Determining Brain Mechanisms that Underpin Analgesia Induced by the Use of Pain Coping Skills.

Objective: Cognitive behavioral therapies decrease pain and improve mood and function in people with osteoarthritis. This study assessed the effects of coping strategies on the central processing of knee pain in people with osteoarthritis of the knees. Methods: Mechanical pressure was applied to exacerbate knee pain in 28 people with osteoarthritis of the knee. Reports of pain intensity and functional magnetic resonance imaging measures of pain-related brain activity were recorded with and without the concurrent use of pain coping skills. Results: Coping skills led to a significant reduction in pain report (Coping = 2.64 ± 0.17, Not Coping = 3.28 ± 0.15, P < 0.001). These strategies were associated with increased activation in pain modulatory regions of the brain (medial prefrontal and rostral anterior cingulate cortices, Pcorrected < 0.05) and decreased pain-related activation in regions that process noxious input (midcingulate cortex, supplementary motor area, secondary somatosensory cortex, and anterior parietal lobule, Pcorrected < 0.05). The magnitude of the decrease in pain report during the use of pain coping strategies was found to be proportional to the decrease in pain-related activation in brain regions that code the aversive/emotional dimension of pain (anterior insula, inferior frontal gyrus, orbitofrontal cortex, Pcorrected < 0.05) but did not differ between groups with and without training in coping skills. However, training in coping skills reduced the extent to which brain responses to noxious input were influenced by anxiety. Conclusions: The results of this study support previous reports of pain modulation by cognitive pain coping strategies and contribute to the current understanding of how analgesia associated with the use of pain coping strategies is represented in the brain.

Functionally connected brain regions in the network activated during capsaicin inhalation.

Coughing and the urge-to-cough are important mechanisms that protect the patency of the airways, and are coordinated by the brain. Inhaling a noxious substance leads to a widely distributed network of responses in the brain that are likely to reflect multiple functional processes requisite for perceiving, appraising, and behaviorally responding to airway challenge. The broader brain network responding to airway challenge likely contains subnetworks that are involved in the component functions required for coordinated protective behaviors. Functional connectivity analyses were used to determine whether brain responses to airway challenge could be differentiated regionally during inhalation of the tussive substance capsaicin. Seed regions were defined according to outcomes of previous activation studies that identified regional brain responses consistent with cough suppression, stimulus intensity coding, and perception of urge-to-cough. The subnetworks during continuous inhalation of capsaicin recapitulated the distributed regions previously implicated in discrete functional components of airway challenge. The outcomes of this study highlight the central representation of airways defence as a distributed network.

Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans.

The perception of airways irritation is represented in a distributed brain network. However, the functional roles of sub-regions of this network are yet to be determined. The aim of this study was to measure brain activation in healthy participants as they inhaled two doses of capsaicin to identify dose-dependent and dose-independent responses. Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measures of brain responses during inhalation of saline, and a low and high dose of capsaicin were made from 16 healthy participants. Subjective ratings of the urge-to-cough were also made during capsaicin challenges. The majority of brain regions that were activated during capsaicin inhalation, including insula and mid cingulate cortex, showed graduated responses to the two doses of capsaicin. Prefrontal and parietal regions had dose-independent activation, whereas premotor regions and the cerebellum activated exclusively at the high dose of capsaicin. Activation in the somatosensory and mid-cingulate cortices correlated with ratings of urge-to-cough. In the brainstem, capsaicin produced dose-dependent activations in respiratory-related regions of the dorsal pons and lateral medulla. These data show dissociable response patterns to capsaicin inhalation that may represent different regional processes involved in monitoring and assessing stimulus intensity, determining the spatial localization of the stimulus and suppressing motor responses.

Central nervous system control of cough: pharmacological implications.

For many years the idea of a cough center in the brain dominated discussions in the field without any substantial progress in defining what this cough center is or how it functions. Substantial progress has now been made and many of the central neural elements involved in coughing are being described. Furthermore, hypothesis driven research into the function of these neural elements is providing exciting new leads for possible therapeutic targets. The concept of a specific, centrally acting drug for cough suppression is fast becoming a reality. This review summarizes the key findings from the past few years and provides a perspective on future directions for the development of novel antitussives.

Investigation of the neural control of cough and cough suppression in humans using functional brain imaging.

Excessive coughing is one of the most common reasons for seeking medical advice, yet the available therapies for treating cough disorders are inadequate. Humans can voluntarily cough, choose to suppress their cough, and are acutely aware of an irritation that is present in their airways. This indicates a significant level of behavioral and conscious control over the basic cough reflex pathway. However, very little is known about the neural basis for higher brain regulation of coughing. The aim of the present study was to use functional brain imaging in healthy humans to describe the supramedullary control of cough and cough suppression. Our data show that the brain circuitry activated during coughing in response to capsaicin-evoked airways irritation is not simply a function of voluntarily initiated coughing and the perception of airways irritation. Rather, activations in several brain regions, including the posterior insula and posterior cingulate cortex, define the unique attributes of an evoked cough. Furthermore, the active suppression of irritant-evoked coughing is also associated with a unique pattern of brain activity, including an involvement of the anterior insula, anterior mid-cingulate cortex, and inferior frontal gyrus. These data demonstrate for the first time that evoked cough is not solely a brainstem-mediated reflex response to irritation of the airways, but rather requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes.

