Correlation and cluster analysis of sensory, pain, and reflex thresholds to various stimulus modalities in symptom-free subjects.

OBJECTIVE: In order to evaluate the possible relation between the psychophysical response and a motor reflex, sensory and pain thresholds to various stimuli were analyzed in combination with the occurrence threshold of the late masseteric exteroceptive suppression (ES2) period. METHODS: Twenty men and 20 women participated. The tactile detection threshold and the filament-prick pain detection threshold were measured on the cheek skin overlying the left masseter muscles. The pressure pain threshold and pressure pain tolerance threshold were measured at the left masseter muscle. The surface EMG was recorded from the left masseter muscle, while electrical stimuli with 13 fixed intensities were applied to the skin above the left mental nerve. The stimulation intensity at which the ES2 appeared for the first time and the lowest stimulus intensity at which the subjects reported to be painful were defined as the ES2 and pain threshold, respectively. RESULTS: There were significant positive correlations between the tactile detection threshold and the pain thresholds determined using the different stimulus modalities, and the ES2 threshold was also significantly correlated with the pain thresholds (P<0.05). Cluster analysis could significantly discriminate two distinct groups with high versus low tactile, pain and ES2 thresholds (P<0.05). CONCLUSIONS: The present findings suggested that the ES2 reflex response has a relation with the individual sensory and pain sensitivity in symptom-free subjects. SIGNIFICANCE: Combined examination of sensory, pain, and ES2 thresholds might provide complementary information on the pathophysiology underlying orofacial pain.     

Sex differences in brain activation to emotional stimuli: a meta-analysis of neuroimaging studies

Substantial sex differences in emotional responses and perception have been reported in previous psychological and psychophysiological studies. For example, women have been found to respond more strongly to negative emotional stimuli, a sex difference that has been linked to an increased risk of depression and anxiety disorders. The extent to which such sex differences are reflected in corresponding differences in regional brain activation remains a largely unresolved issue, however, in part because relatively few neuroimaging studies have addressed this issue. Here, by conducting a quantitative meta-analysis of neuroimaging studies, we were able to substantially increase statistical power to detect sex differences relative to prior studies, by combining emotion studies which explicitly examined sex differences with the much larger number of studies that examined only women or men. We used an activation likelihood estimation approach to characterize sex differences in the likelihood of regional brain activation elicited by emotional stimuli relative to non-emotional stimuli. We examined sex differences separately for negative and positive emotions, in addition to examining all emotions combined. Sex differences varied markedly between negative and positive emotion studies. The majority of sex differences favoring women were observed for negative emotion, whereas the majority of the sex differences favoring men were observed for positive emotion. This valence-specificity was particularly evident for the amygdala. For negative emotion, women exhibited greater activation than men in the left amygdala, as well as in other regions including the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. In contrast, for positive emotion, men exhibited greater activation than women in the left amygdala, as well as greater activation in other regions including the bilateral inferior frontal gyrus and right fusiform gyrus. These meta-analysis findings indicate that the amygdala, a key region for emotion processing, exhibits valence-dependent sex differences in activation to emotional stimuli. The greater left amygdala response to negative emotion for women accords with previous reports that women respond more strongly to negative emotional stimuli, as well as with hypothesized links between increased neurobiological reactivity to negative emotion and increased prevalence of depression and anxiety disorders in women. The finding of greater left amygdala activation for positive emotional stimuli in men suggests that greater amygdala responses reported previously for men for specific types of positive stimuli may also extend to positive stimuli more generally. In summary, this study extends efforts to characterize sex differences in brain activation during emotion processing by providing the largest and most comprehensive quantitative meta-analysis to date, and for the first time examining sex differences as a function of positive vs. negative emotional valence. The current findings highlight the importance of considering sex as a potential factor modulating emotional processing and its underlying neural mechanisms, and more broadly, the need to consider individual differences in understanding the neurobiology of emotion.     

Gender difference in masseteric exteroceptive suppression period and pain perception.

