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Biomedical subjects

Irene Tracey

Publications and source records attributed to Irene Tracey.

At least 19 recordsLinked to original sources
PubMed2006

Anticipatory brainstem activity predicts neural processing of pain in humans.

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

Adult↗
PubMed2006

Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.

Intense itch and urge to scratch are the major symptoms of many chronic skin ailments, which are increasingly common. Vicious itch-scratch cycles are readily established and may diminish quality of life for those afflicted. We investigated peripheral and central processing of two types of itch sensation elicited by skin-prick tests of histamine and allergen solutions. Itch-related skin blood flow changes were measured by laser Doppler in 14 subjects responsive to type I allergens and 14 nonatopic subjects. In addition, this study examined central processing of both types of itch using functional magnetic resonance imaging (fMRI). Itch perception and blood flow changes were significantly greater when itch was induced by allergens compared with histamine. Both types of itch correlated significantly with activity in the genual anterior cingulate, striatum, and thalamus. Moreover, itch elicited by allergens activated orbitofrontal, supplementary motor, and posterior parietal areas. Histamine-induced itch also significantly correlated with activation in the insula bilaterally. The identification of limbic and ventral prefrontal activation in two types of itch processing likely reflects the subjects' desire to relieve the itch sensation by scratching, and these regions have been repeatedly associated with motivation processing. A dysfunction of the striato-thalamo-orbitofrontal circuit is believed to underlie the failure to regulate motivational drive in disorders associated with strong urges, e.g., addiction and obsessive compulsive disorder. The patterns of itch-induced activation reported here may help explain why chronic itch sufferers frequently self-harm through uncontrollable itch-scratch cycles.

Adult↗
PubMed2006

Pharmacological FMRI: measuring opioid effects on the BOLD response to hypercapnia.

Opioid binding to the cerebral blood vessels may affect vascular responsiveness and hence confound interpretation of blood oxygen level-dependent (BOLD) responses, which are usually interpreted as neuronal in origin. Opioid binding varies in different brain regions. It is unclear whether opioids alter neurovascular coupling, or whether their effects are purely neuronal. This study used BOLD functional magnetic resonance imaging (FMRI) to investigate the effect of a mu-opioid agonist remifentanil, on cerebrovascular CO(2) reactivity (being one component of neurovascular coupling). Hypercapnic challenges were delivered to human volunteers, while controlling potential opioid-induced respiratory depression. The BOLD signal increase to hypercapnia was compared before and during remifentanil administration. Remifentanil was shown not to have a generalised effect on CO(2) responsiveness in the cerebral vasculature. However, it caused a significant reduction in the positive BOLD response to hypercapnia in the bilateral primary sensorimotor cortices, bilateral extrastriate visual areas, left insula, left caudate nucleus, and left inferior temporal gyrus. We conclude that remifentanil does not modulate cerebrovascular CO(2) reactivity, as we saw no difference in BOLD response to hypercapnia in areas with high opioid receptor densities. We did however see a focal reduction in areas related to motor control and putative task activation, which we conclude to be related to changes in neuronal activity related to the sedative effects of remifentanil. Our method of controlling CO(2) levels effectively mitigated the potential confound of respiratory depression and allowed comparison over a similar range of CO(2) levels. We suggest that similar methodology should be used when investigating other potentially vasoactive compounds with FMRI.

Adult↗
PubMed2006

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

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

Adult↗
PubMed2006

Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: a diffusion tensor imaging study in healthy controls.

Neuroimaging methods have so far identified various structures in the brain involved in the processing of pain and its control. However, our understanding of their anatomical connectivities is relatively weak. Diffusion tensor imaging (DTI), a magnetic resonance imaging-based method, allows in vivo mapping of the anatomical connections in the human brain and was used to investigate the white matter connections originating from the periaquaductal grey (PAG) and nucleus cuneiformis (NCF). We performed DTI on 8 healthy right-handed male volunteers. Group analysis showed that tract paths could be defined and their likelihood quantified for connections between the PAG and separately for the NCF, to the prefrontal cortex, amygdala, thalamus, hypothalamus and rostroventral medial medulla bilaterally. The connections identified confirm the existence of an anatomical circuitry for the functionally characterised top-down influences on pain processing via brainstem structures in humans.

Adult↗
PubMed2006

The role of fMRI in drug discovery.

