indication of negative affect. This divergence might be explained by subjective ratings being influenced by the instructions. The possibility of reducing the pain affect by suggesting ‘safety’ may be of therapeutic interest.
PMCID: PMC3299036  PMID: 22518363
Affective pain processing; Affective pictures; Startle; Thermal pain
6.  Emotional and autonomic consequences of spinal cord injury explored using functional brain imaging 
Brain : a journal of neurology  2005;129(Pt 3):718-728.
In health, emotions are integrated with autonomic bodily responses. Emotional stimuli elicit changes in somatic (including autonomic) bodily states, which feedback to influence the expression of emotional feelings. In patients with spinal cord injury (SCI), this integration of emotion and bodily arousal is partially disrupted, impairing both efferent generation of sympathetic responses and afferent sensory feedback of visceral state via the spinal cord. A number of theoretical accounts of emotion predict emotional deficits in SCI patients, particularly at the level of emotional feelings, yet evidence for such a deficit is equivocal. We used functional MRI (fMRI) and a basic emotional learning paradigm to investigate the expression of emotion-related brain activity consequent upon SC I. We scanned seven SCI patients and seven healthy controls during an aversive fear conditioning task. Subjects viewed randomized presentations of four angry faces. One of the faces (CS + arm) was associated with delivery of electrical shock to the upper arm on 50% of trials. This shock was painful to all subjects. A face of the same gender acted as a ‘safe’ control stimulus (CS − arm). In both control subjects and SCI patients, painful cutaneous stimulation of the arm evoked enhanced activity within components of a central pain matrix, including dorsal anterior cingulate, right insula and medial temporal lobe. However, SCI patients differed from controls in conditioning-related brain activity. SCI patients showed a relative enhancement of activity within dorsal anterior cingulate, periaqueductal grey matter (PAG) and superior temporal gyrus. Conversely, SCI patients showed relative attenuation of activity in subgenual cingulate, ventromedial prefrontal and posterior cingulate cortices to threat of painful arm stimulation (CS + arm > CS − arm). Our findings provide evidence for differences in emotion-related brain activity in SCI patients. We suggest that the observed functional abnormalities including enhanced anterior cingulate and PAG reflect central sensitization of the pain matrix, while decreased subgenual cingulate activity may represent a substrate underlying affective vulnerability in SCI patients consequent upon perturbation of autonomic control and afferent visceral representation. Together these observations may account for motivational and affective sequelae of SCI in some individuals.
PMCID: PMC2633768  PMID: 16330503
autonomic arousal; emotion; functional magnetic resonance; spinal cord injury
7.  Major Depressive Disorder is Associated with Altered Functional Brain Response During Anticipation and Processing of Heat Pain 
Archives of general psychiatry  2008;65(11):1275-1284.
Chronic pain and depression are highly comorbid conditions, yet little is known about the neurobiological basis of pain processing in major depressive disorder (MDD).
To examine the neural substrates underlying anticipation and processing of heat pain in a group of unmedicated young adults with current MDD.
Functional magnetic resonance neuroimaging (fMRI) data were collected during an event-related factorial experimental pain paradigm. Painful and non-painful heat stimuli were applied to the left volar forearm while different color shapes explicitly signaled the intensity of the upcoming stimulus.
University brain imaging center.
15 (12 F) young adults with current MDD and 15 (10F) healthy subjects with no history of MDD were recruited and matched for age and level of education. The Structured Clinical Interview for DSM-IV was administered to all participants by a board-certified psychiatrist.
Main Outcome measure
Between-group differences in blood oxygen level-dependent fMRI signal change to anticipation and processing of painful versus non-painful temperature stimuli.
MDD compared to healthy controls showed: (1) increased activation in right anterior insular region, dorsal anterior cingulate and right amygdala during anticipation of painful relative to non-painful stimuli, (2) increased activation in right amygdala and decreased activation in periaqueductal gray, rostral anterior cingulate and prefrontal cortices during painful stimulation relative to non-painful stimulation, and (3) in MDD subjects greater activation in the right amygdala during anticipation of pain was associated with greater levels of perceived helplessness.
These findings suggest that increased emotional reactivity during the anticipation of heat pain may lead to an impaired ability to modulate pain experience in MDD. Future studies should examine the degree to which altered functional brain response during anticipatory processing affects ability to modulate negative affective states in MDD, which is a core characteristic of this disorder.
PMCID: PMC2702160  PMID: 18981339
8.  Sustained deep-tissue pain alters functional brain connectivity 
Pain  2013;154(8):1343-1351.
Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically-relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, fronto-parietal control and default mode networks; SMN, SLN, DAN, FCN and DMN) was evaluated with functional-connectivity MRI, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable with no significant changes of subjects’ pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala, was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to inter-individual differences in pain sensitivity.
PMCID: PMC3700646  PMID: 23718988
somatosensory; sensorimotor network; salience network; dorsal attention network; fronto-parietal control network; and functional connectivity
9.  Human brain activity associated with painful mechanical stimulation to muscle and bone 
Journal of Anesthesia  2011;25(4):523-530.