OBJECTIVE: Use of brain stem reflexes in the assessment of orofacial function requires insight into the influence of demographic factors such as gender. The aim of this study was to characterize possible gender differences in the relation between quantitative measures of the masseteric exteroceptive suppression (ES) reflex response and pain perception evoked by incrementally increasing electrical stimulation. METHODS: In 12 men and 12 women, the surface electromyogram was recorded from the left masseter muscle. Thirteen fixed stimulus intensities from 5 to 35 mA at 2.5 mA increments were applied to the skin above the left mental nerve. The stimulation intensity at which the late ES appeared first and the first intensity at which the subjects reported the stimulus intensity to be painful were defined as the reflex threshold (RT) and pain threshold (PT), respectively. Furthermore, data were analyzed using stimulus-response curves, and the reflex appearance levels (RAL), the saturation level, the slope from appearance to saturation of the reflex (SLP), and the pain appearance level (PAL) were determined. RESULTS: The PT was equal to or higher than the RT in 9 of the 12 men, but only in 4 of the 12 women. Further, women had significantly lower PAL, RAL, and SLP (12.7 +/- 0.8, 12.9 +/- 1.4, and 3.0 +/- 0.9 mA, respectively) compared to men (20.3 +/- 1.6 mA, 16.7 +/- 1.1 T, and 4.1 +/- 0.4, respectively) (P < 0.05). CONCLUSIONS: The present results document that women have a lower reflex threshold and pain threshold to cutaneous electrical stimulation than men. SIGNIFICANCE: These findings suggest that gender differences may exist in the sensory-motor integration of primary afferent input from the orofacial region and that these differences should be considered in the design of future reflex studies.     

Pain ratings and somatosensory evoked responses to repetitive intramuscular and intracutaneous stimulation in fibromyalgia syndrome.

To determine the presence of perceptual sensitization and related brain responses we examined 15 patients with fibromyalgia syndrome and 15 healthy controls comparable in age and sex. Multichannel EEG recordings and pain ratings were obtained during the presentation of 800 painful electrical intramuscular and intracutaneous stimuli to the left m. erector spinae and the left m. extensor digitorum. The stimulus intensity was adjusted to 50% between pain threshold and tolerance. Detection and pain thresholds were significantly lower in the fibromyalgia syndrome group. Sensitization occurred for both groups during intramuscular stimulation. In the EEG data the fibromyalgia syndrome patients showed higher N80 amplitudes compared with the healthy controls. Arm stimulation and intramuscular stimulation yielded higher N80 and N150 amplitudes compared with intracutaneous stimulation or stimulation of the back. These results indicate lower pain thresholds in the fibromyalgia syndrome patients after electrical stimulation and a higher N80 amplitude both indicative of enhanced sensory processing in this group.     

Comparison between SI and SII responses as a function of stimulus intensity

In this MEG study we investigated the differences in responses to somatosensory electrical stimuli between primary (SI) and secondary (SII) sensory cortices using 10 different levels of stimulus intensity, starting from below the sensory threshold up to a weak painful level. SI dipole source linearly increased in amplitude as the stimulus intensity raised up to a strong motor level and then saturated at higher stimulation levels. The contralateral and ipsilateral SII dipole source strengths followed the stimulus intensity growing up to the motor threshold, but showed a decrease at the strong motor level, followed by an increase as the stimulus intensity raised towards the weak painful threshold. These results suggest different responses of SI and SII cortices as the intensity of stimulation rises from non-painful to painful values.     

Sex differences in functional activation patterns revealed by increased emotion processing demands

Two [O(15)] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cognitive strategies while women draw more on primary emotional references.     

Facial emotion discrimination: I. Task construction and behavioral findings in normal subjects.

Facial discrimination tasks (age, happy-neutral, and sad-neutral) were developed to address the need for activation tasks that engage emotional processing and can be used during physiologic neuroimaging ("neurobehavioral probes"). The stimuli pictured professional actors and actresses who had been screened for asymmetric features. In experiment I, same-sex stimuli were used to examine the performance of normal subjects (24 men, 15 women) on the three tasks. Performance was better during the emotion-discrimination tasks than during the age-discrimination task, and males had higher sensitivity scores for the detection of sad emotion. However, experiment II showed that the sex of the stimulus interacts with the sex of the subject. Compared with female subjects, male subjects (n = 10) were selectively less sensitive to sad emotion in female faces. Female subjects (n = 10) were more sensitive overall to emotional expression in male faces than in female faces. Thus, men and women differed in performance depending on the sex of the facial stimulus.     

