Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli

Biological systems have acquired effective adaptive strategies to cope with physiological challenges and to maximize biochemical processes under imposed constraints. Striated muscle tissue demonstrates a remarkable malleability and can adjust its metabolic and contractile makeup in response to alterations in functional demands. Activity-dependent muscle plasticity therefore represents a unique model to investigate the regulatory machinery underlying phenotypic adaptations in a fully differentiated tissue. Adjustments in form and function of mammalian muscle have so far been characterized at a descriptive level, and several major themes have evolved. These imply that mechanical, metabolic and neuronal perturbations in recruited muscle groups relay to the specific processes being activated by the complex physiological stimulus of exercise. The important relationship between the phenotypic stimuli and consequent muscular modifications is reflected by coordinated differences at the transcript level that match structural and functional adjustments in the new training steady state. Permanent alterations of gene expression thus represent a major strategy for the integration of phenotypic stimuli into remodeling of muscle makeup. A unifying theory on the molecular mechanism that connects the single exercise stimulus to the multi-faceted adjustments made after the repeated impact of the muscular stress remains elusive. Recently, master switches have been recognized that sense and transduce the individual physical and chemical perturbations induced by physiological challenges via signaling cascades to downstream gene expression events. Molecular observations on signaling systems also extend the long-known evidence for desensitization of the muscle response to endurance exercise after the repeated impact of the stimulus that occurs with training. Integrative approaches involving the manipulation of single factors and the systematic monitoring of downstream effects at multiple levels would appear to be the ultimate method for pinpointing the mechanism of muscle remodeling. The identification of the basic relationships underlying the malleability of muscle tissue is likely to be of relevance for our understanding of compensatory processes in other tissues, species and organisms.

The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions

BACKGROUND: Petasin (Ze 339) was recently introduced on the market as a potent herbal antiallergic drug for treatment of respiratory allergies such as hay fever. Few clinical studies have been performed so far addressing the clinical effectiveness of Ze 339. OBJECTIVE: To evaluate the antiallergic properties of Ze 339 using skin prick tests with different stimuli, such as codeine, histamine, methacholine, and a relevant inhalant allergen. METHODS: A randomized, double-blind, placebo-controlled study was performed in which Ze 339 was compared to acrivastine, a short-acting antihistamine, in 8 patients with respiratory allergy and in 10 nonatopic, healthy volunteers. Antiallergic activity of Ze 339 was determined by analyzing inhibitory potency in skin prick tests with codeine, histamine, methacholine, and an inhalant allergen. Wheal-and-flare reactions were assessed 90 minutes after a double dose of Ze 339, acrivastine, or placebo. An interval of at least 3 days was left between the skin tests. RESULTS: Acrivastine was identified as the only substance that significantly inhibited skin test reactivity to all solutions analyzed in all study subjects. In contrast, no significant inhibition could be demonstrated for Ze 339 with any test solution. Moreover, the results of Ze 339 did not differ significantly from placebo. CONCLUSIONS: In this study we found no antiallergic, particularly antihistaminic, effect of Ze 339 in skin tests using a variety of stimuli often used to evaluate immediate skin test reactivity. The mechanism by which Ze 339 is effective in the treatment of seasonal allergic rhinitis still needs to be elucidated.

Functional neuroimaging of emotional learning and autonomic reactions

This article provides a selective overview of the functional neuroimaging literature with an emphasis on emotional activation processes. Emotions are fast and flexible response systems that provide basic tendencies for adaptive action. From the range of involved component functions, we first discuss selected automatic mechanisms that control basic adaptational changes. Second, we illustrate how neuroimaging work has contributed to the mapping of the network components associated with basic emotion families (fear, anger, disgust, happiness), and secondary dimensional concepts that organise the meaning space for subjective experience and verbal labels (emotional valence, activity/intensity, approach/withdrawal, etc.). Third, results and methodological difficulties are discussed in view of own neuroimaging experiments that investigated the component functions involved in emotional learning. The amygdala, prefrontal cortex, and striatum form a network of reciprocal connections that show topographically distinct patterns of activity as a correlate of up and down regulation processes during an emotional episode. Emotional modulations of other brain systems have attracted recent research interests. Emotional neuroimaging calls for more representative designs that highlight the modulatory influences of regulation strategies and socio-cultural factors responsible for inhibitory control and extinction. We conclude by emphasising the relevance of the temporal process dynamics of emotional activations that may provide improved prediction of individual differences in emotionality.

