"First pain" in humans: convergent and specific forebrain responses

<p>Abstract</p> <p>Background</p> <p>Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).</p> <p>Results</p> <p>Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.</p> <p>Conclusions</p> <p>These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.</p

Large herbivores may alter vegetation structure of semi-arid savannas through soil nutrient mediation

In savannas, the tree–grass balance is governed by water, nutrients, fire and herbivory, and their interactions. We studied the hypothesis that herbivores indirectly affect vegetation structure by changing the availability of soil nutrients, which, in turn, alters the competition between trees and grasses. Nine abandoned livestock holding-pen areas (kraals), enriched by dung and urine, were contrasted with nearby control sites in a semi-arid savanna. About 40 years after abandonment, kraal sites still showed high soil concentrations of inorganic N, extractable P, K, Ca and Mg compared to controls. Kraals also had a high plant production potential and offered high quality forage. The intense grazing and high herbivore dung and urine deposition rates in kraals fit the accelerated nutrient cycling model described for fertile systems elsewhere. Data of a concurrent experiment also showed that bush-cleared patches resulted in an increase in impala dung deposition, probably because impala preferred open sites to avoid predation. Kraal sites had very low tree densities compared to control sites, thus the high impala dung deposition rates here may be in part driven by the open structure of kraal sites, which may explain the persistence of nutrients in kraals. Experiments indicated that tree seedlings were increasingly constrained when competing with grasses under fertile conditions, which might explain the low tree recruitment observed in kraals. In conclusion, large herbivores may indirectly keep existing nutrient hotspots such as abandoned kraals structurally open by maintaining a high local soil fertility, which, in turn, constrains woody recruitment in a negative feedback loop. The maintenance of nutrient hotspots such as abandoned kraals by herbivores contributes to the structural heterogeneity of nutrient-poor savanna vegetation

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis.</p> <p>Methods</p> <p>Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months.</p> <p>Results</p> <p>Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes.</p> <p>Conclusion</p> <p>Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.</p

The RUDY study platform – a novel approach to patient driven research in rare musculoskeletal diseases

Background: Research into rare diseases is becoming more common, with recognition of the significant diagnostic and therapeutic care gaps. Registries are considered a key research methodology to address rare diseases. This report describes the structure of the Rare UK Diseases Study (RUDY) platform that aims to improve research processes and address many of the challenges of carrying out rare musculoskeletal disease research. RUDY is an internet-based platform with online registration, initial verbal consent, online capture of patient reported outcome measures and events within a dynamic consent framework. The database structure, security and governance framework are described. Results: There have been 380 participants recruited into RUDY with completed questionnaire rates in excess of 50 %. There has been one withdrawal and two participants have amended their consent options. Conclusions: The strengths of RUDY include low burden for the clinical team, low research administration costs with high participant recruitment and ease of data collection and access. This platform has the potential to be used as the model for other rare diseases globally

Spatial Patterns in Herbivory on a Coral Reef Are Influenced by Structural Complexity but Not by Algal Traits

Background: Patterns of herbivory can alter the spatial structure of ecosystems, with important consequences for ecosystem functions and biodiversity. While the factors that drive spatial patterns in herbivory in terrestrial systems are well established, comparatively less is known about what influences the distribution of herbivory in coral reefs. Methodology and Principal Findings: We quantified spatial patterns of macroalgal consumption in a cross-section of Ningaloo Reef (Western Australia). We used a combination of descriptive and experimental approaches to assess the influence of multiple macroalgal traits and structural complexity in establishing the observed spatial patterns in macroalgal herbivory, and to identify potential feedback mechanisms between herbivory and macroalgal nutritional quality. Spatial patterns in macroalgal consumption were best explained by differences in structural complexity among habitats. The biomass of herbivorous fish, and rates of herbivory were always greater in the structurally-complex coral-dominated outer reef and reef flat habitats, which were also characterised by high biomass of herbivorous fish, low cover and biomass of macroalgae and the presence of unpalatable algae species. Macroalgal consumption decreased to undetectable levels within 75 m of structurally-complex reef habitat, and algae were most abundant in the structurally-simple lagoon habitats, which were also characterised by the presence of the most palatable algae species. In contrast to terrestrial ecosystems, herbivory patterns were not influenced by the distribution, productivity or nutritional quality of resources (macroalgae), and we found no evidence of a positive feedback between macroalgal consumption and the nitrogen content of algae. Significance: This study highlights the importance of seascape-scale patterns in structural complexity in determining spatial patterns of macroalgal consumption by fish. Given the importance of herbivory in maintaining the ability of coral reefs to reorganise and retain ecosystem functions following disturbance, structural complexity emerges as a critical feature that is essential for the healthy functioning of these ecosystems