The purpose of this study was to elucidate the central processing of painful mechanical stimulation to muscle and bone by measuring blood oxygen level-dependent signal changes using functional magnetic resonance imaging (fMRI).
Twelve healthy volunteers were enrolled. Mechanical pressure on muscle and bone were applied at the right lower leg by an algometer. Intensities were adjusted to cause weak and strong pain sensation at either target site in preliminary testing. Brain activation in response to mechanical nociceptive stimulation targeting muscle and bone were measured by fMRI and analyzed.
Painful mechanical stimulation targeting muscle and bone activated the common areas including bilateral insula, anterior cingulate cortex, posterior cingulate cortex, secondary somatosensory cortex (S2), inferior parietal lobe, and basal ganglia. The contralateral S2 was more activated by strong stimulation than by weak stimulation. Some areas in the basal ganglia (bilateral putamen and caudate nucleus) were more activated by muscle stimulation than by bone stimulation.
The putamen and caudate nucleus may have a more significant role in brain processing of muscle pain compared with bone pain.
PMCID: PMC3152719  PMID: 21633873
Pain; Muscle; Bone; Neuroimaging; fMRI
10.  Decreased frontal regulation during pain anticipation in unmedicated subjects with major depressive disorder 
Translational Psychiatry  2013;3(3):e239-.
Major depressive disorder (MDD) is characterized by impaired processing of negative information, possibly due to dysfunction in both, the bottom-up emotional network and top-down modulatory network. By acquiring functional magnetic resonance imaging (fMRI) on a pain-anticipation task, we tested the hypothesis that individuals with MDD would show increased negative biasing that may be associated with reduced frontal connectivity. Thirty-one (15 females) unmedicated young adults with current MDD and 22 (11 females) healthy subjects with no history of MDD were recruited. Groups did not differ significantly in age, race, level of education, marital status or gender distribution. fMRI data were collected during an event-related pain-anticipation paradigm, during which subjects were cued to anticipate painful heat stimuli of high or low intensity. All temperature stimuli were applied to each subject's left forearm. We found that relative to healthy comparison subjects, participants with MDD showed significantly stronger responses to high versus low pain anticipation within right ventral anterior insula (AI), but overlapping response within right dorsal AI, which correlated positively with the depression symptoms severity in the MDD group. Functional connectivity analyses showed increased functional connectivity between dorsal insula and posterior thalamus and decreased functional connectivity between dorsal insula and the right inferior frontal gyrus in the MDD compared with the non-MDD group. Our results demonstrate that unmedicated individuals with current MDD compared with healthy never-depressed subjects show both differential and overlapping response within AI during anticipation of pain. Furthermore, the overlapping insular response is less regulated by frontal brain systems and is more subservient to affective processing regions in the posterior thalamus in MDD. These results support and provide functional validation of the co-occurring enhanced ‘bottom-up' and attenuated ‘top-down' processing of salient, unpleasant emotional information in MDD.
PMCID: PMC3625914  PMID: 23481626
depression; emotion; fMRI; imaging; insula; modulation
11.  Decoding the perception of pain from fMRI using multivariate pattern analysis 
Neuroimage  2012;63(3):1162-1170.
Pain is known to comprise sensory, cognitive, and affective aspects. Despite numerous previous fMRI studies, however, it remains open which spatial distribution of activity is sufficient to encode whether a stimulus is perceived as painful or not. In this study, we analyzed fMRI data from a perceptual decision-making task in which participants were exposed to near-threshold laser pulses. Using multivariate analyses on different spatial scales, we investigated the predictive capacity of fMRI data for decoding whether a stimulus had been perceived as painful. Our analysis yielded a rank order of brain regions: during pain anticipation, activity in the periaqueductal gray (PAG) and orbitofrontal cortex (OFC) afforded the most accurate trial-by-trial discrimination between painful and non-painful experiences; whereas during the actual stimulation, primary and secondary somatosensory cortex, anterior insula, dorsolateral and ventrolateral prefrontal cortex, and OFC were most discriminative. The most accurate prediction of pain perception from the stimulation period, however, was enabled by the combined activity in pain regions commonly referred to as the ‘pain matrix’. Our results demonstrate that the neural representation of (near-threshold) pain is spatially distributed and can be best described at an intermediate spatial scale. In addition to its utility in establishing structure-function mappings, our approach affords trial-by-trial predictions and thus represents a step towards the goal of establishing an objective neuronal marker of pain perception.
Graphical abstract
► Subjects received a series of near-threshold pain stimuli while undergoing fMRI. ► We studied multivariate patterns of brain activity underlying pain perception. ► PAG, VLPFC, DLPFC, anterior insula, and OFC were highly predictive of pain. ► Yet the highest accuracies were afforded by combinations of these regions. ► This suggests that pain is encoded in a distributed network.
PMCID: PMC3532598  PMID: 22922369
Pain; Decoding; Support vector machine; Permutation test; Classification accuracy
12.  Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans 
Pain  1998;76(1-2):223-229.