Imaging emotional brain functions: conceptual and methodological issues

This article reviews the psychophysiological and brain imaging literature on emotional brain function from a methodological point of view. The difficulties in defining, operationalising and measuring emotional activation and, in particular, aversive learning will be considered. Emotion is a response of the organism during an episode of major significance and involves physiological activation, motivational, perceptual, evaluative and learning processes, motor expression, action tendencies and monitoring/subjective feelings. Despite the advances in assessing the physiological correlates of emotional perception and learning processes, a critical appraisal shows that functional neuroimaging approaches encounter methodological difficulties regarding measurement precision (e.g., response scaling and reproducibility) and validity (e.g., response specificity, generalisation to other paradigms, subjects or settings). Since emotional processes are not only the result of localised but also of widely distributed activation, a more representative model of assessment is needed that systematically relates the hierarchy of high- and low-level emotion constructs with the corresponding patterns of activity and functional connectivity of the brain.

Low social support and poor emotional regulation are associated with increased stress hormone reactivity to mental stress in systemic hypertension

CONTEXT: There is strong evidence for a physiological hyperreactivity to stress in systemic hypertension, but data on associated or potentially moderating psychological factors are scarce. OBJECTIVE: The objective of the study was to identify psychological correlates of physiological stress reactivity in systemic hypertension. DESIGN: This was a cross-sectional, quasi-experimentally controlled study. Study participants underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. SETTING: The study was conducted in the population in the state of Zurich, Switzerland. SUBJECTS: Subjects included 22 hypertensive and 26 normotensive men (mean +/- sem 44 +/- 2 yr). MAIN OUTCOME MEASURES: We assessed the psychological measures social support, emotional regulation, and cognitive appraisal of the stressful situation. Moreover, we measured salivary cortisol and plasma epinephrine and norepinephrine before and after stress and several times up to 60 min thereafter as well as blood pressure and heart rate. RESULTS: We found poorer hedonistic emotional regulation (HER) and lower perceived social support in hypertensives, compared with normotensives (P < 0.01). Compared with normotensives, hypertensives showed higher cortisol, epinephrine, and norepinephrine secretions after stress (P < 0.038) as well as higher systolic and diastolic blood pressure (P < 0.001). Cortisol reactivity and norepinephrine secretion were highest in hypertensive men with low HER (P < 0.05). In contrast, hypertensives with high HER did not significantly differ from normotensives in both cortisol and norepinephrine secretion after stress. Epinephrine secretion was highest in hypertensives with low social support but was not different between hypertensives with high social support and normotensives. CONCLUSIONS: The findings suggest that both low social support and low HER are associated with elevated stress hormone reactivity in systemic hypertension.

Emotional stress reactivity in irritable bowel syndrome

OBJECTIVES: Irritable bowel syndrome (IBS) has been proposed to be a stress-related disorder. Research on stress reactivity in IBS has yielded ambiguous results, regarding responses to physical and mental stress. This study aimed to investigate the responses to emotional stress in IBS patients. METHODS: Twelve IBS patients and 12 healthy individuals underwent public speaking anticipation as an emotional stressor and a control situation. Stress reactivity was quantified by subjective and psychophysiological measures. RESULTS: Stress responses were elicited in healthy controls and IBS patients. Differential stress responses were observed in measurements of heart rate. There was no change in rectal sensitivity under stress, whereas patients exhibited lower discomfort thresholds than healthy controls in all conditions. CONCLUSION: This study measured reactivity to an emotional stressor in IBS. It provides evidence that there is a specific alteration of stress responses in IBS patients, but no overall exaggerated stress response. IBS patients showed a broader and less specific response to emotional stress than healthy controls. Rectal sensitivity was unchanged under emotional stress both in IBS patients and healthy controls.