The effects of sequential stimulation on subjective pain experience

The difference between subjective intensity of pain for repeated identical stimuli was measured at high and low stimulus levels in 20 subjects. A significant (p<0.01) correlation was found between this difference and the stimulus level. For low intensities of stimulus subjective pain diminished; at high intensities it increased. The changeover point was slightly below the severe pain threshold. It is suggested that this may imply the possibility of desensitising people to painful stimuli.     

Separating brain processing of pain from that of stimulus intensity

Regions of the brain network activated by painful stimuli are also activated by nonpainful and even nonsomatosensory stimuli. We therefore analyzed where the qualitative change from nonpainful to painful perception at the pain thresholds is coded. Noxious stimuli of gaseous carbon dioxide (n = 50) were applied to the nasal mucosa of 24 healthy volunteers at various concentrations from 10% below to 10% above the individual pain threshold. Functional magnetic resonance images showed that these trigeminal stimuli activated brain regions regarded as the "pain matrix." However, most of these activations, including the posterior insula, the primary and secondary somatosensory cortex, the amygdala, and the middle cingulate cortex, were associated with quantitative changes in stimulus intensity and did not exclusively reflect the qualitative change from nonpainful to pain. After subtracting brain activations associated with quantitative changes in the stimuli, the qualitative change, reflecting pain-exclusive activations, could be localized mainly in the posterior insular cortex. This shows that cerebral processing of noxious stimuli focuses predominately on the quantitative properties of stimulus intensity in both their sensory and affective dimensions, whereas the integration of this information into the perception of pain is restricted to a small part of the pain matrix.     

Segregation of gustatory cortex in response to salt and umami taste studied through event-related potentials

In this study, we report gustatory event-related potentials in response to stimulation with monosodium glutamate (MSG) and salt (NaCl). We investigated differences in event-related potential related to stimulus quality, stimulus concentration, cortical topography, and participants' sex. Our results showed that amplitudes P1N1 and N1P2 were significantly larger in response to stimulation with NaCl compared with stimulation with MSG and the topographical distribution of amplitudes varied significantly for the two stimuli. In addition, responses were significantly larger in the right hemisphere compared with the left hemisphere for both stimuli, suggesting right hemispheric dominance for gustatory processing. In conclusion, this study shows significant differences in cerebral processing of MSG and NaCl in the human brain.     

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.     

The influence of gender and emotional valence of visual cues on FMRI activation in humans

Emotional neuroscience maps neurocircuits associated with the processing of affective stimuli. To assess gender differences in brain activation elicited by affective stimuli, we used pictures from the International Affective Picture System in a functional magnetic resonance imaging (fMRI) study. Ten male and ten female age-matched healthy volunteers were included and viewed affectively negative versus positive pictures, which were presented in an event related design. There was a significant interaction between valence of emotional stimuli and gender in the sublenticular extended amygdala (SLEA) and the rostral anterior cingulate. fMRI activation in these regions was stronger for negative compared to positive cues in women. In men fMRI activation was independent of stimulus valence. These results suggest to take gender differences into account when emotional paradigms are tested in functional brain imaging.     

Gender Differences in Nasal Chemesthesis: A Study of Detection and Perceived Intensity

Women are generally more intolerant than men to ambient substances, for which sensory irritation plays an important role. The aim of the present study was to compare women and men with respect to response bias and sensitivity in irritation detection and to irritation intensity. Twelve women and 12 men were exposed to six concentrations of amyl acetate generated by a dynamic olfactometer. Each concentration was presented eight times in randomized order. Clean-air presentations were interrandomized among the series of amyl acetate stimuli to assess and control for response bias. Ratings of irritation intensity were performed with a Borg CR-100 scale. No gender difference in overall irritation detection sensitivity was found, but a significantly steeper psychometric detection function for women implies keener detectability at relatively high concentrations and poorer detectability at low concentrations. A higher false-alarm rate and higher intensity ratings for blank stimuli for women compared to men did almost reach statistical significance. The data showed no overall gender difference in irritation intensity, but a less steep power function for irritation intensity for women, with relatively weak concentrations being perceived as stronger by women than by men. The results suggest no overall gender difference in irritation detectability, but a larger increase in detectability among women across the stimulus span. The tendency of gender differences in response bias implies differences in strategies when detecting possible health hazards. These strategies together with weak concentrations being perceived as stronger may contribute to women being more intolerant than men to ambient substances.     

