a-simple-stimulatory-device-for-evoking-point-like-tactile-stimuli

A Simple Stimulatory Device for Evoking Point-like Tactile Stimuli: A Searchlight for LFP to Spike Transitions

Current neurophysiological research has the aim to develop methodologies to investigate the signal route from neuron to neuron, namely in the transitions ...

national research council

The effects of multimodality treatment on the survival of patients with esophageal carcinoma are unclear. The authors performed a prospective, Phase II study to assess the long-term results of chemotherapy plus radiotherapy (RT) on patients with esophageal squamous cell carcinoma.

Ten-year survival with chemotherapy and radiotherapy in patients with squamous cell carcinoma of the esophagus.

We hypothesized that the up-regulated expression of one or more members of the regulator of G protein signaling (RGS) family can cause an attenuation of signaling via Gi/Go-coupled opioid receptors, and thereby play a role in the development of hyperalgesia and accompanying insensitivity to morphine observed in animal models of neuropathic pain. Accordingly, we examined the mRNA expression of several RGS genes in a rat model of chronic neuropathic pain induced by partial ligation of the sciatic nerve. During the development of hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased significantly (up to 230%) in the lumbar spinal cord. In situ hybridization studies confirmed that RGS4 is present in the dorsal horn of the spinal cord where mu-opioid receptors (MORs) are also expressed. Overexpression of RGS4 in human embryonic kidney 293 cells stably expressing mu-opioid receptors predictably attenuated opioid agonist-induced inhibition of adenylyl cyclase. This inhibitory effect was overcome partially at high agonist concentrations, supporting the view that morphine insensitivity is promoted by RGS4 overexpression. These studies provide evidence that the up-regulation of RGS4 expression may contribute to changes in pain signal processing that lead to the development of hyperalgesia, and further affect its modulation by morphine.

Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine.

Wide Dynamic Range (WDR) neurons in the spinal cord receive inputs from the contralateral side that, under normal conditions, are ineffective in generating an active response. These inputs are effective when the target WDRs change their excitability conditions. To further reveal the mechanisms supporting this effectiveness shift, we investigated the weight of the excitation of the contralateral neurons on the target WDR responses. In the circuit of presynaptic (sending) and postsynaptic (receiving) neurons in crossed spinal connections the fibres that form the presynaptic neurons impinge on postsynaptic neurons can be considered the final relay of this contralateral pathway. The enhancement of the presynaptic neuron excitability may thus modify the efficacy of the contralateral input. Pairs of neurons each on a side of the spinal cord, at the L5-L6 lumbar level were simultaneously recorded in intact, anaesthetized, paralysed rats. The excitatory aminoacid NMDA and strychnine, the antagonist of the inhibitory aminoacid glycine, were iontophoretically administrated to presynaptic neurons to increase their excitability. Before and during the drug administration, spontaneous and noxious-evoked activities of the neurons were analysed. During the iontophoresis of the two substances we found that noxious stimuli applied to the receptive field of presynaptic neurons activated up to 50% of the previously unresponsive postsynaptic neurons on the opposite side. Furthermore, the neurons on both sides of the spinal cord showed significantly increased spontaneous activity and amplified responses to ipsilateral noxious stimulation. These findings indicate that the contralateral input participates in the circuit dynamics of spinal nociceptive transmission, by modulating the excitability of the postsynaptic neurons. A possible functional role of such a nociceptive transmission circuit in neuronal sensitization following unilateral nerve injury is hypothesized.

Contralateral input modulates the excitability of dorsal horn neurons involved in noxious signal processes. Potential role in neuronal sensitization.

Heterotopic inputs activate spinal wide dynamic range (WDR) neurons in rats with chronic constriction of one sciatic nerve (CCI rats). A possible contribution from these inputs, to long-lasting afterdischarges (ADs) of noxious evoked responses, was investigated during reversible input blockade from adjacent saphenous nerve and contralateral peripheral nerve territories. The results show significant AD reduction or suppression, indicating that heterotopic afferences contribute to mechanisms underlying prolonged ADs.

Heterotopic inputs facilitate poststimulus afterdischarges of spinal WDR neurons in rats with chronic nerve constriction.

