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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 ...

University of Manchester

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.

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.

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.

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.

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.

Riccardo Storchi

Faculty of Life Sciences

University of Manchester

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