Denoising task-related fMRI: Balancing noise reduction against signal loss.

Preprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high-pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise-reduction techniques, for example, CompCor, FIX, and ICA-AROMA have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting-state fMRI and, only rarely, in task-related fMRI. Application of noise-reduction techniques to task-related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. Little remains known about the impact of these techniques on the retention of signal in tasks that may be associated with systemic physiological changes. In this paper, we compared two ICA-based, that is FIX and ICA-AROMA, two CompCor-based noise-reduction techniques, that is aCompCor, and tCompCor, and standard preprocessing using a large (n = 101) fMRI dataset including noxious heat and non-noxious auditory stimulation. Results show that preprocessing using FIX performs optimally for data obtained using noxious heat, conserving more signals than CompCor-based techniques and ICA-AROMA, while removing only slightly less noise. Similarly, for data obtained during non-noxious auditory stimulation, FIX noise-reduction technique before analysis with a covariate of interest outperforms the other techniques. These results indicate that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise during task-related fMRI.

Dissociation between individual differences in self-reported pain intensity and underlying fMRI brain activation.

Pain is an individual experience. Previous studies have highlighted changes in brain activation and morphology associated with within- and interindividual pain perception. In this study we sought to characterize brain mechanisms associated with between-individual differences in pain in a sample of healthy adolescent and adult participants (N = 101). Here we show that pain ratings varied widely across individuals and that individuals reported changes in pain evoked by small differences in stimulus intensity in a manner congruent with their pain sensitivity, further supporting the utility of subjective reporting as a measure of the true individual experience. Furthermore, brain activation related to interindividual differences in pain was not detected, despite clear sensitivity of the Blood Oxygenation Level-Dependent (BOLD) signal to small differences in noxious stimulus intensities within individuals. These findings suggest fMRI may not be a useful objective measure to infer reported pain intensity.

Contagious itch in humans: a study of visual 'transmission' of itch in atopic dermatitis and healthy subjects.

BACKGROUND: Anecdotal evidence suggests that 'contagious' itch occurs in daily life when we see other people itch and scratch. This phenomenon has not previously been studied systematically, and factors which can amplify itch perception were unknown. OBJECTIVES: We investigated whether exposure to visual cues of itch can induce or intensify itch in healthy subjects and patients with atopic dermatitis (AD). METHODS: Participants received histamine or a saline control delivered to the forearm and were asked to watch short video clips of people scratching. Spontaneous scratching induced by visual cues was monitored and analysed. RESULTS: Patients with AD reported a higher itch intensity and scratched more frequently while watching itch videos, even in the presence of mock itch stimuli. CONCLUSIONS: Human susceptibility to develop itch when exposed to visual cues is confirmed; it appears to be amplified in patients with AD. These findings suggest that interpersonal social cues can dramatically alter the subjective sensory experience of itch.

Ethnic differences in pain, itch and thermal detection in response to topical capsaicin: African Americans display a notably limited hyperalgesia and neurogenic inflammation.

BACKGROUND: Topical application of capsaicin commonly produces burning, stinging and itching as well as hyperalgesia to heat stimuli via activation of transient receptor potential vanilloid subtype 1. OBJECTIVES: To investigate whether there are differences in sensory response and neurogenic inflammation to topical capsaicin in four different ethnic populations with different skin types. METHODS: The study was performed in 40 healthy subjects consisting of 10 African Americans, 10 East Asians, 10 Hispanics and 10 Caucasians. Warmth sensation and heat pain detection thresholds, as well as pain intensity, were measured before and after application of capsaicin or placebo on forearms along with skin blood flow and the extent of the flare reaction. RESULTS: In African Americans the heat pain detection threshold, pain intensity and skin blood flow did not change significantly after capsaicin application, while in the other three ethnic groups a significant change occurred characterized by hyperalgesia and vasodilatation. The postcapsaicin warmth sensation threshold increased in African Americans and decreased in Hispanics, the latter also uniquely experiencing postcapsaicin itch. CONCLUSIONS: Our observations indicate that African Americans display a limited hypersensitivity following topical capsaicin, compared with the three other ethnic groups.

Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.