The purpose of the present study was to determine whether gender differences exist in the forebrain cerebral activation patterns of the brain during pain perception. Accordingly, positron emission tomography (PET) with intravenous injection of H215O was used to detect increases in regional cerebral blood flow (rCBF) in normal right-handed male and female subjects as they discriminated differences in the intensity of innocuous and noxious heat stimuli applied to the left forearm. Each subject was instructed in magnitude estimation based on a scale for which 0 indicated ‘no heat sensation’; 7, ‘just barely painful’ and 10, ‘just barely tolerable’. Thermal stimuli were 40°C or 50°C heat, applied with a thermode as repetitive 5-s contacts to the volar forearm. Both male and female subjects rated the 40°C stimuli as warm but not painful and the 50°C stimuli as painful but females rated the 50°C stimuli as significantly more intense than did the males (P = 0.0052). Both genders showed a bilateral activation of premotor cortex in addition to the activation of a number of contralateral structures, including the posterior insula, anterior cingulate cortex and the cerebellar vermis, during heat pain. However, females had significantly greater activation of the contralateral prefrontal cortex when compared to the males by direct image subtraction. Volume of interest comparison (t-statistic) also suggested greater activation of the contralateral insula and thalamus in the females (P < 0.05). These pain-related differences in brain activation may be attributed to gender, perceived pain intensity, or to both factors.
PMCID: PMC1828033  PMID: 9696477
Pain; Gender difference; Positron emission tomography; Prefrontal cortex; Insula; Thalamus
13.  Evidence for Thalamic Involvement in the Thermal Grill Illusion: An fMRI Study 
PLoS ONE  2011;6(11):e27075.
Perceptual illusions play an important role in untangling neural mechanisms underlying conscious phenomena. The thermal grill illusion (TGI) has been suggested as a promising model for exploring percepts involved in neuropathic pain, such as cold-allodynia (pain arising from contact with innocuous cold). The TGI is an unpleasant/painful sensation from touching juxtapositioned bars of cold and warm innocuous temperatures.
To develop an MRI-compatible TGI-unit and explore the supraspinal correlates of the illusion, using fMRI, in a group of healthy volunteers.
We constructed a TGI-thermode allowing the rapid presentation of warm(41°C), cold(18°C) and interleaved(41°C+18°C = TGI) temperatures in an fMRI-environment. Twenty volunteers were tested. The affective-motivational (“unpleasantness”) and sensory-disciminatory (“pain-intensity”) dimensions of each respective stimulus were rated. Functional images were analyzed at a corrected α-level <0.05.
The TGI was rated as significantly more unpleasant and painful than stimulation with each of its constituent temperatures. Also, the TGI was rated as significantly more unpleasant than painful. Thermal stimulation versus neutral baseline revealed bilateral activations of the anterior insulae and fronto-parietal regions. Unlike its constituent temperatures the TGI displayed a strong activation of the right (contralateral) thalamus. Exploratory contrasts at a slightly more liberal threshold-level also revealed a TGI-activation of the right mid/anterior insula, correlating with ratings of unpleasantness(rho = 0.31).
To the best of our knowledge, this is the first fMRI-study of the TGI. The activation of the anterior insula is consistent with this region's putative role in processing of homeostatically relevant feeling-states. Our results constitute the first neurophysiologic evidence of thalamic involvement in the TGI. Similar thalamic activity has previously been observed during evoked cold-allodynia in patients with central neuropathic pain. Our results further the understanding of the supraspinal correlates of the TGI-phenomenon and pave the way for future inquiries into if and how it may relate to neuropathic pain.
PMCID: PMC3214046  PMID: 22096519
14.  Single subject pharmacological-MRI (phMRI) study: Modulation of brain activity of psoriatic arthritis pain by cyclooxygenase-2 inhibitor 
Molecular Pain  2005;1:32.
We use fMRI to examine brain activity for pain elicited by palpating joints in a single patient suffering from psoriatic arthritis. Changes in these responses are documented when the patient ingested a single dose of a selective cyclooxygenase-2 inhibitor (COX-2i). We show that mechanical stimulation of the painful joints exhibited a cortical activity pattern similar to that reported for acute pain, with activity primarily localized to the thalamus, insular, primary and secondary somatosensory cortices and the mid anterior cingulum. COX-2i resulted in significant decreased in reported pain intensity and in brain activity after 1 hour of administration. The anterior insula and SII correlated with pain intensity, however no central activation site for the drug was detected. We demonstrate the similarity of the activation pattern for palpating painful joints to brain activity in normal subjects in response to thermal painful stimuli, by performing a spatial conjunction analysis between these maps, where overlap is observed in the insula, thalamus, secondary somatosensory cortex, and anterior cingulate. The results demonstrate that one can study effects of pharmacological manipulations in a single subject where the brain activity for a clinical condition is delineated and its modulation by COX-2i demonstrated. This approach may have diagnostic and prognostic utility.
PMCID: PMC1291397  PMID: 16266429
15.  Pain Facilitation Brain Regions Activated by Nalbuphine Are Revealed by Pharmacological fMRI 
PLoS ONE  2013;8(1):e50169.
Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.
PMCID: PMC3540048  PMID: 23341872
16.  Modification of Electrical Pain Threshold by Voluntary Breathing-Controlled Electrical Stimulation (BreEStim) in Healthy Subjects 
PLoS ONE  2013;8(7):e70282.
