Showing papers on "Summation published in 2012"

Experimental approaches in the study of pain in the elderly.

Abstract: The present review summarizes experimental data on age-related changes in pain processing. These data suggest an increase in pain threshold and a decrease in tolerance threshold, which both are dependent on the physical nature of the stressor, as well as a developing deficiency in endogenous pain inhibition, which might be paralleled by an enhanced disposition to central sensitization (stronger temporal summation). These findings are arranged in a model that allows for explaining the two seemingly divergent perspectives: age both dulls the pain sense and increases the prevalence of pain complaints. This model is based on the assumption that both excitatory and inhibitory processes are dampened with age but that the later processes age at a faster rate, leading to increasingly unbalanced pain excitation.

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Abstract: Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca2+-activated K+ channels are known to control spike frequency in central neurons, Ca2+-activated K+ channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca2+ channels at the nanodomain level to support a previously undescribed transient voltage- and Ca2+-dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca2+ influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.

Selective Functional Interactions between Excitatory and Inhibitory Cortical Neurons and Differential Contribution to Persistent Activity of the Slow Oscillation

Abstract: The neocortex depends upon a relative balance of recurrent excitation and inhibition for its operation. During spontaneous Up states, cortical pyramidal cells receive proportional barrages of excitatory and inhibitory synaptic potentials. Many of these synaptic potentials arise from the activity of nearby neurons, although the identity of these cells is relatively unknown, especially for those underlying the generation of inhibitory synaptic events. To address these fundamental questions, we developed an in vitro submerged slice preparation of the mouse entorhinal cortex that generates robust and regular spontaneous recurrent network activity in the form of the slow oscillation. By performing whole-cell recordings from multiple cell types identified with green fluorescent protein expression and electrophysiological and/or morphological properties, we show that distinct functional subpopulations of neurons exist in the entorhinal cortex, with large variations in contribution to the generation of balanced excitation and inhibition during the slow oscillation. The most active neurons during the slow oscillation are excitatory pyramidal and inhibitory fast spiking interneurons, receiving robust barrages of both excitatory and inhibitory synaptic potentials. Weak action potential activity was observed in stellate excitatory neurons and somatostatin-containing interneurons. In contrast, interneurons containing neuropeptide Y, vasoactive intestinal peptide, or the 5-hydroxytryptamine (serotonin) 3a receptor, were silent. Our data demonstrate remarkable functional specificity in the interactions between different excitatory and inhibitory cortical neuronal subtypes, and suggest that it is the large recurrent interaction between pyramidal neurons and fast spiking interneurons that is responsible for the generation of persistent activity that characterizes the depolarized states of the cortex.

Theory and data for area summation of contrast with and without uncertainty: evidence for a noisy energy model.

Abstract: Contrast sensitivity improves with the area of a sine-wave grating, but why? Here we assess this phenomenon against contemporary models involving spatial summation, probability summation, uncertainty, and stochastic noise. Using a two-interval forced-choice procedure we measured contrast sensitivity for circular patches of sine-wave gratings with various diameters that were blocked or interleaved across trials to produce low and high extrinsic uncertainty, respectively. Summation curves were steep initially, becoming shallower thereafter. For the smaller stimuli, sensitivity was slightly worse for the interleaved design than for the blocked design. Neither area nor blocking affected the slope of the psychometric function. We derived model predictions for noisy mechanisms and extrinsic uncertainty that was either low or high. The contrast transducer was either linear (c1.0) or nonlinear (c2.0), and pooling was either linear or a MAX operation. There was either no intrinsic uncertainty, or it was fixed or proportional to stimulus size. Of these 10 canonical models, only the nonlinear transducer with linear pooling (the noisy energy model) described the main forms of the data for both experimental designs. We also show how a cross-correlator can be modified to fit our results and provide a contemporary presentation of the relation between summation and the slope of the psychometric function.

Temporal Summation of Pain Is Not Amplified in a Large Proportion of Fibromyalgia Patients

Abstract: Background. Recently, it has been proposed that fibromyalgia (FM), a chronic widespread pain syndrome, results from overactive endogenous excitatory pain mechanisms. Experimental studies using temporal summation paradigms have confirmed this hypothesis but have included small samples of patients, prompting our group to perform a large-scale study. Methods. Seventy-two female FM patients and 39 healthy females participated in the study. The temporal summation test consisted of a 2-minute continuous and constant heat pulse administered with a thermode on the participants' left forearm. Experimental temperature was set at a value individually predetermined to induce a 50/100 pain rating. Results. Relative to controls, FM patients had lower thermal pain thresholds and lower temporal summation of pain. However, 37 FM patients required experimental temperatures lower than the minimal temperature used in controls (45°C). Nevertheless, temporal summation was not increased in the other FM subgroup, relative to controls, despite equivalent experimental temperatures. Discussion. Our results suggest that temporal summation of pain is normal, rather than increased, in a large proportion of FM patients. Future studies on temporal summation in FM will need to be careful since some FM patients require abnormally low experimental temperatures that may confound results and make necessary to separate patients into subgroups.