We investigated in different experimental rat models the potential facilitatory contribution of the medullary dorsal reticular nucleus (DRt) descending pathway to the expressions of the sensory spinal neuron sensitization such as increased spontaneous and noxious evoked activities, responsivity to heterotopic afferences stimulation and long lasting afterdischarges (ADs). We carried out experiments by recording from ipsilateral lumbar Wide Dynamic Range (WDR) neurons and by simultaneously monitoring the DRt neuron activity in neuropathic pain rats with chronic constriction injury of one sciatic nerve (CCI), in sham-operated and in "intact" rats. In particular, we recorded the spinal neuron spontaneous activities and the activities evoked by noxious stimulations of ipsi- and contralateral sciatic supplied areas before and during DRt activity blockade. Additionally, in "intact rats" we modulated WDR activity by iontophoretic NMDA to mimic CCI WDR hyperactivity without peripheral damage. We found that during DRt activity blockade in CCI rat neurons and in "intact" rat NMDA-treated neurons, the spontaneous activity was significantly reduced, the responses to contralateral sciatic area stimulation were reduced or suppressed, the responses to ipsilateral sciatic area were poorly affected (slightly reduced or unaffected), except for the poststimulus afterdischarges that were mostly suppressed. In sham-operated rats, the neuronal activity was not affected by DRt blockade. The finding that during the DRt nucleus blockade some expressions of spinal neurons sensitization, seemingly associated to sensory disorders in neuropathic pain, fade or extinguish designates a likely facilitatory role of DRt in the maintenance of neuronal sensitization and thus a contribution to neuropathic pain state.

Contribution by DRt descending facilitatory pathways to maintenance of spinal neuron sensitization in rats.

The Authors present their experience in the surgical treatment of Morton's neuroma via a dorsal approach. The assessed results have been very good in terms of a clear clinical improvement and no recurrences in all the treated cases. The histological examination carried out on all the removed samples have shown that the thickening of the nerve first occurs due to perineural fibrosis and successively associated with sclerohyalinosis of the tissue, which is in line with the already existing literature reports. The Authors of the article reckon the adopted surgical technique to be simple, safe and highly effective.

Operative treatment of interdigital Morton's neuroma.

Isolated pure dislocations of the fifth carpo-metacarpal joint are extremely rare injuries. The dorsal form was described in mere 12 cases. The diagnosis can be easily missed. The lesion is also often overlooked in the routine diagnostic X-ray. Lateral and oblique views are important for the recognition of the true extent of the lesion. Treatment of these injures is still controversial and both closed reduction with percutaneous pinning or open reduction with internal fixation are advocated. The goal of treatment is early reduction and fixation of the metacarpal. Early diagnosis is the key to success. The aim of this paper is to review literature and present two new cases.

Pure isolated dorsal dislocation of the fifth carpometacarpal joint.

Methadone (Racemic methadone) exerts its antinociceptive effect by activation of mu-opioid receptors and/or blockade of NMDA receptors. The aim of this study is to determine whether the methadone analgesic effect on neuropathic pain is achieved only by the agonism of the mu-opioid receptors or cooperatively with the antagonism of the NMDA receptors. To this purpose, in rats with neuropathic pain model of chronic constriction of one sciatic nerve (CCI rats), we administered methadone before or after opioid receptor blockade with naloxone and checked its effects on the spinal Wide Dynamic Range (WDR) neuron dynamics in three experimental conditions: on the spontaneous and noxious evoked neuronal activities in control rats (sham operated and naïve); on iontophoretic NMDA induced neuronal hyperactivity in intact rats; on pain-related spontaneous and noxious evoked hyperactivities in CCI rats. The results, as from the spike-frequency analysis, show that: (i) in control rats, methadone inhibits the noxious evoked neuronal activity and naloxone prevents or reverses about 94% of methadone inhibitory effect; (ii) in intact rats, pretreated with naloxone, methadone reduces the NMDA induced neuronal hyperactivity; (iii) in CCI rats, methadone inhibits the neuronal spontaneous and noxious evoked hyperactivities, and naloxone prevents or reverses about 60% of methadone inhibitory effect. These findings allow to conclude that methadone inhibition of the noxious evoked activity in normal rats is achieved predominantly through the agonism of the mu-opioid receptors, while the inhibition of the pain-related hyperactivity in rats with signs of neuropathic pain (CCI rats), involves also the NMDA receptors antagonism.

Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain.

Given the increasing demand for tissue-sparing surgery, the surgical approach is the subject of lively debate in total hip replacement. The aim of this paper is to compare the efficacy of the minimally invasive direct anterior approach and the standard lateral approach to total hip replacement surgery by observing intra- and perioperative outcomes.