Pain has a distinct sensory and affective (i.e., unpleasantness) component. BreEStim, during which electrical stimulation is delivered during voluntary breathing, has been shown to selectively reduce the affective component of post-amputation phantom pain. The objective was to examine whether BreEStim increases pain threshold such that subjects could have improved tolerance of sensation of painful stimuli.
Eleven pain-free healthy subjects (7 males, 4 females) participated in the study. All subjects received BreEStim (100 stimuli) and conventional electrical stimulation (EStim, 100 stimuli) to two acupuncture points (Neiguan and Weiguan) of the dominant hand in a random order. The two different treatments were provided at least three days apart. Painful, but tolerable electrical stimuli were delivered randomly during EStim, but were triggered by effortful inhalation during BreEStim. Measurements of tactile sensation threshold, electrical sensation and electrical pain thresholds, thermal (cold sensation, warm sensation, cold pain and heat pain) thresholds were recorded from the thenar eminence of both hands. These measurements were taken pre-intervention and 10−min post-intervention.
There was no difference in the pre-intervention baseline measurement of all thresholds between BreEStim and EStim. The electrical pain threshold significantly increased after BreEStim (27.5±6.7% for the dominant hand and 28.5±10.8% for the non-dominant hand, respectively). The electrical pain threshold significantly decreased after EStim (9.1±2.8% for the dominant hand and 10.2±4.6% for the non–dominant hand, respectively) (F[1, 10] = 30.992, p = .00024). There was no statistically significant change in other thresholds after BreEStim and EStim. The intensity of electrical stimuli was progressively increased, but no difference was found between BreEStim and EStim.
Voluntary breathing controlled electrical stimulation selectively increases electrical pain threshold, while conventional electrical stimulation selectively decreases electrical pain threshold. This may translate into improved pain control.
PMCID: PMC3722161  PMID: 23894632
17.  Imaging the functional connectivity of the Periaqueductal Gray during genuine and sham electroacupuncture treatment 
Molecular Pain  2010;6:80.
Electroacupuncture (EA) is currently one of the most popular acupuncture modalities. However, the continuous stimulation characteristic of EA treatment presents challenges to the use of conventional functional Magnetic Resonance Imaging (fMRI) approaches for the investigation of neural mechanisms mediating treatment response because of the requirement for brief and intermittent stimuli in event related or block designed task paradigms. A relatively new analysis method, functional connectivity fMRI (fcMRI), has great potential for studying continuous treatment modalities such as EA. In a previous study, we found that, compared with sham acupuncture, EA can significantly reduce Periaqueductal Gray (PAG) activity when subsequently evoked by experimental pain. Given the PAG's important role in mediating acupuncture analgesia, in this study we investigated functional connectivity with the area of the PAG we previously identified and how that connectivity was affected by genuine and sham EA.
Forty-eight subjects, who were randomly assigned to receive either genuine or sham EA paired with either a high or low expectancy manipulation, completed the study. Direct comparison of each treatment mode's functional connectivity revealed: significantly greater connectivity between the PAG, left posterior cingulate cortex (PCC), and precuneus for the contrast of genuine minus sham; significantly greater connectivity between the PAG and right anterior insula for the contrast of sham minus genuine; no significant differences in connectivity between different contrasts of the two expectancy levels.
Our findings indicate the intrinsic functional connectivity changes among key brain regions in the pain matrix and default mode network during genuine EA compared with sham EA. We speculate that continuous genuine EA stimulation can modify the coupling of spontaneous activity in brain regions that play a role in modulating pain perception.
PMCID: PMC2993660  PMID: 21080967
18.  Sensitivity of quantitative sensory models to morphine analgesia in humans 
Journal of Pain Research  2014;7:717-726.
Opioid analgesia can be explored with quantitative sensory testing, but most investigations have used models of phasic pain, and such brief stimuli may be limited in the ability to faithfully simulate natural and clinical painful experiences. Therefore, identification of appropriate experimental pain models is critical for our understanding of opioid effects with the potential to improve treatment.
The aim was to explore and compare various pain models to morphine analgesia in healthy volunteers.
The study was a double-blind, randomized, two-way crossover study. Thirty-nine healthy participants were included and received morphine 30 mg (2 mg/mL) as oral solution or placebo. To cover both tonic and phasic stimulations, a comprehensive multi-modal, multi-tissue pain-testing program was performed.
Tonic experimental pain models were sensitive to morphine analgesia compared to placebo: muscle pressure (F=4.87, P=0.03), bone pressure (F=3.98, P=0.05), rectal pressure (F=4.25, P=0.04), and the cold pressor test (F=25.3, P<0.001). Compared to placebo, morphine increased tolerance to muscle stimulation by 14.07%; bone stimulation by 9.72%; rectal mechanical stimulation by 20.40%, and reduced pain reported during the cold pressor test by 9.14%. In contrast, the more phasic experimental pain models were not sensitive to morphine analgesia: skin heat, rectal electrical stimulation, or rectal heat stimulation (all P>0.05).