The impact of Alzheimer's disease on the functional connectivity between brain regions underlying pain perception.

Patients with Alzheimer's disease (AD) are administered fewer analgesics and report less clinical pain compared with their cognitively-intact peers, prompting much speculation about the likely impact of neurodegeneration on pain perception and processing. This study used functional connectivity analysis to examine the impact of AD on the integrated functioning of brain regions mediating the sensory, emotional, and cognitive aspects of pain. Fourteen patients with AD and 15 controls attended two experimental sessions. In an initial psychophysical testing session, a random staircase procedure was used to assess sensitivity to noxious mechanical pressure applied to the thumbnail. In a subsequent brain imaging session, fMRI data were collected as participants received noxious or innocuous thumbnail pressure, delivered at intensities corresponding with previously identified subjective pain thresholds. Two approaches to functional connectivity analysis were utilised. A seed-based correlation method was first used to identify regions showing significant functional connectivity with the right dorsolateral prefrontal cortex (DLPFC). Functional connectivity between a network of 17 predefined pain processing regions was then assessed. Between-group comparisons revealed enhanced functional connectivity between the DLPFC and the anterior mid cingulate cortex, periaqueductal grey, thalamus, hypothalamus, and several motor areas in patients with AD compared with control group. Likewise, inter-regional functional connectivity across most regions of the predefined pain network was shown to be greater in the patient group, with the enhanced functional connectivity centred on three nodes: the DLPFC-R, hypothalamus, and PAG. The results of this study support previous research suggesting an interplay between pain and cognitive processes in patients with AD.

Age-related differences in pain sensitivity and regional brain activity evoked by noxious pressure.

Compared with young adults, older people report more chronic pain complaints, and show reduced tolerance to experimental pain. Atrophy of brain parenchyma in normal ageing is well documented, with grey matter reduction occurring across many regions known to be involved in pain processing. However, the functional consequences of these changes, in particular their contribution toward age-related differences in pain perception and report, are yet to be elucidated. The present study investigated the effects of ageing on supraspinal pain processing by comparing regional brain responses to noxious pressure stimulation in 15 young (aged 26+/-3 years) and 15 older (aged 79+/-4 years) adults. Both groups showed significant pain-related activity in a common network of areas including the insula, cingulate, posterior parietal and somatosensory cortices. However, compared with older adults, young subjects showed significantly greater activity in the contralateral putamen and caudate, which could not be accounted for by increased age-associated shrinkage in these regions. The age-related difference in pain-evoked activity seen in the present study may reflect reduced functioning of striatal pain modulatory mechanisms with advancing age.

Pain sensitivity and fMRI pain-related brain activity in Alzheimer's disease.

People with Alzheimer's disease are administered fewer analgesics and report less clinical pain than cognitively intact peers with similar painful diseases or injuries, prompting speculation about the likely impact of neurodegeneration on central pain processing. The present study measured pain ratings and functional MRI (fMRI) brain responses following mechanical pressure simulation in 14 patients with Alzheimer's disease and 15 age-matched controls. Contrary to the prevailing hypothesis that this disease is likely to differentially reduce emotional responses to pain, we show that activity in both medial and lateral pain pathways is preserved. Moderate pain was evoked with similar stimuli in both groups, and was associated with a common network of pain-related activity incorporating cingulate, insula and somatosensory cortices. Between-group analyses showed no evidence of diminished pain-related activity in Alzheimer's disease patients compared with controls. In fact, compared with controls, patients showed greater amplitude and duration of pain-related activity in sensory, affective and cognitive processing regions consistent with sustained attention to the noxious stimulus. The results of this study show that pain perception and processing are not diminished in Alzheimer's disease, thereby raising concerns about the current inadequate treatment of pain in this highly dependent and vulnerable patient group.

Human medullary responses to cooling and rewarming the skin: a functional MRI study.

A fall in skin temperature precipitates a repertoire of thermoregulatory responses that reduce the likelihood of a decrease in core temperature. Studies in animals suggest that medullary raphé neurons are essential for cold-defense, mediating both the cutaneous vasoconstrictor and thermogenic responses to ambient cooling; however, the involvement of raphé neurons in human thermoregulation has not been investigated. This study used functional MRI with an anatomically guided region of interest (ROI) approach to characterize changes in the blood oxygen level-dependent (BOLD) signal within the human medulla of nine normal subjects during non-noxious cooling and rewarming of the skin by a water-perfused body suit. An ROI covering 4.9 +/- 0.3 mm(2) in the ventral midline of the medulla immediately caudal to the pons (the rostral medullary raphé) showed an increase in BOLD signal of 3.9% (P < 0.01) during periods of skin cooling, compared with other times. Overall, that signal showed a strong inverse correlation (R = 0.48, P < 0.001) with skin temperature. A larger ROI covering the internal medullary cross section at the same level (area, 126 +/- 15 mm(2)) showed no significant change in mean BOLD signal with cooling (+0.2%, P > 0.05). These findings demonstrate that human rostral medullary raphé neurons are selectively activated in response to a thermoregulatory challenge and point to the location of thermoregulatory neurons homologous to those of the raphé pallidus nucleus in rodents.