BACKGROUND: Little is known about brain mechanisms supporting the experience of chronic puritus in disease states. OBJECTIVES: To examine the difference in brain processing of histamine-induced itch in patients with active atopic dermatitis (AD) vs. healthy controls with the emerging technique of functional magnetic resonance imaging (fMRI) using arterial spin labelling (ASL). METHODS: Itch was induced with histamine iontophoresis in eight patients with AD and seven healthy subjects. RESULTS: We found significant differences in brain processing of histamine-induced itch between patients with AD and healthy subjects. Patients with AD exhibited bilateral activation of the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), retrosplenial cingulate cortex and dorsolateral prefrontal cortex (DLPFC) as well as contralateral activation of the caudate nucleus and putamen. In contrast, healthy subjects activated the primary motor cortex, primary somatosensory cortex and superior parietal lobe. The PCC and precuneus exhibited significantly greater activity in patients vs. healthy subjects. A significant correlation between percentage changes of brain activation was noted in the activation of the ACC and contralateral insula and histamine-induced itch intensity as well as disease severity in patients with AD. In addition, an association was noted between DLPFC activity and disease severity. CONCLUSIONS: Our results demonstrate that ASL fMRI is a promising technique to assess brain activity in chronic itch. Brain activity of acute itch in AD seems to differ from that in healthy subjects. Moreover, the activity in cortical areas involved in affect and emotion correlated to measures of disease severity.

Comparison of PET [15O]water studies with 6-minute and 10-minute interscan intervals: single-subject and group analyses.

The authors recently showed that [15O]water PET data obtained with a short interscan interval (6 minutes) produced similar results whether or not the residual background from the previous scan is subtracted. The purpose of the present study was to compare scans obtained during motor activation using a short (6-minute) interscan interval protocol with those obtained with a standard (10-minute) protocol in the same scanning session. Single-subject and group analyses were performed using Worsley's method, which uses a pooled variance estimate and statistical parametric mapping with a local variance estimate. High consistency in both the activation maps, i.e., the number of activated motor brain structures and the Talairach coordinates of peak intensities of the activated regions, was obtained in the 6- and 10-minute studies in both single-subject and group analyses. However, in comparison to the 6-minute studies, a larger cluster size of activated brain regions and an approximately 20% higher peak activation in these regions were observed in the 10-minute studies with the same number of replicates. Analysis of these results suggests that using a 6-minute interval with an increased number of replications, i.e., without changing the subject's total study duration, should produce comparable statistical power to that of the 10-minute interval for group analysis and increased statistical power for single-subject analyses that use a local variance estimate because of increased degrees of freedom. Alternatively, with a small increase in the number of scans and the use of a 6-minute interscan interval, a comparable level of statistical significance may be achieved for single-subject experiments that use a local variance estimate, with an overall shortening of the study duration.

Global cerebral blood flow decreases during pain.

Positron emission tomography studies have identified a common set of brain regions activated by pain. No studies, however, have quantitatively examined pain-induced CBF changes. To better characterize CBF during pain, 14 subjects received positron emission tomography scans during rest, during capsaicin-evoked pain (250 micrograms, intradermal injection), and during innocuous vibration. Using the H215O intravenous bolus method with arterial blood sampling, global CBF changes were assessed quantitatively. Painful stimulation produced a 22.8% decrease in global CBF from resting levels (P < 0.0005). This decrease was not accounted for by arterial PCO2 or heart rate changes. Although the exact mechanism remains to be determined, this pain-induced global decrease represents a previously unidentified response of CBF.

Positron emission tomography [15O]water studies with short interscan interval for single-subject and group analysis: influence of background subtraction.

Use of short interscan interval [15O]water positron emission tomography (PET) studies reduces the overall study duration and may allow an increased number of scans for single-subject analysis of unique cases (e.g., stroke). The purpose of this study was to examine how subtraction of residual radioactivity from the previous injection (corrected scan) compared to nonsubtraction (uncorrected scan) in a PET short interscan interval (6 minutes) study affects single-subject and group data analysis using a motor activation task. Two currently widely used analytic strategies, Worsley's method and the SPM technique, were applied. Excellent agreement between activation maps obtained from corrected and uncorrected data sets was obtained both in single-subject analyses performed on data sets from the six normal subjects and three stroke (subcortical infarct) patients, and in group analysis (six normal subjects) within a particular statistical method. The corrected and uncorrected data were very similar in the (1) number of activated brain regions; (2) size of clusters of activated brain voxels; (3) Talairach coordinates of the activated region; and (4) t or Z value of the peak intensity for every significantly activated motor brain structure (both for large activations such as in motor cortex and small activations such as in putamen and thalamus). [15O]Water PET data obtained with a short interscan interval (6 minutes) produce similar results whether or not the background is subtracted. Thus, if injection dose and timing are constant, one can achieve the advantage of a short interscan interval without the added complexity of correcting for background radioactivity.

Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation.

The present study examined the effects of intrathecal (i.t.) injection of calcitonin gene-related peptide (CGRP) on caudally directed biting and scratching induced by i.t. substance P (SP), bombesin (BBS), strychnine (STR), and kainic acid (KA). CGRP alone (5.25, 10.5 and 21 nmol) had no effect on these behaviors, but CGRP pretreatment produced a dose-related enhancement of behaviors induced by SP or BBS, but not by KA or STR. 2-Amino-5-phosphonovaleric acid (APV, 25 nmol), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, did not block the CGRP potentiation of SP and BBS induced behaviors. CGRP, however, failed to enhance scratching and biting induced by a SP analogue [pGlu5-Mephe8-MeGly9]SP(5-11) (Dime-C7) that is resistant to enzymatic degradation by SP endopeptidase. These findings demonstrate that CGRP potentiates SP induced behavioral responses via inhibition of neuropeptide degradation and that this mechanism may serve as a physiological mechanism of SP modulation.

Post-injury treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy.

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.

Regional changes in spinal cord glucose metabolism in a rat model of painful neuropathy.

Spinal cord patterns of metabolic activity in a model of neuropathic pain were assessed in unanesthetized rats by the [14C]-2-deoxyglucose (2-DG) technique. Rats used in this procedure had demonstrable thermal hyperalgesia ipsilateral to sciatic nerve ligation and ipsilateral hindpaws that were lifted in a guarded position. The latter indicated possible spontaneous pain. Sciatic nerve ligation produced significant increases in glucose utilization in the dorsal and ventral horns of both sides, with greater activity present on the ipsilateral as compared to the contralateral side. Peak activity was in laminae V-VI, a region involved in nociceptive processing. Thus, a chronic increase in neuronal activity in these regions may reflect spontaneous neuropathic pain.

Paradoxical opiate specific paralytic effects of high doses of intracerebroventricular etorphine and fentanyl in rats.

Injections of high doses of etorphine (0.0625, 0.25, or 1.0 mumol) or equimolar fentanyl into the cerebral ventricles of rats induced a sequence of motor effects including catatonia, a novel flaccid paralysis, and recurrent catatonia. These effects were dose related, naloxone reversible, and reveal an opiate specific organization of a central motor hierarchy.

Opioid inhibition of kainic acid-induced scratching: mediation by mu and sigma but not delta and kappa receptors.

Scratching induced by intrathecal (IT) administration of kainic acid (0.5 nmol) to rats was inhibited by IT pretreatment with the selective mu agonists levorphanol (30 and 90 nmol), [D-Ala2,N-Met-Phe4,Gly5-ol]-enkephalin (DAGO, 0.4 and 1.1 nmol), or morphine (90 nmol), the mixed mu-delta agonist [D-Ala2,D-Leu5]-enkephalinamide (DADLE, 10 and 30 nmol), or the sigma/phenycyclidine (PCP) agonists dextrorphan (90 nmol) or (+)-N-allyl-N-normetazocine ([+]-NAM, 90 nmol). The kappa agonists dynorphin (1.1 nmol) and ethylketocyclazocine (EKC, 90 nmol) had no significant effect, nor did the selective delta agonist [D-Pen2,D-Pen5]-enkephalinamide (DPDPE, 90 nmol). The nonopioids (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([+]-3-PPP, 90 nmol) and PCP (90 nmol), selective for sigma and PCP sites, respectively, both antagonized kainic-induced scratching. Levorphanol- and DADLE-induced attenuation of scratching was partially antagonized by naltrexone. These findings suggest that opioid inhibition of kainic acid-induced scratching is mediated by classical mu receptors as well as sigma and PCP sites.

Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information.

The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a µ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a µ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

Mindfulness meditation-related pain relief: evidence for unique brain mechanisms in the regulation of pain.

The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain.

Repetitive scratching and noxious heat do not inhibit histamine-induced itch in atopic dermatitis.

