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  • Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans.

    24 October 2018

    Converging evidence from different functional imaging studies indicates that the intensity of activation of different nociceptive areas (including the operculoinsular cortex, the primary somatosensory cortex, and the anterior cingulate gyrus) correlates with perceived pain intensity in the human brain. Brief radiant laser pulses excite selectively Adelta and C nociceptors in the superficial skin layers, provide a purely nociceptive input, and evoke brain potentials (laser-evoked potentials, LEPs) that are commonly used to assess nociceptive pathways in physiological and clinical studies. Adelta-related LEPs are constituted of different components. The earliest is a lateralised, small negative component (N1) which could be generated by the operculoinsular cortex. The major negative component (N2) seems to be mainly the result of activation in the bilateral operculoinsular cortices and contralateral primary somatosensory cortex, and it is followed by a positive component (P2) probably generated by the cingulate gyrus. Currently, early and late LEP components are considered to be differentially sensitive to the subjective variability of pain perception: the late N2-P2 complex strongly correlates with perceived pain, whereas the early N1 component is thought to be a pre-perceptual sensory response. To obtain physiological information on the roles of the pain-related brain areas in healthy humans, we examined the relationship between perceived pain intensity and latency and amplitude of the early (N1) and late (N2, P2) LEP components. We found that the amplitude of the N1 component correlated significantly with the subjective pain ratings, both within and between subjects. Furthermore, we showed that the N2 and P2 late LEP components are differentially sensitive to the perceived sensation, and demonstrated that the N2 component mainly explains the previously described correlation between perceived pain and the amplitude of the N2-P2 vertex complex of LEPs. Our findings confirm the notion that pain intensity processing is distributed over several brain areas, and suggest that the intensity coding of a noxious stimulus occurs already at the earliest stage of perception processing, in the operculoinsular region and, possibly, the primary somatosensory area.

  • Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness.

    24 October 2018

    Visceral and somatic pain perception differs in several aspects: poor localization of visceral pain and the ability of visceral pain to be referred to somatic structures. The perception of pain intensity and affect in visceral and somatic pain syndromes is often different, with visceral pain reported as more unpleasant. To determine whether these behavioral differences are due to differences in the central processing of visceral and somatic pain, non-invasive imaging tools are required to examine the neural correlates of visceral and somatic events when the behavior has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of somatic and visceral sensations and imaged the neural representation of this perception using functional magnetic resonance imaging in 10 healthy right-handed subjects. Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum while being scanned. Stimuli were matched to the same unpleasantness rating, producing mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. Visceral stimuli induced deactivation of the perigenual cingulate bilaterally with a relatively greater activation of the right anterior insula-i.e. regions encoding affect. Somatic pain induced left dorso-lateral pre-frontal cortex and bilateral inferior parietal cortex activation i.e. regions encoding spatial orientation and assessing perceptual valence of the stimulus. We believe that the observed patterns of activation represent the differences in cortical process of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness.

  • Evidence for asymmetric frontal-lobe involvement in episodic memory from functional magnetic resonance imaging and patients with unilateral frontal-lobe excisions.

    24 October 2018

    Recently, there has been considerable debate regarding the involvement of the left and right prefrontal cortices in the encoding and retrieval of episodic memory. In a previous PET study, we found that the use of easily verbalisable material may lead to activation predominantly in the left lateral frontal cortex whilst the use of non-easily verbalisable material may lead to activation predominantly in the right lateral frontal cortex, in both cases irrespective of encoding and retrieval processes. In order to replicate and extend these findings, the same task was modified for use with fMRI. Six healthy volunteers were scanned while encoding and then recalling stimuli that either emphasised visual or verbal processes. It was found that, in comparison to a baseline condition, the encoding of visual stimuli led to a bilateral activation of the prefrontal cortex whilst the encoding of verbal stimuli led to a preferential activation of the left prefrontal cortex. An effect of stimulus type was less evident during retrieval, with both visual and verbal stimuli leading to bilateral prefrontal cortex activation. Overall, encoding and retrieval activated similar regions of the prefrontal cortex suggesting that these areas mediate processes that are fundamental to both aspects of memory. To extend these findings further, the tasks used in the fMRI study were used to assess a group of patients with unilateral frontal lesions and a group of healthy control volunteers. The patients were significantly impaired compared to the healthy volunteers, although no significant differences were found in performance between the right- and left-sided lesioned patients. This result suggests that the memory-related asymmetries observed during functional neuroimaging studies may not be critical for task performance.

  • Pharmacological fMRI: A new tool for drug development in humans

    24 October 2018

    Until now, our understanding of human brain pharmacology has depended on indirect assessments or animal models. The advent of pharmacological functional magnetic resonance imaging (phMRI) has enabled researchers to focus directly on human pharmacology and brain function. Functional MRI, with its increased spatial and temporal resolution, has a further advantage over other neuroimaging methods in that being totally noninvasive, it allows serial, longitudinal studies to be performed on the same subject. This opens the door to a new era of phMRI, as the effects of drugs can be readily monitored in one subject (control or patient) overtime. In addition, sophisticated paradigms can be developed that can isolate specific brain regions of activation. These regions can then be subsequently targeted and challenged with appropriate drugs. This allows for a "battery" of paradigms aimed at determining a drug's mechanism and site of action, which would be valuable for drug development and discovery.

  • Metabolic consequences of the cytochrome c oxidase deficiency in brain of copper-deficient Mo(vbr) mice.

    24 October 2018

    Biochemical micromethods were used for the investigation of changes in mitochondrial oxidative phosphorylation associated with cytochrome c oxidase deficiency in brain cortex from Mo(vbr) (mottled viable brindled) mice, an animal model of Menkes' copper deficiency syndrome. Enzymatic analysis of cortex homogenates from Mo(vbr) mice showed an approximately twofold decrease in cytochrome c oxidase and a 1.4-fold decrease in NADH:cytochrome c reductase activities as compared with controls. Assessment of mitochondrial respiratory function was performed using digitonin-treated homogenates of the cortex, which exhibited the main characteristics of isolated brain mitochondria. Despite the substantial changes in respiratory chain enzyme activities, no significant differences were found in maximal pyruvate or succinate oxidation rates of brain cortex homogenates from Mo(vbr) and control mice. Inhibitor titrations were used to determine flux control coefficients of NADH:CoQ oxidoreductase and cytochrome c oxidase on the rate of mitochondrial respiration. Application of amobarbital to titrate the activity of NADH:CoQ oxidoreductase showed very similar flux control coefficients for control and mutant animals. Alternately, titration of respiration with azide revealed for Mo(vbr) mice significantly sharper inhibition curves than for controls, indicating a more than twofold elevated flux control coefficient of cytochrome c oxidase. Owing to the reserve capacity of respiratory chain enzymes, the reported changes in activities do not seem to affect whole-brain high-energy phosphates, as observed in a previous study using 31P NMR.