Pain models with deep tonic stimulation including C fiber activation and and/or endogenous pain modulation were more sensitive to morphine analgesia. To avoid false negative results in future studies, we recommend inclusion of reproducible tonic pain models in deep tissues, mimicking clinical pain to a higher degree.
PMCID: PMC4266386  PMID: 25525384
pain; opioid; experiment pain model
19.  First-Person Perspective Effects on Theory of Mind without Self-Reference 
PLoS ONE  2011;6(4):e19320.
This study examined dissociations between brain networks involved in theory of mind, which is needed for guessing others' mental states, and the self, which might constitute the basis for theory of mind's development. We used event-related fMRI to compare a condition that required participants to guess the mental state of a subject featured in first-person perspective sentences (1stPP condition) with a third-person perspective sentence condition (3rdPP condition). The caudate nucleus was marginally more activated in the 1stPP than in the 3rdPP condition, while the left dorsolateral prefrontal cortex (DLPFC) was significantly more activated in the 3rdPP condition as compared to the 1stPP condition. Furthermore, we examined the correlation between activation (signal intensity) of the caudate nucleus and left DLPFC with that of the right DLPFC, which is thought to be closely connected with sense of self. We found a significant correlation between caudate nucleus and right DLPFC activation in the 1stPP condition, and between left and right DLPFC activation in the 3rdPP condition. Although theory of mind and the self both appear to recruit the right DLPFC, this region seems to be accessed through the left DLPFC during theory of mind tasks, but through the caudate nucleus when tasks require self reference.
PMCID: PMC3084809  PMID: 21559448
20.  Changes of Spontaneous Oscillatory Activity to Tonic Heat Pain 
PLoS ONE  2014;9(3):e91052.
Transient painful stimuli could induce suppression of alpha oscillatory activities and enhancement of gamma oscillatory activities that also could be greatly modulated by attention. Here, we attempted to characterize changes in cortical activities during tonic heat pain perception and investigated the influence of directed/distracted attention on these responses. We collected 5-minute long continuous Electroencephalography (EEG) data from 38 healthy volunteers during four conditions presented in a counterbalanced order: (A) resting condition; (B) innoxious-distracted condition; (C) noxious-distracted condition; (D) noxious-attended condition. The effects of tonic heat pain stimulation and selective attention on oscillatory activities were investigated by comparing the EEG power spectra among the four experimental conditions and assessing the relationship between spectral power difference and subjective pain intensity. The change of oscillatory activities in condition D was characterized by stable and persistent decrease of alpha oscillation power over contralateral-central electrodes and widespread increase of gamma oscillation power, which were even significantly correlated with subjective pain intensity. Since EEG responses in the alpha and gamma frequency band were affected by attention in different manners, they are likely related to different aspects of the multidimensional sensory experience of pain. The observed contralateral-central alpha suppression (conditions D vs. B and D vs. C) may reflect primarily a top-down cognitive process such as attention, while the widespread gamma enhancement (conditions D vs. A) may partly reflect tonic pain processing, representing the summary effects of bottom-up stimulus-related and top-down subject-driven cognitive processes.
PMCID: PMC3946288  PMID: 24603703
21.  Theta burst stimulation-induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set-shifting task – a TMS–[11C]raclopride PET study 
The European journal of neuroscience  2008;28(10):2147-2155.
The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card-sorting tasks requiring planning and set-shifting [e.g. Montreal-card-sorting-task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set-shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [11C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate–anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [11C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS-induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.
PMCID: PMC2967524  PMID: 19046396 CAMSID: cams1540
basal ganglia; executive function; positron emission tomography; transcranial magnetic stimulation
22.  Monoarticular antigen-induced arthritis leads to pronounced bilateral upregulation of the expression of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion neurons of rats 
Arthritis Research  2000;2(5):424-427.
This study describes the upregulation of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion (DRG) neurons in the course of antigen-induced arthritis (AIA) in the rat knee. In the acute phase of AIA, which was characterized by pronounced hyperalgesia, there was a substantial bilateral increase in the proportion of lumbar DRG neurons that express neurokinin 1 receptors (activated by substance P) and bradykinin 2 receptors. In the chronic phase the upregulation of bradykinin 2 receptors persisted on the side of inflammation. The increase in the receptor expression is relevant for the generation of acute and chronic inflammatory pain.
Ongoing pain and hyperalgesia (enhanced pain response to stimulation of the tissue) are major symptoms of arthritis. Arthritic pain results from the activation and sensitization of primary afferent nociceptive nerve fibres ('pain fibres') supplying the tissue (peripheral sensitization) and from the activation and sensitization of nociceptive neurons in the central nervous system (central sensitization). After sensitization, nociceptive neurons respond more strongly to mechanical and thermal stimulation of the tissue, and their activation threshold is lowered. The activation and sensitization of primary afferent fibres results from the action of inflammatory mediators such as bradykinin (BK), prostaglandins and others on membrane receptors located on these neurons. BK is a potent pain-producing substance that is contained in inflammatory exudates. Up to 50% of the primary afferent nerve fibres have receptors for BK. When primary afferent nerve fibres are activated they can release neuropeptides such as substance P (SP) and calcitonin gene-related peptide from their sensory endings in the tissue. SP contributes to the inflammatory changes in the innervated tissue (neurogenic inflammation), and it might also support the sensitization of nociceptive nerve fibres by binding to neurokinin 1 (NK1) receptors. NK1 receptors are normally expressed on a small proportion of the primary afferent nerve fibres.