Frequency dependence and gender effects in visual cortical regions involved in temporal frequency dependent pattern processing

Neural response to flickering stimuli has been shown to be frequency dependent in the primary visual cortex. Controversial gender differences in blood oxygen level dependent (BOLD) amplitude upon 6 and 8 Hz visual stimulation have been reported. In order to analyze frequency and gender effects in early visual processing we employed a passive graded task paradigm with a dartboard stimulus combining eight temporal frequencies from 0 to 22 Hz in one run. Activation maps were calculated within Statistical Parametric Mapping, and BOLD amplitudes were estimated for each frequency within the striate and extrastriate visual cortex. The BOLD amplitude was found to steadily rise up to 8 Hz in BA 17 and 18 with an activation plateau at higher frequencies. In addition, we observed a laterality effect in the striate cortex with higher BOLD contrasts in the right hemisphere in men and in women. BOLD response rises similarly in men and women up to 8 Hz but with lower amplitudes in women at 4, 8, and 12 Hz (30% lower). No frequency effect above 1 Hz was found in the extrastriate visual cortex. There was also a regional specific gender difference. Men activated more in the right lingual gyrus (BA 18) and the right cerebellum compared with women, whereas women showed more activation in the right inferior temporal gyrus (BA 17). The study indicates that frequency dependent processing at the cortical level is limited to the striate cortex and may be associated with a more global information processing (right hemisphere dominance), particularly in men. The finding of significantly lower BOLD amplitudes in women despite previously shown larger VEP (visual evoked potential) amplitudes might suggest gender differences in cerebral hemodynamics (baseline rCBV, rCBF, or neurovascular coupling). The regional distinction points at additional differences in psychological processing even when using a simple visual stimulus.     

SI nociceptive neurons participate in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation

The activity of primary somatosensory (SI) cortical nociceptive neurons was recorded while the monkeys performed a psychophysical task in which they detected small increases in skin temperature superimposed on noxious levels of thermal stimulation. The detection latency to these stimuli, expressed as detection speed, was used as a measure of the perceived intensity of sensation. Two-thirds of the neurons that responded to noxious thermal stimulation increased their discharge in response to graded increases in stimulus intensity. The remaining neurons responded to noxious thermal stimulation, but did not grade their response with the intensity of the stimulus. The response of SI nociceptive neurons that encode the intensity of noxious thermal stimulation was significantly correlated with the monkey's detection speed. We conclude that SI nociceptive neurons are involved in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation.     

Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study.

OBJECTIVE: To investigate, using functional MRI (fMRI), the neural network that is activated by the pain component of capsaicin-induced secondary mechanical hyperalgesia. BACKGROUND: Mechanical hyperalgesia (i.e., pain to innocuous tactile stimuli) is a distressing symptom of neuropathic pain syndromes. Animal experiments suggest that alterations in central pain processing occur that render tactile stimuli capable of activating central pain-signaling neurons. A similar central sensitization can be produced experimentally with capsaicin. METHODS: In nine healthy individuals the cerebral activation pattern resulting from cutaneous nonpainful mechanical stimulation at the dominant forearm was imaged using fMRI. Capsaicin was injected adjacent to the stimulation site to induce secondary mechanical hyperalgesia. The identical mechanical stimulation was then perceived as painful without changing the stimulus intensity and location. Both activation patterns were compared to isolate the specific pain-related component of mechanical hyperalgesia from the tactile component. RESULTS: The pattern during nonpainful mechanical stimulation included contralateral primary sensory cortex (SI) and bilateral secondary sensory cortex (SII) activity. During hyperalgesia, significantly higher activation was found in the contralateral prefrontal cortex: the middle (Brodmann areas [BAs] 6, 8, and 9) and inferior frontal gyrus (BAs 44 and 45). No change was present within SI, SII, and the anterior cingulate cortex. CONCLUSIONS: Prefrontal activation is interpreted as a consequence of attention, cognitive evaluation, and planning of motor behavior in response to pain. The lack of activation of the anterior cingulate contrasts with physiologic pain after C-nociceptor stimulation. It might indicate differences in the processing of hyperalgesia and C-nociceptor pain or it might be due to habituation of affective sensations during hyperalgesia compared with acute capsaicin pain.     