Anxiety sensitivity does not enhance pain signaling at the spinal level.

Abstract: OBJECTIVES Anxiety sensitivity (AS) is the fear of anxiety-related sensations and its perceived harmful consequences. AS is associated with enhanced pain and worsened pain outcomes, suggesting it is a contributing factor in acute and chronic pain. However, the mechanisms that mediate the relationship between AS and pain are currently unknown. This study assessed the relationship between AS and 2 measures of spinal nociceptive processes (ie, nociceptive flexion reflex and temporal summation of nociceptive flexion reflex) and measures of subjective pain. This allowed us to determine whether AS engages descending cerebrospinal processes to facilitate pain signaling at spinal levels. METHODS AS was assessed in healthy men and women using the Anxiety Sensitivity Index-Revised. Then pain processing was assessed from electric pain threshold, nociceptive flexion reflex threshold, temporal summation of pain, temporal summation of nociceptive flexion reflex, and McGill Pain Questionnaire sensory and affective pain ratings. Associations among variables were assessed using Winsorized correlations (a robust and statistically powerful analytic method). RESULTS AS was positively associated with sensory pain ratings, affective pain ratings, and temporal summation of pain, but was unrelated to all other outcomes. DISCUSSION Given that AS was not significantly associated with measures of spinal nociception, these results suggest that AS may exert its influence on pain processing at the supraspinal, rather than the spinal level.

Tissue characteristics during temporal summation of pressure-evoked pain

Abstract: Temporal summation due to repeated pain stimulation of deep somatic structures is facilitated in chronic musculoskeletal pain. In this study, the relation between repeated pressure-induced pain and stress/strain distribution within the deep tissue was evaluated to understand whether tissue characteristics may change during repeated stimulation. This information is important for interpret the pain-evoked responses. The muscle pain intensity was recorded on a 10-cm visual analogue scale (VAS) during ten computer-controlled pressure stimulations (3-s interstimulus interval) at pain threshold intensity. The experimental data validated computer models describing the stress/strain time relationship in the deep tissue during pressure stimulation. VAS scores increased progressively with 2.5 ± 0.7 cm during the ten stimuli (P < 0.02) in contrast to the tissue indentation assessed by ultrasound, which was non-significantly changing leading to a mean of 3.4 ± 0.4 mm. The principal stress peaked in the skin was reduced to 16 % in the underlying muscle tissue and not different during the ten stimuli. The peak principal strain in adipose tissue was 0.12; in muscle tissue, it was 0.108 during the first stimulus and increased by 16 % in the tenth stimulus. In a model of a one-stimulus paradigm, it was found that a VAS increase of 2.5 cm required a 47 % increase in muscle strain. These findings show that the increase in muscle strain during repeated pressure stimulations is not sufficient to explain the VAS increase; the temporal summation of deep-tissue pain evoked by repetitive pressure stimulations is not likely to be fully explained by peripheral tissue changes.

Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR)

Abstract: Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n = 46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS-pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain).

The Impact of Adverse Childhood Events on Temporal Summation of Second Pain

Abstract: The Impact of Adverse Childhood Events on Temporal Summation of Second Pain. (August 2012) Dokyoung Sophia You, B.S.N., Hanyang University; B.A., Case Western Reserve University Chair of Advisory Committee: Dr. Mary W. Meagher Adverse childhood events have been identified as a risk factor for developing chronic pain conditions in adulthood. However, previous studies have inconsistently supported the link between adverse childhood events and hypersensitivity to laboratoryinduced pain. Therefore, this study intended to investigate the effects of adverse childhood events on temporal summation of second pain (TSSP). A group of 38 healthy and pain-free college students participated in laboratory pain tests after being screened for childhood trauma history. Half of participants (47.5% female) were positive for childhood trauma and the other half (63.2% female) reported no adverse childhood event. The laboratory pain tests measured TSSP using 10 thermal pulses per trial over four consecutive trials. The trauma group showed a tendency of greater sensitization within TSSP trials and lack of habituation over repeated TSSP trials. In sum, adverse childhood events predisposed adults to enhanced TSSP, which is potentially linked to an increased likelihood to develop chronic pain problems.

Temporal summation of intrinsically photosensitive Retinal Ganglion Cell (ipRGC) contributions to the human pupil light reflex [Conference Abstract]

Abstract: Purpose: IpRGCs mediate non-image forming functions including photoentrainment and the pupil light reflex (PLR) Temporal summation increases visual sensitivity and decreases temporal resolution for image forming vision, but the summation properties of nonimage forming vision are unknown We investigated the temporal summation of inner (ipRGC) and outer (rod/cone) retinal inputs to the PLR Method: The consensual PLR of the left eye was measured in six participants with normal vision using a Maxwellian view infrared pupillometer Temporal summation was investigated using a double-pulse protocol (100 ms stimulus pairs; 0–1024 ms inter-stimulus interval, ISI) presented to the dilated fellow right eye (Tropicamide 1%) Stimulus lights (blue λmax = 460 nm; red λmax = 638 nm) biased activity to inneror outer retinal inputs to non-image forming vision Temporal summation was measured suprathreshold (152 log photonscm−2s−1 at the cornea) and subthreshold (114 log photonscm−2s−1 at the cornea) Results: RM-ANOVAs showed the suprathreshold and subthreshold 6 second post illumination pupil response (PIPR: expressed as percentage baseline diameter) did not significantly vary for red or blue stimuli (p > 05) The PIPR for a subthreshold red 16 ms double-pulse control condition did not significantly differ with ISI (p > 05) The maximum constriction amplitude for red and blue 100 ms double- pulse stimuli did not significantly vary with ISI (p > 05) Conclusion: The non-significant changes in suprathreshold PIPR and subthreshold maximum pupil constriction indicate that inner retinal ipRGC inputs and outer retinal photoreceptor inputs to the PLR do not show temporal summation The results suggest a fundamental difference between the temporal summation characteristics of image forming and non-image forming vision

