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

Changes in neuronal excitability due to increase in excitatory transmitters and/or removal of local inhibition underlie central neuron sensitization and altered responsiveness related to painful sensory disorders. To distinguish the contribution of each of the two mechanisms, they have been mimicked separately in intact rats, by iontophoretically applying excitatory (NMDA) and disinhibitory (the glycine antagonist strychnine) substances during dorsal horn neuron recording. Wide dynamic range (WDR) neurons were extracellularly recorded at the L5-L6 lumbar level in anesthetized and paralyzed rats and an analysis was made, before and during the substance application, of the characteristics of the response to noxious stimuli applied to areas supplied by the ipsilateral sciatic nerve and the contralateral sciatic and saphenous nerves ("inappropriate" areas). The results show that the neuronal response properties were modified differently during the NMDA-induced hyperexcitability and strychnine-induced release of inhibition. Both manipulations brought about the unmasking of responses to previously ineffective, noxious stimuli applied to the contralateral sciatic and saphenous nerve areas, and the enhancement of the responses to noxious stimulation of the ipsilateral sciatic nerve area. However, it was only during the increased excitation induced by NMDA that the neurons exhibited hyperresponsiveness, with long-lasting afterdischarge, to noxious stimulation of the ipsi- and contralateral areas. Such response features resemble those described in sensitized neurons in neuropathic rats and associated with behavioral signs of hyperalgesia. This suggests, by inference, a crucial contribution of the NMDA-induced increased excitability to the expression of neuronal sensitization related to this painful sensory disorder.

NMDA and strychnine diversely modulate spinal dorsal horn noxious responsiveness in normal rats: potential significance to sensory disorders in neuropathic pain.

In rats with chronic constriction of one sciatic nerve (CCI rats), showing behavioural signs of neuropathic pain, 6-methyl-2-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, was intraperitoneally administered at 0.75, 1.0 and 1.5 mg/kg or spinally microejected and the effects on the lumbar wide dynamic range neurons activity were investigated. In CCI rats MPEP at 1.0 and 1.5 (but not at 0.75) mg/kg, or spinally microejected induced a significant reduction of the spontaneous (SA) and noxious evoked activity (NEA), and a significant decrease of the suppression of the afterdischarge duration. In sham rats SA was unaffected and NEA was significantly reduced by 1.0 and 1.5 mg/kg MPEP dosages. These findings indicate that the metabotropic GluR5 receptor plays a role in the spinal cord processes underlying neuropathic pain and represents a potential target for new therapeutic approaches.

The mGluR5 selective antagonist 6-methyl-2-(phenylethynyl)-pyridine reduces the spinal neuron pain-related activity in mononeuropathic rats.

N-methyl-D-aspartic acid (NMDA) is an agonist at the homonymous receptor implicated in the development of neuronal sensitization and its behavioral correlates. An effective modulation of the NMDA effects, achieved also by uncompetitive antagonists, could contribute to controlling pain symptoms in several neuropathic syndromes. Because nefopam is a known analgesic derivative of orphenadrine and of its congener diphenhydramine, both uncompetitive NMDA receptor antagonists, we tested the effect of nefopam on the developing pain and neuronal anomalies in an animal model of chronic pain with NMDA receptor involvement. A single intraperitoneal injection of nefopam was administered twenty minutes prior to the chronic constriction injury of the sciatic nerve (CCI rats). In the first 10 days, nefopam (30 mg/kg) significantly decreased behavioral signs of neuropathic pain and the stimulus-evoked electrophysiological anomalies in recordings at 14 days, with only slight manifestation afterwards. The dose of 20 mg/kg was ineffective. Nefopam injected after constriction was ineffective. In normal non-operated rats, Nefopam had no effect on the electrophysiological and behavioral parameters. Iontophoretic nefopam (1 mM, 50-80 nA, positive current) in normal rats did not change the spontaneous neuronal activity, but reduced the mean response to noxious stimuli and the concurrent iontophoretic NMDA evoked activity. In CCI rats, iontophoretic nefopam did not significantly modify the spontaneous hyperactivity but reduced significantly both the frequency of the responses to noxious stimuli, and the duration of the afterdischarge. We propose that nefopam exerts a preventive analgesic effect, with a possible role in modulating NMDA receptor-mediated effects in central sensitization.

Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.

Nociceptin (NC), administered microiontophoretically at different concentrations, significantly reduced the spontaneous and stimulus-evoked activity on WDR neuron in rats with chronic constriction of one sciatic nerve and showing signs of neuropathic pain. The effect was not antagonized by Naloxone. The same concentrations of NC were ineffective on the noxious stimulus evoked responses of WDR neurons in sham and intact rats. This result indicates a facilitated inhibitory action of NC on nociceptive transmission in this pain model.