Because the expression of receptors on the primary afferent neurons is essential for the pain-producing action of inflammatory mediators and neuropeptides, we investigated in the present study whether the expression of BK and NK1 receptors on primary afferent neurons is altered during the acute and chronic phases of an antigen-induced arthritis (AIA). AIA resembles in many aspects the inflammatory process of human rheumatoid arthritis. Because peptide receptors are expressed not only in the terminals of the primary afferent units but also in the cell bodies, we removed dorsal root ganglia (DRGs) of both sides from control rats and from rats with the acute or chronic phase of AIA and determined, after short-term culture of the neurons, the proportion of DRG neurons that expressed the receptors in the different phases of AIA. We also characterized the inflammatory process and the nociceptive behaviour of the rats in the course of AIA.
Materials and methods:
In 33 female Lewis rats 10 weeks old, AIA was induced in the right knee joint. First the rats were immunized in two steps with methylated bovine serum albumin (m-BSA) emulsified with Freund's complete adjuvant, and heat-inactivated Bordetella pertussis. After immunization, m-BSA was injected into the right knee joint cavity to induce arthritis. The joint swelling was measured at regular intervals. Nociceptive (pain) responses to mechanical stimulation of the injected and the contralateral knee were monitored in the course of AIA. Groups of rats were killed at different time points after the induction of AIA, and inflammation and destruction in the knee joint were graded by histological examination. The DRGs of both sides were dissected from segments L1–L5 and C1–C7 from arthritic rats, from eight immunized rats without arthritis and from ten normal control rats. Excised DRGs were dissociated into single cells which were cultured for 18 h.
The expression of the receptors was determined by assessment of the binding of SP-gold or BK-gold to the cultured neurons. For this purpose the cells were slightly fixed. Binding of SP-gold or BK-gold was detected by using enhancement with silver and subsequent densitometric analysis of the relative grey values of the neurons. Displacement controls were performed with SP, the specific NK1 receptor agonist [Sar9, Met(O2)11]-SP, BK, the specific BK 1 (B1) receptor agonist D-Arg (Hyp3-Thi5,8-D-Phe7)-BK and the specific BK 2 (B2) receptor agonist (Des-Arg10)-Lys-BK.
The inflammatory process in the injected right knee joint started on the first day after induction of AIA and persisted throughout the observation period of 84 days (Fig. 1). The initial phase of AIA was characterized by strong joint swelling and a predominantly granulocytic infiltration of the synovial membrane and the joint cavity (acute inflammatory changes). In the later phases of AIA (10–84 days after induction of AIA) the joint showed persistent swelling, and signs of chronic arthritic alterations such as infiltration of mononuclear leucocytes, hyperplasia of synovial lining layer (pannus formation) and erosions of cartilage and bone were predominant. The contralateral knee joints appeared normal at all time points. Destruction was observed only in the injected knee but some proteoglycan loss was also noted in the non-injected, contralateral knee. In the acute and initial chronic phases of AIA (1–29 days) the rats showed mechanical hyperalgesia in the inflamed knee (limping, withdrawal response to gentle pressure onto the knee). In the acute phase (up to 9 days) a pain response was also seen when gentle pressure was applied to the contralateral knee.
Figure 2 displays the changes in the receptor expression in the DRG neurons during AIA. The expression of SP–gold-binding sites in lumbar DRG neurons (Fig. 2a) was substantially increased in the acute phase of arthritis. In untreated control rats (n = 5), 7.7 ± 3.8% of the DRG neurons from the right side and 10.0 ± 1.7% of the DRG neurons from the left side showed labelling with SP–gold. The proportion of SP–gold-labelled neurons in immunized animals without knee injection (n = 3) was similar. By contrast, at days 1 (n = 2 rats) and 3 (n = 5 rats) of AIA in the right knee, approximately 50% of the DRG neurons exhibited labelling with SP–gold, and this was seen both on the side of the injected knee and on the opposite side. At day 10 of AIA (n = 3 rats), 26.3 ± 6.1% of the ipsilateral DRG neurons but only 15.7 ± 0.6% of the contralateral neurons exhibited binding of SP–gold. At days 21 (n = 5 rats), 42 (n = 3 rats) and 84 (n = 5 rats) of AIA, the proportion of SP–gold-positive neurons had returned to the control values, although the arthritis, now with signs of chronic inflammation, was still present. Compared with the DRG neurons of the untreated control rats, the increase in the proportion of labelled neurons was significant on both sides in the acute phase (days 1 and 3) and the intermediate phase (day 10) of AIA (Mann–Whitney U-test). The size distribution of the neurons was similar in the DRG neurons of all experimental groups. Under all conditions and at all time points, SP–gold binding was found mainly in small and medium-sized (less than 700 μm2) neurons. In the cervical DRGs the expression of NK1 receptors did not change in the course of AIA. The binding of SP–gold to the neurons was suppressed by the coadministration of the specific NK1 receptor agonist [Sar9, Met(O2)11]–SP in three experiments, showing that SP–gold was bound to NK1 receptors.