Influence of diffuse noxious inhibitory control, temporal summation and expectation on pain perception in healthy volunteers.

Abstract: ....................................................................................................................................... 6 Introduction .................................................................................................................................. 8 Objectives ................................................................................................................................ 8 Methods ..................................................................................................................................... 10 Trial ......................................................................................................................................... 11 Subjects ................................................................................................................................. 10 Data Analysis ........................................................................................................................ 11 Statistical Analysis ................................................................................................................ 12 Results ....................................................................................................................................... 13 Diffuse Noxious Inhibitory Control...................................................................................... 14 Temporal Summation ........................................................................................................... 20 Expectation ............................................................................................................................ 23 Discussion ................................................................................................................................. 25 DNIC ....................................................................................................................................... 25 Temporal Summation ........................................................................................................... 27 Expectation ............................................................................................................................ 28 In Conclusion ......................................................................................................................... 29 References ................................................................................................................................ 31 Resumo ...................................................................................................................................... 33 Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto

Cav3-KCa3.1 complex enhances detection of facilitating parallel fiber inputs in cerebellar Purkinje cells

Abstract: The ability for a neuron to distinguish important input signals from background noise is essential for proper circuit function. Several mechanisms exist to enhance signal detection. For example, short-term facilitation enhances burst transmission, while information from single spikes is transmitted more effectively through synapses that exhibit depression [1]. However, in the case of cerebellar Purkinje cells, where thousands of parallel fiber (PF) synaptic inputs impinge on the dendritic tree, postsynaptic mechanisms must play a role in increasing signal-to-noise ratio. Specifically, mechanisms must exist in Purkinje cells that allow transmission of granule cell bursts carrying sensory information while filtering out background input. Recently, we demonstrated that low voltage activated Cav3 calcium channels form a complex with intermediate conductance calcium-activated potassium channels (KCa3.1) in Purkinje cells [2]. We proposed that the Cav3-KCa3.1 complex enhances signal detection capabilities by selectively suppressing non-facilitating background inputs while allowing facilitating parallel fiber inputs to generate Purkinje cell spike output. We used a combination of modeling and experimental methods to examine the role of the Cav3-KCa3.1 complex in simultaneously enhancing detection of parallel fiber bursts and suppressing background inputs. The Cav3-KCa3.1 complex was simulated using a calcium-diffusion model with 10 hemispherical compartments around the Cav3 channel and the KCa3.1 channel placed within 50 nm of the calcium source. The Cav3-KCa3.1 complex was included in a single-compartment membrane model with HCN and synaptic conductances to determine its effect on excitatory postsynaptic potential (EPSP) summation. Whole-cell current-clamp recordings of Purkinje cells were also made from acute slices of rat cerebellum (P18-P25). Parallel fibers were stimulated using a monopolar stimulating electrode in the cerebellar molecular layer. We simulated 5 pulse 50 Hz trains of facilitating and non-facilitating EPSPs in the model. The Cav3-KCa3.1 complex reduced the summation of both sets of inputs. However, the facilitating inputs achieved a higher degree of summation than non-facilitating inputs, even though charge transfer for both trains was identical. Examination of the KCa3.1 current showed that synaptic facilitation compensated for the increase in KCa3.1 activation during the input train, allowing EPSPs to summate to higher voltages. When the Cav3-KCa3.1 complex was not included in the model, facilitating and non-facilitating inputs reached similar degrees of summation. Our computational results were confirmed by our current clamp recordings. Facilitating inputs evoked by direct PF stimulation generated more depolarization and spikes in Purkinje cells than non-facilitating simulated EPSPs (simEPSPs). During trains of simEPSPs, a supralinear increase in the rate of EPSP decay was observed for consecutive inputs, indicating an increased recruitment of hyperpolarizing current during the train. Application of Ni2+ (100 μM) to block Cav3 current removed this supralinear increase in rate of decay, confirming that the Cav3-KCa3.1 complex dynamically changes temporal summation during repetitive input trains. Our results demonstrate that the Cav3-KCa3.1 complex significantly affects the temporal summation of synaptic inputs. Specifically, the Cav3-KCa3.1 complex allows facilitating inputs from single PF sources to summate and generate spike output in Purkinje cells, while background inputs are quickly suppressed, improving the ability to respond to important sensory information.