Comparison of primary total hip replacements performed with a direct anterior approach versus the standard lateral approach: perioperative findings.

The subcutaneous rupture of the Achilles tendon is a frequently observed lesion. Its treatment, however, remains controversial. The treatment to be applied varies between the conservative method, open surgical procedure and percutaneous or minimally invasive techniques. While conservative treatment results in a high percentage of re-ruptures, the open surgical treatment also has its complications. Surgical wound dehiscence, delayed cutaneous healing due to infection, delayed weight-bearing capacity, and consequent hypertrophic scarring account for 4-19% of all complications. The need for a technique that minimizes these complications has led to the development of percutaneous techniques. From August 2005 to March 2009, 35 consecutive patients underwent reparative surgery of the Achilles tendon using a minimally invasive technique with the Achillon device. All patients were available for follow-up. Dynamometric evaluation was possible on 15 patients. Twenty-five patients reported being very satisfied and 10 as being satisfied. The average AOFAS score was 93.4 (range 88-100 points). No complications occurred as a result of surgery (re-rupture, infection, lesion of the sural nerve, wound complication). All patients returned to work within 2 months, to jogging within 3 months, and to their previous level of sporting activity within 6 months. The authors believe that the minimally invasive technique using the Achillon device is a reliable surgical treatment and provides satisfactory results with a low rate of complication.

Minimally invasive repair of acute Achilles tendon ruptures with Achillon device.

Authors present a case of rupture of the distal end of the biceps femoris. Injuries at this site are relatively rare. Clinical assessment can be aided by instrumental examinations such as ultrasound and especially NMR. Delayed treatment because of erroneous diagnosis or failure of conservative therapy can result in proximal retraction and atrophy of the muscle belly, requiring more complex surgery. Despite the limited data in the literature, Authors favor immediate surgical treatment of both complete and partial injury of the biceps femoris tendon, particularly in a patient who requires a high level of function.

Isolated rupture of biceps femoris tendon.

Local Field Potentials (LFPs) integrate multiple neuronal events like synaptic inputs and intracellular potentials. LFP spatiotemporal features are particularly relevant in view of their applications both in research (e.g. for understanding brain rhythms, inter-areal neural communication and neuronal coding) and in the clinics (e.g. for improving invasive Brain-Machine Interface devices). However the relation between LFPs and spikes is complex and not fully understood. As spikes represent the fundamental currency of neuronal communication this gap in knowledge strongly limits our comprehension of neuronal phenomena underlying LFPs. We investigated the LFP-spike relation during tactile stimulation in primary somatosensory (S-I) cortex in the rat. First we quantified how reliably LFPs and spikes code for a stimulus occurrence. Then we used the information obtained from our analyses to design a predictive model for spike occurrence based on LFP inputs. The model was endowed with a flexible meta-structure whose exact form, both in parameters and structure, was estimated by using a multi-objective optimization strategy. Our method provided a set of nonlinear simple equations that maximized the match between models and true neurons in terms of spike timings and Peri Stimulus Time Histograms. We found that both LFPs and spikes can code for stimulus occurrence with millisecond precision, showing, however, high variability. Spike patterns were predicted significantly above chance for 75% of the neurons analysed. Crucially, the level of prediction accuracy depended on the reliability in coding for the stimulus occurrence. The best predictions were obtained when both spikes and LFPs were highly responsive to the stimuli. Spike reliability is known to depend on neuron intrinsic properties (i.e. on channel noise) and on spontaneous local network fluctuations. Our results suggest that the latter, measured through the LFP response variability, play a dominant role.

Predicting spike occurrence and neuronal responsiveness from LFPs in primary somatosensory cortex.

The analysis of the brain in terms of integrated neural networks may offer insights on the reciprocal relation between structure and information processing. Even with inherent technical limits, many studies acknowledge neuron spatial arrangements and communication modes as key factors. In this perspective, we investigated the functional organization of neuronal networks by explicitly assuming a specific functional topology, the small-world network. We developed two different computational approaches. Firstly, we asked whether neuronal populations actually express small-world properties during a definite task, such as a learning task. For this purpose we developed the Inductive Conceptual Network (ICN), which is a hierarchical bio-inspired spiking network, capable of learning invariant patterns by using variable-order Markov models implemented in its nodes. As a result, we actually observed small-world topologies during learning in the ICN. Speculating that the expression of small-world networks is not solely related to learning tasks, we then built a de facto network assuming that the information processing in the brain may occur through functional small-world topologies. In this de facto network, synchronous spikes reflected functional small-world network dependencies. In order to verify the consistency of the assumption, we tested the null-hypothesis by replacing the small-world networks with random networks. As a result, only small world networks exhibited functional biomimetic characteristics such as timing and rate codes, conventional coding strategies and neuronal avalanches, which are cascades of bursting activities with a power-law distribution. Our results suggest that small-world functional configurations are liable to underpin brain information processing at neuronal level.