Neural correlates of antinociception in borderline personality disorder

CONTEXT: A characteristic feature of borderline personality disorder (BPD) is self-injurious behavior in conjunction with stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with BPD, but the neural correlates of antinociceptive mechanisms in BPD are unknown. We predicted that heat stimuli in patients with BPD would activate brain areas concerned with cognitive and emotional evaluation of pain. OBJECTIVE: To assess the psychophysical properties and neural correlates of altered pain processing in patients with BPD. DESIGN: Case-control study. SETTING: A university hospital. PARTICIPANTS: Twelve women with BPD and self-injurious behavior and 12 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and blood oxygen level-dependent functional magnetic resonance imaging during heat stimulation with fixed-temperature heat stimuli and individual-temperature stimuli adjusted for equal subjective pain in all the participants. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes during heat pain stimulation. RESULTS: Patients with BPD had higher pain thresholds and smaller overall volumes of activity than controls in response to identical heat stimuli. When the stimulus temperature was individually adjusted for equal subjective pain level, overall volumes of activity were similar, although regional patterns differed significantly. Patient response was greater in the dorsolateral prefrontal cortex and smaller in the posterior parietal cortex. Pain also produced neural deactivation in the perigenual anterior cingulate gyrus and the amygdala in patients with BPD. CONCLUSION: The interaction between increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala is associated with an antinociceptive mechanism in patients with BPD.

Learning real-world stimuli in a neural network with spike-driven synaptic dynamics

We present a model of spike-driven synaptic plasticity inspired by experimental observations and motivated by the desire to build an electronic hardware device that can learn to classify complex stimuli in a semisupervised fashion. During training, patterns of activity are sequentially imposed on the input neurons, and an additional instructor signal drives the output neurons toward the desired activity. The network is made of integrate-and-fire neurons with constant leak and a floor. The synapses are bistable, and they are modified by the arrival of presynaptic spikes. The sign of the change is determined by both the depolarization and the state of a variable that integrates the postsynaptic action potentials. Following the training phase, the instructor signal is removed, and the output neurons are driven purely by the activity of the input neurons weighted by the plastic synapses. In the absence of stimulation, the synapses preserve their internal state indefinitely. Memories are also very robust to the disruptive action of spontaneous activity. A network of 2000 input neurons is shown to be able to classify correctly a large number (thousands) of highly overlapping patterns (300 classes of preprocessed Latex characters, 30 patterns per class, and a subset of the NIST characters data set) and to generalize with performances that are better than or comparable to those of artificial neural networks. Finally we show that the synaptic dynamics is compatible with many of the experimental observations on the induction of long-term modifications (spike-timing-dependent plasticity and its dependence on both the postsynaptic depolarization and the frequency of pre- and postsynaptic neurons).

Processing of temporal unpredictability in human and animal amygdala

The amygdala has been studied extensively for its critical role in associative fear conditioning in animals and humans. Noxious stimuli, such as those used for fear conditioning, are most effective in eliciting behavioral responses and amygdala activation when experienced in an unpredictable manner. Here, we show, using a translational approach in mice and humans, that unpredictability per se without interaction with motivational information is sufficient to induce sustained neural activity in the amygdala and to elicit anxiety-like behavior. Exposing mice to mere temporal unpredictability within a time series of neutral sound pulses in an otherwise neutral sensory environment increased expression of the immediate-early gene c-fos and prevented rapid habituation of single neuron activity in the basolateral amygdala. At the behavioral level, unpredictable, but not predictable, auditory stimulation induced avoidance and anxiety-like behavior. In humans, functional magnetic resonance imaging revealed that temporal unpredictably causes sustained neural activity in amygdala and anxiety-like behavior as quantified by enhanced attention toward emotional faces. Our findings show that unpredictability per se is an important feature of the sensory environment influencing habituation of neuronal activity in amygdala and emotional behavior and indicate that regulation of amygdala habituation represents an evolutionary-conserved mechanism for adapting behavior in anticipation of temporally unpredictable events.