BACKGROUND: Repetitive scratching is the most common behavioural response to itch in atopic dermatitis (AD). Patients with chronic itch often report that very hot showers inhibit itch. We recently reported that scratching and noxious heat stimuli inhibit histamine-induced itch in healthy subjects. However, no psychophysical studies have been performed in AD to assess the effects of repetitive heat pain stimuli and scratching on histamine-induced itch. OBJECTIVES: To examine the effects of repetitive noxious heat and scratching on itch intensity in patients with AD using quantitative sensory testing devices. METHODS: Itch was induced with histamine iontophoresis in 16 patients with AD in both lesional and nonlesional skin as well as in 10 healthy subjects. Repetitive noxious heat and scratching were applied 3 cm distal to the area of histamine iontophoresis. Subjects rated their perceived intensity of histamine-induced itch with a computerized visual analogue scale. RESULTS: Our results demonstrate that repetitive noxious heat and scratching do not inhibit itch intensity in lesional and nonlesional AD skin but do so in healthy skin. Of note, both these stimuli increase itch intensity in lesional AD skin. CONCLUSIONS: Our results strongly suggest that scratching and noxious thermal stimuli have a different effect upon histamine-induced itch perception in patients with AD when compared with healthy controls. This difference may be associated with both peripheral and central sensitization of nerve fibres in AD.

Scratching and noxious heat stimuli inhibit itch in humans: a psychophysical study.

BACKGROUND: Patients who suffer from chronic itch employ creative techniques to alleviate their itch, often using painful thermal stimuli, such as hot and very cold showers, as well as mechanical stimuli, such as scratching. OBJECTIVES: The present study examined whether the sensory perception of itch is attenuated by remote interactions between both thermal and mechanical stimuli and afferent information related to itch. PATIENTS AND METHODS: Itch was induced with histamine iontophoresis in 21 healthy young subjects. Repetitive thermal stimuli including innocuous warmth, innocuous cool, noxious cold and noxious heat as well as scratching were applied 3-cm distal to the area of histamine iontophoresis. Subjects rated their perceived intensity of histamine-induced itch with a computerized visual analogue scale. RESULTS: Itch intensity ratings were significantly reduced during each period of scratching and repeated noxious heat and cold. Innocuous cooling and warming did not significantly alter itch intensity ratings. Inter-individual differences in histamine-induced itch sensitivity were unrelated to inter-individual differences in pain sensitivity. CONCLUSIONS: The present psychophysical study demonstrates that repetitive noxious thermal and scratching stimuli inhibit itch and do not require direct physical interaction with the area of the skin from which itch originates.

Imaging of pain: recent developments.

Brain imaging of pain has made remarkable strides in the past year and a half. The basic regional activation pattern after acute nociceptive stimulation is now fairly well clarified. The extension of imaging studies from normal subjects to include cohorts of pathological pain patients is occurring. The techniques of positron emission tomography, functional magnetic resonance imaging and single photon emission computed tomography have all been applied to the study of human pain processing and the assessment of physiological interventions or psychological manipulations. Studies using labelled ligands to trace receptor alterations have also been conducted. Although more work could be done on the pharmacology and physiology of anesthesiology, the resulting set of observations provides a deeper understanding of the basic human neurophysiology of pain and a potential neural framework for better pain management.

Hemispheric lateralization of somatosensory processing.

Processing of both painful and nonpainful somatosensory information is generally thought to be subserved by brain regions predominantly contralateral to the stimulated body region. However, lesions to right, but not left, posterior parietal cortex have been reported to produce a unilateral tactile neglect syndrome, suggesting that components of somatosensory information are preferentially processed in the right half of the brain. To better characterize right hemispheric lateralization of somatosensory processing, H(2)(15)O positron emission tomography (PET) of cerebral blood flow was used to map brain activation produced by contact thermal stimulation of both the left and right arms of right-handed subjects. To allow direct assessment of the lateralization of activation, left- and right-sided stimuli were delivered during separate PET scans. Both innocuous (35 degrees C) and painful (49 degrees C) stimuli were employed to determine whether lateralized processing occurred in a manner related to perceived pain intensity. Subjects were also scanned during a nonstimulated rest condition to characterize activation that was not related to perceived pain intensity. Pain intensity-dependent and -independent changes in activation were identified in separate multiple regression analyses. Regardless of the side of stimulation, pain intensity--dependent activation was localized to contralateral regions of the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, and bilateral regions of the cerebellum, putamen, thalamus, anterior cingulate cortex, and frontal operculum. No hemispheric lateralization of pain intensity-dependent processing was detected. In sharp contrast, portions of the thalamus, inferior parietal cortex (BA 40), dorsolateral prefrontal cortex (BA 9/46), and dorsal frontal cortex (BA 6) exhibited right lateralized activation during both innocuous and painful stimulation, regardless of the side of stimulation. Thus components of information arising from the body surface are processed, in part, by right lateralized systems analogous to those that process auditory and visual spatial information arising from extrapersonal space. Such right lateralized processing can account for the left somatosensory neglect arising from injury to brain regions within the right cerebral hemisphere.