Detection thresholds for electrical stimulation of forebrain and midbrain loci in the rat

Current intensity thresholds for the detection of electrical brain stimulation were determined from a variety of forebrain and midbrain sites in rats. In a discrete trial, instrumental paradigm, the detection stimulus delivered via one electrode acted as a cue for the availability of response contingent rewarding brain stimulation delivered via a second electrode in the posterolateral hypothalamus. The current intensity of the detection stimulus (20 Hz) was varied according to a modification of the psychophysical method of constant stimuli, while the intensity of contingent rewarding stimulation (160 Hz) was fixed at a highly reinforcing level. Detection thresholds measured from forebrain sites were significantly lower than thresholds from midbrain sites. This difference in detection thresholds was not related to any variability between subjects in site or parameters of the rewarding stimulus used to maintain behavior. Lower detection thresholds from forebrain loci may be due to greater sensitivity to electrical stimuli at the detection site or of the pathways from those sites to areas mediating perception or conditioning.     

Individual and sex‐related differences in pain and relief responsiveness are associated with differences in resting‐state functional networks in healthy volunteers

Pain processing is associated with neural activity in a number of widespread brain regions. Here, we investigated whether functional connectivity at rest between these brain regions is associated with individual and sex‐related differences in thermal pain and relief responsiveness. Twenty healthy volunteers (ten females) were scanned with functional magnetic resonance imaging in resting conditions. Half an hour after scanning, we administered thermal pain on the back of their right hand and collected pain and relief ratings in two separate runs of twelve stimuli each. Across the whole group, mean pain ratings were associated with decreased connectivity at rest between brain regions belonging to the default mode and the visual resting‐state network. In men, pain measures correlated with increased connectivity within the visual resting‐state network. In women, in contrast, decreased connectivity between this network and parietal and prefrontal brain regions implicated in affective cognitive control were associated with both pain and relief ratings. Our findings indicate that the well documented individual variability and sex differences in pain sensitivity may be explained, at least in part, by network dynamics at rest in these brain regions.     

Neural correlates of antinociception in borderline personality disorder

CONTEXT: A characteristic feature of borderline personality disorder (BPD) is self-injurious behavior in conjunction with stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with BPD, but the neural correlates of antinociceptive mechanisms in BPD are unknown. We predicted that heat stimuli in patients with BPD would activate brain areas concerned with cognitive and emotional evaluation of pain. OBJECTIVE: To assess the psychophysical properties and neural correlates of altered pain processing in patients with BPD. DESIGN: Case-control study. SETTING: A university hospital. PARTICIPANTS: Twelve women with BPD and self-injurious behavior and 12 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and blood oxygen level-dependent functional magnetic resonance imaging during heat stimulation with fixed-temperature heat stimuli and individual-temperature stimuli adjusted for equal subjective pain in all the participants. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes during heat pain stimulation. RESULTS: Patients with BPD had higher pain thresholds and smaller overall volumes of activity than controls in response to identical heat stimuli. When the stimulus temperature was individually adjusted for equal subjective pain level, overall volumes of activity were similar, although regional patterns differed significantly. Patient response was greater in the dorsolateral prefrontal cortex and smaller in the posterior parietal cortex. Pain also produced neural deactivation in the perigenual anterior cingulate gyrus and the amygdala in patients with BPD. CONCLUSION: The interaction between increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala is associated with an antinociceptive mechanism in patients with BPD.     

Sex and hemisphere differences when mentally rotating meaningful and meaningless stimuli

The purpose of the current study was to investigate the influence of stimulus type and sex on strategy use and hemispheric processing during the mental rotation task. Participants included 67 right-handed men and women who completed three mental rotation tasks, all presented bilaterally. Participants rotated human stick figures, alphanumeric stimuli, and a two-dimensional (2D) meaningless object. No hemispheric differences were observed when rotating human stick figures, suggesting that men and women may rely on the same strategy. A left hemisphere advantage was observed in women when rotating alphanumeric stimuli, suggesting they may be relying on a verbal strategy, whereas no hemispheric differences were observed for men. Finally, inconsistent with predictions, no hemisphere differences were observed when rotating two-dimensional objects. The findings from the current study suggest that both the meaningfulness and the type of stimulus presented may influence strategy use differently for men and women.