Small-world networks in neuronal populations: a computational perspective.

Small-World Networks (SWNs) represent a fundamental model for the comprehension of many complex man-made and biological networks. In the central nervous system, SWN models have been shown to fit well both anatomical and functional maps at the macroscopic level. However, the functional microscopic level, where the nodes of a network are represented by single neurons, is still poorly understood. At this level, although recent evidences suggest that functional connection graphs exhibit small-world organization, it is not known whether and how these maps, potentially distributed in multiple brain regions, change across different conditions, such as spontaneous and stimulus-evoked activities. We addressed these questions by analyzing the data from simultaneous multi-array extracellular recordings in three brain regions of rats, diversely involved in somatosensory information processing: the ventropostero-lateral thalamic nuclei, the primary somatosensory cortex and the centro-median thalamic nuclei. From both spike and Local Field Potential (LFP) recordings, we estimated the functional connection graphs by using the Normalized Compression Similarity for spikes and the Phase Synchrony for LFPs. Then, by using graph-theoretical statistics, we characterized the functional topology both during spontaneous activity and sensory stimulation. Our main results show that: (i) spikes and LFPs show SWN organization during spontaneous activity; (ii) after stimulation onset, while substantial functional graph reconfigurations occur both in spike and LFPs, small-worldness is nonetheless preserved; (iii) the stimulus triggers a significant increase of inter-area LFP connections without modifying the topology of intra-area functional connections. Finally, investigating computationally the functional substrate that supports the observed phenomena, we found that (iv) the fundamental concept of cell assemblies, transient groups of activating neurons, can be described by small-world networks. Our results suggest that activity of neurons from multiple areas of the rat somatosensory system contributes to the integration of local computations arisen in distributed functional cell assemblies according to the principles of SWNs.

Article	Year
Ten-year survival with chemotherapy and radiotherapy in patients with squamous cell carcinoma of the esophagus. Cancer\| PubMed ID: 11900221	2002
Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine. The Journal of pharmacology and experimental therapeutics\| PubMed ID: 12604710	2003
Contralateral input modulates the excitability of dorsal horn neurons involved in noxious signal processes. Potential role in neuronal sensitization. Somatosensory & motor research\| PubMed ID: 15763906	2004
Heterotopic inputs facilitate poststimulus afterdischarges of spinal WDR neurons in rats with chronic nerve constriction. Brain research\| PubMed ID: 16797491	2006
Contribution by DRt descending facilitatory pathways to maintenance of spinal neuron sensitization in rats. Brain research\| PubMed ID: 18054897	2008
Operative treatment of interdigital Morton's neuroma. La Chirurgia degli organi di movimento\| PubMed ID: 18343980	2008
Pure isolated dorsal dislocation of the fifth carpometacarpal joint. La Chirurgia degli organi di movimento\| PubMed ID: 19711009	2009
Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of ... Pharmacological research : the official journal of the Italian Pharmacological Society\| PubMed ID: 19717013	2009
Comparison of primary total hip replacements performed with a direct anterior approach versus the standard lateral approach: perioperative findings. Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology\| PubMed ID: 21748384	2011
Minimally invasive repair of acute Achilles tendon ruptures with Achillon device. Musculoskeletal surgery\| PubMed ID: 21773696	2012
Isolated rupture of biceps femoris tendon. Musculoskeletal surgery\| PubMed ID: 22042648	2013
Predicting spike occurrence and neuronal responsiveness from LFPs in primary somatosensory cortex. PloS one\| PubMed ID: 22586452	2012
Small-world networks in neuronal populations: a computational perspective. Neural networks : the official journal of the International Neural Network Society\| PubMed ID: 23632438	2013
Neuronal functional connection graphs among multiple areas of the rat somatosensory system during spontaneous and evoked activities. PLoS computational biology\| PubMed ID: 23785273	2013

Maurizio Valente

Biography

JoVE Journal Publications

Other Publications