A non-spatial bias favouring fixated stimuli revealed in patients with spatial neglect

The cardinal feature of spatial neglect is severely impaired exploration of the contralesional space, a failure resulting in unawareness of many contralesional stimuli. This deficit is exacerbated by a reflexive attentional bias toward ipsilesional items. Here we show that, in addition to these spatially lateralized failures, neglect patients also exhibit a severe bias favouring stimuli presented at fixation. We tested neglect patients and matched healthy and right-hemisphere damaged patients without neglect in a task requiring saccade execution to targets in the left or right hemifield. Targets were presented alone or simultaneously with a distracter that appeared in the same hemifield, in the opposite hemifield, or at fixation. We found two fundamental biases in saccade initiation of neglect patients: irrelevant distracters presented in the preserved hemifield tended to capture gaze reflexively, resulting in a large number of saccades erroneously directed toward the distracter. Additionally, distracters presented at fixation severely disrupted saccade initiation irrespective of saccade direction, leading to disproportionately increased latencies of left and right saccades. This latency increase was specific to oculomotor responses of neglect patients and was not observed when a manual response was required. These results show that, in addition to their failure to inhibit reflexive glances toward ipsilesional items neglect patients exhibit a strong oculomotor bias favouring fixated stimuli. We conclude that impaired initiation of saccades in any direction contributes to the deficits of spatial exploration that characterize spatial neglect.

Mechanical circulatory support as a bridge to heart transplantation: what remains? Long-term emotional sequelae in patients and spouses

Implantation of a ventricular assist device (VAD) reduces short-term mortality and morbidity and provides patients with reasonable quality of life even though it may also be a long-lasting emotional burden. This study was conducted to analyze the long-time emotional consequences of VAD implantation, followed by heart transplantation in patients and spouses.

Effects of butorphanol on the withdrawal reflex using threshold, suprathreshold and repeated subthreshold electrical stimuli in conscious horses

OBJECTIVE: To assess the effects of a single intravenous dose of butorphanol (0.1 mg kg(-1)) on the nociceptive withdrawal reflex (NWR) using threshold, suprathreshold and repeated subthreshold electrical stimuli in conscious horses. STUDY DESIGN: 'Unblinded', prospective experimental study. ANIMALS: Ten adult horses, five geldings and five mares, mean body mass 517 kg (range 487-569 kg). METHODS: The NWR was elicited using single transcutaneous electrical stimulation of the palmar digital nerve. Repeated stimulations were applied to evoke temporal summation. Surface electromyography was performed to record and quantify the responses of the common digital extensor muscle to stimulation and behavioural reactions were scored. Before butorphanol administration and at fixed time points up to 2 hours after injection, baseline threshold intensities for NWR and temporal summation were defined and single suprathreshold stimulations applied. Friedman repeated-measures analysis of variance on ranks and Wilcoxon signed-rank test were used with the Student-Newman-Keul's method applied post-hoc. The level of significance (alpha) was set at 0.05. RESULTS: Butorphanol did not modify either the thresholds for NWR and temporal summation or the reaction scores, but the difference between suprathreshold and threshold reflex amplitudes was reduced when single stimulation was applied. Upon repeated stimulation after butorphanol administration, a significant decrease in the relative amplitude was calculated for both the 30-80 and the 80-200 millisecond intervals after each stimulus, and for the whole post-stimulation interval in the right thoracic limb. In the left thoracic limb a decrease in the relative amplitude was found only in the 30-80 millisecond epoch. CONCLUSION: Butorphanol at 0.1 mg kg(-1) has no direct action on spinal Adelta nociceptive activity but may have some supraspinal effects that reduce the gain of the nociceptive system. CLINICAL RELEVANCE: Butorphanol has minimal effect on sharp immediate Adelta-mediated pain but may alter spinal processing and decrease the delayed sensations of pain.