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  • Regulation of human metabolism by hypoxia-inducible factor.

    11 May 2018

    The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

  • Cortical processing of lateral skin stretch stimulation in humans.

    3 May 2018

    Direction discrimination of a moving tactile stimulus requires intact dorsal columns and provides a sensitive clinical test of somatosensory dysfunction. Cortical mechanisms are poorly understood. We have applied tangential skin pulls to the right lower leg during functional magnetic resonance imaging. Healthy subjects judged the direction of the skin pulls (task experiment, n = 7) or received skin pulls passively (no task experiment, n = 8). Second somatosensory cortex (S2) was activated in the task as well as no task experiment, and there was no significant difference in cortical activation between the two experiments. Within S2 nearly all subjects had prominent activations in the caudal and superficial part, i.e., in the opercular parietal (OP) area 1. S1 was activated in only one of the subjects. Thus, S2 and especially OP 1 seems to be important for processing of lateral skin stretch stimulation. The finding suggests that a lesion of this area might cause a disturbance in tactile direction discrimination which should be relevant for clinical testing.

  • Discriminative touch and emotional touch.

    12 December 2017

    Somatic sensation comprises four main modalities, each relaying tactile, thermal, painful, or pruritic (itch) information to the central nervous system. These input channels can be further classified as subserving a sensory function of spatial and temporal localization, discrimination, and provision of essential information for controlling and guiding exploratory tactile behaviours, and an affective function that is widely recognized as providing the afferent neural input driving the subjective experience of pain, but not so widely recognized as also providing the subjective experience of affiliative or emotional somatic pleasure of touch. The discriminative properties of tactile sensation are mediated by a class of fast-conducting myelinated peripheral nerve fibres--A-beta fibres--whereas the rewarding, emotional properties of touch are hypothesized to be mediated by a class of unmyelinated peripheral nerve fibres--CT afferents (C tactile)--that have biophysical, electrophysiological, neurobiological, and anatomical properties that drive the temporally delayed emotional somatic system. CT afferents have not been found in the glabrous skin of the hand in spite of numerous electrophysiological explorations of this area. Hence, it seems reasonable to conclude that they are lacking in the glabrous skin. A full understanding of the behavioural and affective consequences of the differential innervation of CT afferents awaits a fuller understanding of their function.

  • The skin as a social organ.

    27 April 2018

    In general, social neuroscience research tends to focus on visual and auditory channels as routes for social information. However, because the skin is the site of events and processes crucial to the way we think about, feel about, and interact with one another, touch can mediate social perceptions in various ways. This review situates cutaneous perception within a social neuroscience framework by discussing evidence for considering touch (and to some extent pain) as a channel for social information. Social information conveys features of individuals or their interactions that have potential bearing on future interactions, and attendant mental and emotional states. Here, we discuss evidence for an affective dimension of touch and explore its wider implications for the exchange of social information. We consider three important roles for this affective dimension of the cutaneous senses in the transmission and processing of social information: first, through affiliative behavior and communication; second, via affective processing in skin-brain pathways; and third, as a basis for intersubjective representation.

  • Tactile direction discrimination and vibration detection in diabetic neuropathy.

    12 December 2017

    OBJECTIVE: To evaluate the clinical usefulness of quantitative testing of tactile direction discrimination (TDD) in patients with diabetic neuropathy. MATERIALS AND METHODS: TDD and vibration detection were examined on the dorsum of the feet in 43 patients with type 1 diabetes mellitus and clinical signs and symptoms indicating mild neuropathy, and abnormal results for neurography, temperature detection, or heart rate variability. Test-retest examination of TDD was performed in nine of the patients. RESULTS: Twenty-six of the patients had abnormal TDD (sensitivity 0.60) and 20 had abnormal vibration detection (sensitivity 0.46). Ten of the patients had abnormal TDD and normal vibration detection. Four of the patients had abnormal vibration detection and normal TDD. Test-retest examination of TDD showed a high degree of reproducibility (r = 0.87). CONCLUSION: TDD seems more useful than vibration detection in examination of diabetic neuropathy.

  • Coding of pleasant touch by unmyelinated afferents in humans.

    23 May 2018

    Pleasant touch sensations may begin with neural coding in the periphery by specific afferents. We found that during soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities (1-10 cm s(-1)), which were perceived by subjects as being the most pleasant. Our results indicate that C-tactile afferents constitute a privileged peripheral pathway for pleasant tactile stimulation that is likely to signal affiliative social body contact.

  • Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch.

    30 April 2018

    We examined patients with a heritable disorder associated with a mutation affecting the nerve growth factor beta gene. Their condition has been classified as hereditary sensory and autonomic neuropathy type V. Carriers of the mutation show a reduction in density of thin and unmyelinated nerve fibres, including C afferents. A distinct type of unmyelinated, low-threshold mechanoreceptive C fibre, the C-tactile afferent, is present in hairy but not glabrous skin of humans and other mammals. They have been implicated in the coding of pleasant, hedonic touch of the kind that occurs in affiliative social interactions. We addressed the relationship between C fibre function and pleasant touch perception in 10 individuals from a unique population of mutation carriers in Sweden. We also investigated the effect of reduced C-fibre density on patients' evaluation of observed interpersonal touch (empathy). Results showed that patients perceived gentle, slow arm stroking, optimal for eliciting C-tactile afferent responses (1-10  cm/s), as less pleasant than did matched controls and also differed in their rating patterns across stimulation velocities. Further, patients' blood-oxygen-level-dependent responses in posterior insular cortex--a target for C afferents--were not modulated by stimulation optimal for activating C-tactile afferents. Hence, perception of the hedonic aspect of dynamic touch likely depends on C-tactile afferent density. Closely similar patterns between individuals' ratings of felt and seen touch suggest that appraisal of others' touch is anchored in one's own perceptual experience, whether typical or atypical.

  • Somatotopic organization of gentle touch processing in the posterior insular cortex.

    23 May 2018

    A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.