The expression of BK–gold-binding sites in the lumbar DRG neurons showed also changes in the course of AIA, but the pattern was different (Fig. 2b). In untreated control rats (n = 5), 42.3 ± 3.1% of the DRG neurons of the right side and 39.6 ± 2.6% of the DRG neurons of the left side showed binding of BK–gold. At days 1 (n = 2 rats) and 3 (n = 5 rats) of AIA, approximately 80% of the DRG neurons on the side of the knee injection (ipsilateral) and approximately 70% on the opposite side were labelled. In comparison with the untreated control group, the increase in the proportion of labelled neurons was significant on both sides. The proportion of labelled neurons in the ipsilateral DRGs remained significantly increased in both the intermediate phase (day 10, n = 3 rats) and chronic phase (days 21, n = 5 rats, and 42, n = 3 rats) of inflammation. At 84 days after the induction of AIA (n = 5 rats), 51.0 ± 12.7% of the neurons showed an expression of BK–gold-binding sites and this was close to the prearthritic values. However, in the contralateral DRG of the same animals the proportion of BK–gold-labelled neurons declined in the intermediate phase (day 10) and chronic phase (days 21–84) of AIA and was not significantly different from the control value. Thus the increase in BK–gold-labelled neurons was persistent on the side where the inflammation had been induced, and transient on the opposite side. The size distribution of the DRG neurons of the different experimental groups was similar. In the cervical DRGs the expression of BK receptors did not change in the course of AIA. In another series of experiments, we determined the subtype(s) of BK receptor(s) that were expressed in DRGs L1–L5 in different experimental groups. In neither untreated control animals (n = 5) nor immunized rats without knee injection (n = 5) nor in rats at 3 days (n = 5) and 42 days (n = 5) of AIA was the binding of BK–gold decreased by the coadministration of BK–gold and the B1 agonist. By contrast, in these experimental groups the binding of BK–gold was suppressed by the coadministration of the B2 agonist. These results show that B2 receptors, but not B1 receptors, were expressed in both normal animals and in animals with AIA.
These results show that in AIA in the rat the expression of SP-binding and BK-binding sites in the perikarya of DRGs L1–L5 is markedly upregulated in the course of knee inflammation. Although the inflammation was induced on one side only, the initial changes in the binding sites were found in the lumbar DRGs of both sides. No upregulation of SP-binding or BK-binding sites was observed in the cervical DRGs. The expression of SP-binding sites was upregulated only in the first days of AIA, that is, in the acute phase, in which the pain responses to mechanical stimulation were most pronounced. By contrast, the upregulation of BK-binding sites on the side of AIA persisted for up to 42 days, that is, in the acute and chronic phase of AIA. Only the B2 receptor, not the B1 receptor, was upregulated. The coincidence of the enhanced expression of NK1 and BK receptors on sensory neurons and the pain behaviour suggests that the upregulation of these receptors is relevant for the generation and maintenance of arthritic pain.
In the acute phase of AIA, approximately 50% of the lumbar DRG neurons showed an expression of SP-binding sites. Because peptide receptors are transported to the periphery, the marked upregulation of SP-binding receptors probably leads to an enhanced density of receptors in the sensory endings of the primary afferent units. This will permit SP to sensitize more neurons under inflammatory conditions than under normal conditions. However, the expression of NK1 receptors was upregulated only in the acute phase of inflammation, suggesting that SP and NK1 receptors are less important for the generation of hyperalgesia in the chronic phase of AIA.
Because BK is one of the most potent algesic compounds, the functional consequence of the upregulation of BK receptors is likely to be of immediate importance for the generation and maintenance of inflammatory pain. The persistence of the upregulation of BK receptors on the side of inflammation suggests that BK receptors should be an interesting target for pain treatment in the acute and chronic phases. Only B2 receptors were identified in normal animals and in rats with AIA. This is surprising because previous pharmacological studies have provided evidence that, during inflammation, B1 receptors can be newly expressed.
Receptor upregulation in the acute phase of AIA was bilateral and almost symmetrical. However, hyperalgesia was much more pronounced on the inflamed side. It is most likely that receptors on the contralateral side were not readily activated because in the absence of gross inflammation the local concentration of the ligands BK and SP was probably quite low. We hypothesize that the bilateral changes in receptor expression are generated at least in part by mechanisms involving the nervous system. Symmetrical segmental changes can be produced only by the symmetrical innervation, involving either the sympathetic nervous system or the primary afferent fibres. Under inflammatory conditions, primary afferent fibres can be antidromically activated bilaterally in the entry zone of afferent fibres in the spinal cord, and it was proposed that this antidromic activation might release neuropeptides and thus contribute to neurogenic inflammation. Because both sympathetic efferent fibres and primary afferent nerve fibres can aggravate inflammatory symptoms, it is also conceivable that they are involved in the regulation of receptor expression in primary afferent neurons. A neurogenic mechanism might also have been responsible for the bilateral degradation of articular cartilage in the present study.