Brain structural changes and neuropsychological impairments in male polydipsic schizophrenia

BACKGROUND: Polydipsia frequently occurs in schizophrenia patients. The excessive water loading in polydipsia occasionally induces a hyponatremic state and leads to water intoxication. Whether polydipsia in schizophrenic patients correlates with neuropsychological impairments or structural brain changes is not clear and remains controversial. METHODS: Eight polydipsic schizophrenia patients, eight nonpolydipsic schizophrenia patients, and eight healthy controls were recruited. All subjects underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural abnormalities were analyzed using a voxel-based morphometry (VBM) approach, and patients’ neuropsychological function was assessed using the Brief Assessment of Cognition in Schizophrenia, Japanese version (BACS-J). RESULTS: No significant differences were found between the two patient groups with respect to the clinical characteristics. Compared with healthy controls, polydipsic patients showed widespread brain volume reduction and neuropsychological impairment. Furthermore, the left insula was significantly reduced in polydipsic patients compared with nonpolydipsic patients. These nonpolydipsic patients performed intermediate to the other two groups in the neuropsychological function test. CONCLUSIONS: It is possible that polydipsia or the secondary hyponatremia might induce left insula volume reduction. Furthermore, this structural brain change may indirectly induce more severe neuropsychological impairments in polydipsic patients. Thus, we suggest that insula abnormalities might contribute to the pathophysiology of polydipsic patients

Altered oscillatory brain dynamics after repeated traumatic stress

Kolassa I-T, Wienbruch C, Neuner F, et al. Altered oscillatory brain dynamics after repeated traumatic stress. BMC Psychiatry. 2007;7(1): 56.BACKGROUND: Repeated traumatic experiences, e.g. torture and war, lead to functional and structural cerebral changes, which should be detectable in cortical dynamics. Abnormal slow waves produced within circumscribed brain regions during a resting state have been associated with lesioned neural circuitry in neurological disorders and more recently also in mental illness. METHODS: Using magnetoencephalographic (MEG-based) source imaging, we mapped abnormal distributions of generators of slow waves in 97 survivors of torture and war with posttraumatic stress disorder (PTSD) in comparison to 97 controls. RESULTS: PTSD patients showed elevated production of focally generated slow waves (1-4 Hz), particularly in left temporal brain regions, with peak activities in the region of the insula. Furthermore, differential slow wave activity in right frontal areas was found in PTSD patients compared to controls. CONCLUSION: The insula, as a site of multimodal convergence, could play a key role in understanding the pathophysiology of PTSD, possibly accounting for what has been called posttraumatic alexithymia, i.e., reduced ability to identify, express and regulate emotional responses to reminders of traumatic events. Differences in activity in right frontal areas may indicate a dysfunctional PFC, which may lead to diminished extinction of conditioned fear and reduced inhibition of the amygdala

Interoception in anxiety and depression

We review the literature on interoception as it relates to depression and anxiety, with a focus on belief, and alliesthesia. The connection between increased but noisy afferent interoceptive input, self-referential and belief-based states, and top-down modulation of poorly predictive signals is integrated into a neuroanatomical and processing model for depression and anxiety. The advantage of this conceptualization is the ability to specifically examine the interface between basic interoception, self-referential belief-based states, and enhanced top-down modulation to attenuate poor predictability. We conclude that depression and anxiety are not simply interoceptive disorders but are altered interoceptive states as a consequence of noisily amplified self-referential interoceptive predictive belief states