Pharmacological functional (phMRI) studies are making a significant contribution to our understanding of drug-effects on brain systems. Pharmacological fMRI has an additional contribution to make in the translation of disease models and candidate compounds from preclinical to clinical investigation and in the early clinical stages of drug development. Here it can demonstrate a proof-of-concept of drug action in a small human cohort and thus contribute substantially to decision-making in drug development. We review the methods underlying pharmacological fMRI studies and the links that can be made between animal and human investigations. We discuss the potential fMRI markers of drug effect, experimental designs and caveats in interpreting hemodynamic fMRI data as reflective of changes in neuronal activity. Although there are no current published examples of fMRI applied to novel compounds, we illustrate the potential of fMRI across a range of applications and with specific reference to processing of pain in the human brain and pharmacological analgesia. Pharmacological fMRI is developing to meet the neuroscientific challenges. Electrophysiological methods can be used to corroborate the drug effects measured hemodynamically with fMRI. In future, pharmacological fMRI is likely to extend to examinations of the spinal cord and into pharmacogenetics to relate genetic polymorphisms to differential responses of the brain to drugs.

Animals↗
PubMed2006

Pharmacological FMRI in the development of new analgesic compounds.

Chronic pain is a major problem for the individual and for society. Despite a range of drugs being available to treat chronic pain, only inadequate pain relief can be achieved for many patients. There is therefore a need for the development of new analgesic compounds. The assessment of pain depends to date entirely on the subjective report of the patient, in contrast to many other clinical conditions where biomarkers that help determine the severity and stage of the disease enable the physician to monitor the course of the disease and treatment effects longitudinally. In this article, we illustrate that magnetic resonance-based imaging techniques have the potential to provide sensitive and specific biomarkers of the pain experience, as well as clarifying disease mechanisms. Functional magnetic resonance imaging (FMRI) is particularly suited to investigating the effects of pharmacological agents on pain processing within the human central nervous system. Combination of FMRI and drug administration is termed pharmacological FMRI (phFMRI). In addition to outlining several methodological considerations that have to be taken into account when performing phFMRI, we discuss phFMRI studies that have already used this technique to study the effects of analgesic compounds. These studies provide promising data for the use of phFMRI as sensitive tool in assessing a potential drug effect. Such pharmacodynamic readouts obtained early in the process of drug development would not only save the pharmaceutical industry substantial amounts of money, but would also avoid the unnecessary exposure of patients to molecules with limited or no therapeutic value. We are therefore optimistic that phFMRI will be used as a tool with high sensitivity and specificity for evaluating analgesic agents in early drug development and clinical studies.

Analgesics↗
PubMed2006

Imaging pain in patients: is it meaningful?

PURPOSE OF REVIEW: Neuroimaging methods are widely used by researchers and clinicians interested in better understanding the functioning of the human brain in health and disease. Advances have been made in understanding how nociceptive processing within the healthy human central nervous system generates a conscious perception of pain. The focus has now shifted towards patient-related research, harnessing earlier developments to test specific hypotheses in a broad range of chronic pain disorders. The timing is ideal to assess the utility of data generated from these studies. RECENT FINDINGS: This review discusses how clinical pain is represented in the human brain as compared with the processing of acute pain in healthy controls. The imaging literature is reviewed for hypotheses that have been tested in patients regarding mechanisms that might contribute towards the development of chronic pain. Issues related to plasticity, central sensitization, psychological confounds, genetics, and necrosis are examined. SUMMARY: Results to date strongly support the notion that neuroimaging will aid our understanding of basic mechanisms contributing to the generation of chronic pain states. These techniques might help diagnose a patient's pain condition in a more objective and robust way, enabling better targeting of therapies and rapid development of compounds to alleviate pain.

Central Nervous System↗
PubMed2005

Quantitative assessment of the reproducibility of functional activation measured with BOLD and MR perfusion imaging: implications for clinical trial design.

