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  • A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.

    24 October 2018

    Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole-brain functional magnetic resonance imaging at 3T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired t-test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (Z>2.3, corrected P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.

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

    24 October 2018

    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).

  • Neuroanatomy of impaired self-awareness in Alzheimer's disease and mild cognitive impairment

    24 October 2018

    Introduction: Patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be unaware of their cognitive impairment. The neuroanatomical mechanisms underlying this symptom, termed anosognosia or impaired self-awareness, are still poorly understood. In the present study we aimed to explore the functional correlates of self-awareness in patients with MCI and AD. Methods: Fifty-one participants (17 healthy elderly, 17 patients with MCI, and 17 patients with AD), each accompanied by a study partner, took part in a functional magnetic resonance imaging (fMRI) study, in which they were presented with questions regarding themselves (Self condition) or their study partner (Other condition). The study partner was asked to complete a paper questionnaire answering the same questions so the responses of participant and study partner could be compared and "discrepancy" scores calculated for each of the 2 conditions (Self and Other). Results: Behavioural results showed that AD patients had significantly higher "Self discrepancy scores" than controls and MCI patients, whereas there were no significant differences between groups for "Other discrepancy scores" Imaging results showed a significant group-by-condition interaction in brain activation in medial prefrontal and anterior temporal regions, with AD patients showing significantly decreased activation in these regions only for the Self condition. There were no significant differences between Self and Other conditions in either control or MCI groups, suggesting that, in these groups, Self- and Other-appraisal share similar neuroanatomical substrates. Conclusions: Decreased functional activation of medial prefrontal and anterior temporal cortices is associated with impaired self-awareness in AD patients. This dysfunction, which is specific for Self- but not for Other-appraisal, may be a contributing factor to anosognosia in AD. © 2012 Elsevier Ltd.

  • The importance of context: When relative relief renders pain pleasant

    24 October 2018

    Context can influence the experience of any event. For instance, the thought that "it could be worse" can improve feelings towards a present misfortune. In this study we measured hedonic feelings, skin conductance, and brain activation patterns in 16 healthy volunteers who experienced moderate pain in two different contexts. In the "relative relief context," moderate pain represented the best outcome, since the alternative outcome was intense pain. However, in the control context, moderate pain represented the worst outcome and elicited negative hedonic feelings. The context manipulation resulted in a "hedonic flip," such that moderate pain elicited positive hedonics in the relative relief context. Somewhat surprisingly, moderate pain was even rated as pleasant in this context, despite being reported as painful in the control context. This "hedonic flip" was corroborated by physiological and functional neuroimaging data. When moderate pain was perceived as pleasant, skin conductance and activity in insula and dorsal anterior cingulate were significantly attenuated relative to the control moderate stimulus. "Pleasant pain" also increased activity in reward and valuation circuitry, including the medial orbitofrontal and ventromedial prefrontal cortices. Furthermore, the change in outcome hedonics correlated with activity in the periacqueductal grey (PAG) of the descending pain modulatory system (DPMS). The context manipulation also significantly increased functional connectivity between reward circuitry and the PAG, consistent with a functional change of the DPMS due to the altered motivational state. The findings of this study point to a role for brainstem and reward circuitry in a context-induced "hedonic flip" of pain. © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  • The importance of context: when relative relief renders pain pleasant.

    24 October 2018

    Context can influence the experience of any event. For instance, the thought that "it could be worse" can improve feelings towards a present misfortune. In this study we measured hedonic feelings, skin conductance, and brain activation patterns in 16 healthy volunteers who experienced moderate pain in two different contexts. In the "relative relief context," moderate pain represented the best outcome, since the alternative outcome was intense pain. However, in the control context, moderate pain represented the worst outcome and elicited negative hedonic feelings. The context manipulation resulted in a "hedonic flip," such that moderate pain elicited positive hedonics in the relative relief context. Somewhat surprisingly, moderate pain was even rated as pleasant in this context, despite being reported as painful in the control context. This "hedonic flip" was corroborated by physiological and functional neuroimaging data. When moderate pain was perceived as pleasant, skin conductance and activity in insula and dorsal anterior cingulate were significantly attenuated relative to the control moderate stimulus. "Pleasant pain" also increased activity in reward and valuation circuitry, including the medial orbitofrontal and ventromedial prefrontal cortices. Furthermore, the change in outcome hedonics correlated with activity in the periacqueductal grey (PAG) of the descending pain modulatory system (DPMS). The context manipulation also significantly increased functional connectivity between reward circuitry and the PAG, consistent with a functional change of the DPMS due to the altered motivational state. The findings of this study point to a role for brainstem and reward circuitry in a context-induced "hedonic flip" of pain.

  • Cold or calculating? Reduced activity in the subgenual cingulate cortex reflects decreased emotional aversion to harming in counterintuitive utilitarian judgment.

    24 October 2018

    Recent research on moral decision-making has suggested that many common moral judgments are based on immediate intuitions. However, some individuals arrive at highly counterintuitive utilitarian conclusions about when it is permissible to harm other individuals. Such utilitarian judgments have been attributed to effortful reasoning that has overcome our natural emotional aversion to harming others. Recent studies, however, suggest that such utilitarian judgments might also result from a decreased aversion to harming others, due to a deficit in empathic concern and social emotion. The present study investigated the neural basis of such indifference to harming using functional neuroimaging during engagement in moral dilemmas. A tendency to counterintuitive utilitarian judgment was associated both with 'psychoticism', a trait associated with a lack of empathic concern and antisocial tendencies, and with 'need for cognition', a trait reflecting preference for effortful cognition. Importantly, only psychoticism was also negatively correlated with activation in the subgenual cingulate cortex (SCC), a brain area implicated in empathic concern and social emotions such as guilt, during counterintuitive utilitarian judgments. Our findings suggest that when individuals reach highly counterintuitive utilitarian conclusions, this need not reflect greater engagement in explicit moral deliberation. It may rather reflect a lack of empathic concern, and diminished aversion to harming others.

  • Structural and functional bases of visuospatial associative memory in older adults.

    24 October 2018

    Impaired visuospatial associative memory may be one of the earliest changes predicting cognitive impairment and Alzheimer's disease. We explored the relationship between performance on a visuospatial associative memory task (the Placing Test) and brain structure and function in cognitively healthy older adults. First, we performed a voxel-based morphometry correlational analysis on structural magnetic resonance imaging (MRI) data from 144 healthy older adults with their scores on the Placing Test. Second, we carried out a functional MRI study on another group of 28 healthy older adults who performed a similar task during functional MRI. Decreased performance on the Placing Test was associated with increased atrophy in medial-temporal regions. Functional activation of the same regions-controlling for the effect of atrophy-occurred during successful performance of the same task. The colocalization of structural and functional MRI correspondents of visuospatial associative test performance within medial-temporal regions validates multimodal imaging in describing behaviorally relevant variability in the aging brain and suggests that the Placing Test has the potential for detecting early cognitive changes occurring in preclinical phases of Alzheimer's disease.