Efficacy of nociceptin inhibition on WDR neuron activity is enhanced in mononeuropathic rats.

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.

Neural activation patterns proceed often by schemes or motifs distributed across the involved cortical networks. As neurons are correlated, the estimate of all possible dependencies quickly goes out of control. The complex nesting of different oscillation frequencies and their high non-stationariety further hamper any quantitative evaluation of spiking network activities. The problem is exacerbated by the intrinsic variability of neural patterns.

Extraction and characterization of essential discharge patterns from multisite recordings of spiking ongoing activity.

The possibility to measure the metabolic activity of the brain cortex, with submillimeter spatial and subsecond temporal resolution, would open up enticing scenarios in addressing basic issues on the relation between different structural components of brain signal processing, and in providing an operational pathway to interaction with (dis)functional signal patterns. In the present article, we report the description of a simple system that allows the detection of the minute changes that occur in the optical backscattering of the cortex as a metabolic response to external stimuli. The simplicity of the system is compatible with scalability to an implantable probe. We validate the system on an animal model, and we propose an algorithm to extract meaningful data from the measured signal. We thus show the detection of individual haemodynamic cortical responses to individual stimulation events, and we provide operational considerations on the signal structure.

Probing for local activity-related modulation of the infrared backscattering of the brain cortex.

To ascertain the existence of contralateral painful muscle areas mirroring phantom pain and to evaluate the short-term effects of anaesthetic vs saline, injected contra notlaterally to control phantom and phantom limb pain.

Phantom limb pain relief by contralateral myofascial injection with local anaesthetic in a placebo-controlled study: preliminary results.

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.

We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease (PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [(123)I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.

A role for locus coeruleus in Parkinson tremor.

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 response of many neurons in the whisker somatosensory system depends on the direction in which a whisker is deflected. Although it is known that the spike count conveys information about this parameter, it is not known how important spike timing might be. The aim of this study was to compare neural codes based on spike count and first-spike latency, respectively. We extracellularly recorded single units from either the rat trigeminal ganglion (primary sensory afferents) or ventroposteromedial (VPM) thalamic nucleus in response to deflection in different directions and quantified alternative neural codes using mutual information. We found that neurons were diverse: some (58% in ganglion, 32% in VPM) conveyed information only by spike count; others conveyed additional information by latency. An issue with latency coding is that latency is measured with respect to the time of stimulus onset, a quantity known to the experimenter but not directly to the subject's brain. We found a potential solution using the integrated population activity as an internal timing signal: in this way, 91% of the first-spike latency information could be recovered. Finally, we asked how well direction could be decoded. For large populations, spike count and latency codes performed similarly; for small ones, decoding was more accurate using the latency code. Our findings indicate that whisker deflection direction is more efficiently encoded by spike timing than by spike count. Spike timing decreases the population size necessary for reliable information transmission and may thereby bring significant advantages in both wiring and metabolic efficiency.

Comparison of latency and rate coding for the direction of whisker deflection in the subcortical somatosensory pathway.

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.

Article	Year
NMDA and strychnine diversely modulate spinal dorsal horn noxious responsiveness in normal rats: potential significance to sensory disorders in neuropathic pain. Somatosensory & motor research\| PubMed ID: 11962642	2002
The mGluR5 selective antagonist 6-methyl-2-(phenylethynyl)-pyridine reduces the spinal neuron pain-related activity in mononeuropathic rats. Neuroscience letters\| PubMed ID: 12727324	2003
Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine. Journal of neurotrauma\| PubMed ID: 12906743	2003
Efficacy of nociceptin inhibition on WDR neuron activity is enhanced in mononeuropathic rats. Brain research\| PubMed ID: 14751598	2004
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
Extraction and characterization of essential discharge patterns from multisite recordings of spiking ongoing activity. PloS one\| PubMed ID: 19173006	2009
Probing for local activity-related modulation of the infrared backscattering of the brain cortex. Journal of biophotonics\| PubMed ID: 19405019	2009
Phantom limb pain relief by contralateral myofascial injection with local anaesthetic in a placebo-controlled study: preliminary results. Journal of rehabilitation medicine : official journal of the UEMS European Board of Physical and Rehabilitation Medicine\| PubMed ID: 19479153	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
A role for locus coeruleus in Parkinson tremor. Frontiers in human neuroscience\| PubMed ID: 22287946	2011
Predicting spike occurrence and neuronal responsiveness from LFPs in primary somatosensory cortex. PloS one\| PubMed ID: 22586452	2012
Comparison of latency and rate coding for the direction of whisker deflection in the subcortical somatosensory pathway. Journal of neurophysiology\| PubMed ID: 22815402	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

Gabriele E.M. Biella

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