BOLD contrast is the most commonly used functional MRI method for studies of brain activity. However, the underlying physiological processes giving rise to measured BOLD signal changes (which include contribution from changes in cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2)) vary substantially between sessions and subjects. To determine whether direct CBF measurement is a more reliable technique, we compared the localisation of activation and reproducibility of relative signal change measured by optimised BOLD versus CBF measured using the arterial spin labelling (ASL) technique. Data were collected within the primary sensorimotor cortex in normal healthy controls performing a simple finger-tapping task over three imaging sessions (two on same day and one on a different day). The displacement between the foci of BOLD and CBF activation was less than the linear dimension of one voxel (2.4 mm), however, BOLD activation was significantly closer to the nearest draining vein compared to CBF activation (P=0.030). For the relative signal change measurement, we found that CBF has a lower inter-subject variation than BOLD (P<0.05), enabling a smaller sample size for any given effect size, although the intra-subject variation across sessions for CBF was not significantly different from BOLD. BOLD imaging provides the optimal contrast for exploratory brain activation mapping, however, for a single time-point group study, CBF has reduced variance. In addition, the reduction of variance over time using CBF measurements (non-significant) suggests it could potentially provide a more useful approach when assessing longitudinal activation changes.

Adult↗
PubMed2005

A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging.

Evidence from both human and animal studies has demonstrated a key role for brainstem centers in the control of ascending nociceptive input. Nuclei such as the rostral ventromedial medulla and periaqueductal gray (PAG) are able to both inhibit and facilitate the nociceptive response. It has been proposed that altered descending modulation may underlie many of the chronic pain syndromes (both somatic and visceral). We used functional magnetic resonance imaging to image the neural correlates of visceral and somatic pain within the brainstem. Ten healthy subjects were scanned twice at 3 tesla, during which they received matched, moderately painful, electrical stimuli to either the midline lower abdomen or rectum. Significant activation was observed in regions consistent with the PAG, nucleus cuneiformis (NCF), ventral tegmental area/substantia nigra, parabrachial nuclei/nucleus ceruleus, and red nucleus bilaterally to both stimuli. Marked spatial similarities in activation were observed for visceral and somatic pain, although significantly greater activation of the NCF (left NCF, p = 0.02; right NCF, p = 0.01; Student's paired t test, two-tailed) was observed in the visceral pain group compared with the somatic group. Right PAG activity correlated with anxiety during visceral stimulation (r = 0.74; p < 0.05, Pearson's r, two-tailed) but not somatic stimulation. We propose that the differences in NCF and right PAG activation observed may represent a greater nocifensive response and greater emotive salience of visceral over somatic pain.

Abdomen↗
PubMed2005

Nociceptive processing in the human brain.

Since the advent of modern neuroimaging techniques, studies have been carried out to examine nociceptive processing within the human brain non-invasively. Combined with advances in immunohistochemistry, histology and genetics, we have been able to correlate more objective measures of nociceptive processing with the subjective experience that is pain. The result has produced a dramatic shift in our thinking about the neural circuitry involved in nociceptive processing, revealing that pain is much more than a submodality of the sense of touch.

Afferent Pathways↗
PubMed2005

From nociception to pain perception: imaging the spinal and supraspinal pathways.

Functional imaging techniques have allowed researchers to look within the brain, and revealed the cortical representation of pain. Initial experiments, performed in the early 1990s, revolutionized pain research, as they demonstrated that pain was not processed in a single cortical area, but in several distributed brain regions. Over the last decade, the roles of these pain centres have been investigated and a clearer picture has emerged of the medial and lateral pain system. In this brief article, we review the imaging literature to date that has allowed these advances to be made, and examine the new frontiers for pain imaging research: imaging the brainstem and other structures involved in the descending control of pain; functional and anatomical connectivity studies of pain processing brain regions; imaging models of neuropathic pain-like states; and going beyond the brain to image spinal function. The ultimate goal of such research is to take these new techniques into the clinic, to investigate and provide new remedies for chronic pain sufferers.

Brain↗
PubMed2004

Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal.

Carbon dioxide is a potent cerebral vasodilator. We have identified a significant source of low-frequency variation in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal at 3 T arising from spontaneous fluctuations in arterial carbon dioxide level in volunteers at rest. Fluctuations in the partial pressure of end-tidal carbon dioxide (Pet(CO(2))) of +/-1.1 mm Hg in the frequency range 0-0.05 Hz were observed in a cohort of nine volunteers. Correlating with these fluctuations were significant generalized grey and white matter BOLD signal fluctuations. We observed a mean (+/-standard error) regression coefficient across the group of 0.110 +/- 0.033% BOLD signal change per mm Hg CO(2) for grey matter and 0.049 +/- 0.022% per mm Hg in white matter. Pet(CO(2))-related BOLD signal fluctuations showed regional differences across the grey matter, suggesting variability of the responsiveness to carbon dioxide at rest. Functional magnetic resonance imaging (fMRI) results were corroborated by transcranial Doppler (TCD) ultrasound measurements of the middle cerebral artery (MCA) blood velocity in a cohort of four volunteers. Significant Pet(CO(2))-correlated fluctuations in MCA blood velocity were observed with a lag of 6.3 +/- 1.2 s (mean +/- standard error) with respect to Pet(CO(2)) changes. This haemodynamic lag was adopted in the analysis of the BOLD signal. Doppler ultrasound suggests that a component of low-frequency BOLD signal fluctuations is mediated by CO(2)-induced changes in cerebral blood flow (CBF). These fluctuations are a source of physiological noise and a potentially important confounding factor in fMRI paradigms that modify breathing. However, they can also be used for mapping regional vascular responsiveness to CO(2).