PMCID: PMC17819  PMID: 11056677
antigen-induced arthritis; bradykinin receptor; dorsal root ganglion neurons; neurokinin 1 receptor; pain
23.  Roles of the Insular Cortex in the Modulation of Pain: Insights from Brain Lesions 
Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively-oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remain poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectible insular activity. Taken together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately utilize prior cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.
PMCID: PMC2748680  PMID: 19261863
Pain Asymbolia; Anterior Cingulate Cortex; Dorsolateral Prefrontal Cortex; Somatosensory; Hyperalgesia; Stroke
24.  Distinctive neural responses to pain stimuli during induced sadness in patients with somatoform pain disorder: An fMRI study☆ 
NeuroImage : Clinical  2013;2:782-789.
Pain is a multidimensional phenomenon. Patients with somatoform pain disorder suffer from long-lasting pain, with the pathology being closely associated with cognitive–emotional components. Differences between these patients and controls in cerebral responses to pain stimuli have been reported. However, to our knowledge, no studies of somatoform pain disorder have evaluated altered pain-related brain activation as modulated by emotional dysregulation. We examined the distinct neural mechanism that is engaged in response to two different pain intensities in a sad emotional condition, performing functional magnetic resonance imaging (fMRI) on a group of 11 somatoform pain patients and an age-matched control group. Our results showed that the ratio for low-pain intensity ratings between the sad and neutral conditions in patients was higher than in controls. They also showed significant increased activation in the anterior/posterior insula in the low pain sadness condition. Furthermore, there was specific functional connectivity between the anterior insula and the parahippocampus in patients during presentation of low-pain stimuli in the sad context. These findings suggest that a negative emotional context such as sadness contributes to dysfunctional pain processing in somatoform pain disorder. Greater sensitivity to low levels of pain in an emotional context of sadness might be an important aspect of the psychopathology of somatoform pain disorder.
•Patients show higher pain sensitivities for low pain under sadness.•The insula to low-pain stimuli are particularly changeable in patients.•There was strong connectivity between the insula and the parahippocampus in patients.•We suggest potential importance of emotional context in somatoform pain disorder.
PMCID: PMC3777689  PMID: 24179828
Pain; Sadness; Somatoform pain disorder; fMRI; Insula; Parahippocampus
25.  Interpretive monitoring in the caudate nucleus 
eLife  2014;3:e03727.
In a dynamic environment an organism has to constantly adjust ongoing behavior to adapt to a given context. This process requires continuous monitoring of ongoing behavior to provide its meaningful interpretation. The caudate nucleus is known to have a role in behavioral monitoring, but the nature of these signals during dynamic behavior is still unclear. We recorded neuronal activity in the caudate nucleus in monkeys during categorization behavior that changed rapidly across contexts. We found that neuronal activity maintained representation of the identity and context of a recently categorized stimulus, as well as interpreted the behavioral meaningfulness of the maintained trace. The accuracy of this cognitive monitoring signal was highest for behavior for which subjects were prone to make errors. Thus, the caudate nucleus provides interpretive monitoring of ongoing behavior, which is necessary for contextually specific decisions to adapt to rapidly changing conditions.
eLife digest
The ability to adapt behavior in a changing environment is a hallmark of intelligent systems. From adjusting our driving speed to match road conditions to responding to a last-minute change of plans, mental flexibility underpins much of our day-to-day functioning.
To perform optimally, an animal must continuously monitor its own behavior and adjust it according to circumstances. A region of the brain called the caudate nucleus is thought to contribute to this process by keeping track of the relation between an action and its outcomes, but it is not clear how it monitors cognitive aspects of ongoing behavior.
Yanike and Ferrera have clarified this process by recording electrical activity from the caudate nucleus in two monkeys as they categorized visual stimuli. The monkeys viewed a moving stimulus and classified it as ‘fast’ or ‘slow’ relative to a reference speed that varied from trial to trial. The monkeys were trained to use two different references speeds and were told which reference speed to use at the start of each trial. They used an eye movement to indicate their decision.
Most neurons within the caudate nucleus responded after the monkey had made a decision, suggesting that these neurons might be involved in evaluating the decision that had just been made. The response of the neurons depended on the stimulus speed, and also on the category (fast or slow) in which the stimulus belonged. This observation indicates that the caudate nucleus tracked the context (reference speed) as well as the stimulus speed.
Yanike and Ferrera also showed that the response of the entire population of caudate neurons could be decoded to reveal both the speed of the stimulus and whether the monkey had categorized it as fast or slow. This shows that after a decision has been made, neurons continue to signal both the stimulus and the context in which that stimulus was presented. Such ‘post-decision’ monitoring is important for anticipating the outcome of the decision. Overall the results suggest that the caudate nucleus helps animals to adapt their behavior to rapidly changing circumstances by supporting decision-making that takes context into account.
PMCID: PMC4238052  PMID: 25415238
nonhuman primates; basal ganglia; electrophysiology; neuronal populations; cognition; decision making; other

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