Adult↗
PubMed2004

Lateralisation of nociceptive processing in the human brain: a functional magnetic resonance imaging study.

Nociceptive processing within the human brain takes place within two distinct and parallel systems: the lateral and medial pain systems. Current knowledge indicates that the lateral system is involved in processing the sensory-discriminative aspects of pain, and that the medial system is involved in processing the affective-motivational aspects of pain. Hemispheric differences in brain activation (lateralisation) during nociceptive processing were studied to further clarify the division of function between the lateral and medial pain systems. Hemispheric lateralisation was studied by applying painful CO(2) laser stimuli of 3-s duration sequentially to the left and right medial lower calves of five normal right-handed human subjects. The resultant brain activity was measured using 3-T functional magnetic resonance imaging, by determining significant changes in blood oxygen level dependent (BOLD) signal and applying a general linear modelling approach. Volumes of interest were defined for the primary and secondary somatosensory cortices (SI and SII), the insular cortex, and the thalamus, on individual subjects' high-resolution structural scans. Hemispheric lateralisation was quantified by comparing the level of activation between brain hemispheres within each volume of interest. In SII, no significant hemispheric difference in activation was detected. In the insula, activation was significantly greater in the left hemisphere than the right. In both SI and the thalamus, activation in response to painful stimulation was significantly greater in the hemisphere contralateral to the stimulus, which is consistent with these areas being involved in processing the sensory-discriminative aspects of pain.

Adult↗
PubMed2004

Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.

To understand and exploit centrally acting drugs requires reliable measures of their time course of action in the human brain. Functional magnetic resonance imaging (fMRI) is able to measure noninvasively, drug-induced changes in task-related brain activity. Here, we have characterized, in a specific region of the brain, the time of onset of action and the half-life of action of a clinically relevant dose of a potent opioid analgesic agent, remifentanil. These times were established from the temporal variation of the amplitude of the blood oxygen level-dependent response in the insular cortex contralateral to a painfully hot thermal stimulus, in volunteers receiving a remifentanil infusion. The insular cortex has repeatedly been reported as activated by noxious thermal stimulation. The times of onset and offset of drug action were each characterized by a half-life for changes in fMRI signal from within the insula. These characteristic times agreed with the observed drug-induced analgesia and previous pharmacokinetic-pharmacodynamic measurements for remifentanil. We have successfully measured, for the first time using fMRI, temporal pharmacological parameters for a CNS-active drug based on its effect on task-related activity in a specific brain region. Comparison of the time course of regional brain activity with pain perception could reveal those regions engaged in drug-induced analgesia.

Adult↗
PubMed2004

An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.

BACKGROUND: Anatomic sites within the brain, which activate in response to noxious stimuli, can be identified with the use of functional magnetic resonance imaging. The aim of this study was to determine whether the analgesic effects of ketamine could be imaged. METHODS: Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations: 0 (saline), 50 (subanalgesic), and 200 ng/ml (analgesic, subanesthetic). Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet. Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures. RESULTS: The analgesic subanesthetic dose of ketamine significantly reduced the pain scores, and this matched a decrease in activity within brain regions that activate in response to noxious stimuli, in particular, the insular cortex and thalamus. A different pattern of activation was observed in response to an auditory task. In comparison, smaller behavioral and imaging changes were found for the motor paradigm. The lower dose of ketamine gave similar but smaller nonsignificant effects. CONCLUSION: The analgesic effect can be measured within a more global effect of ketamine as shown by auditory and motor tasks, and the analgesia produced by ketamine occurs with a smaller degree of cortical processing in pain-related regions.

Acoustic Stimulation↗