Ventral Posterolateral Research Articles

Selective deficiencies in descending inhibitory modulation in neuropathic rats: implications for enhancing noradrenergic tone.

Pontine noradrenergic neurones form part of a descending inhibitory system that influences spinal nociceptive processing. Weak or absent descending inhibition is a common feature of chronic pain patients. We examined the extent to which the descending noradrenergic system is tonically active, how control of spinal neuronal excitability is integrated into thalamic relays within sensory-discriminative projection pathways, and how this inhibitory control is altered after nerve injury. In vivo electrophysiology was performed in anaesthetised spinal nerve-ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus (VPL). In sham rats, spinal block of α2-adrenoceptors with atipamezole resulted in enhanced stimulus-evoked and spontaneous firing in the VPL, and produced conditioned place avoidance. However, in SNL rats, these conditioned avoidance behaviours were absent. Furthermore, inhibitory control of evoked neuronal responses was lost, but spinal atipamezole markedly increased spontaneous firing. Augmenting spinal noradrenergic tone in neuropathic rats with reboxetine, a selective noradrenergic reuptake inhibitor, modestly reinstated inhibitory control of evoked responses in the VPL but had no effect on spontaneous firing. By contrast, clonidine, an α2 agonist, inhibited both evoked and spontaneous firing, and exhibited increased potency in SNL rats compared with sham controls. These data suggest descending noradrenergic inhibitory pathways are tonically active in sham rats. Moreover, in neuropathic states, descending inhibitory control is diminished, but not completely absent, and distinguishes between spontaneous and evoked neuronal activity. These observations may have implications for how analgesics targeting the noradrenergic system provide relief.

Cerebral Ischemia Changed the Effect of Metabosensitive Muscle Afferents on Somatic Reflex Without Affecting Thalamic Activity.

The purpose of the present study was to examine the contribution of group III and IV metabosensitive afferents at spinal and supraspinal levels in rats subjected to middle cerebral artery occlusion (MCAO) with reperfusion during the acute phase. Animals were randomized in Control (n = 23), SHAM (n = 18), MCAO-D1 (n = 10), and MCAO-D7 (n = 20) groups. Rats performed the Electrical Von Frey and the Adhesive removal tests before the surgery and at day 1 (D1), D3, and D7 after MCAO. Animals were subjected to electrophysiological recordings including the responses of group III/IV metabosensitive afferents to combinations of chemical activators and the triceps brachii somatic reflex activity at D1 or D7. The response of ventral posterolateral (VPL) thalamic nuclei was also recorded after group III/IV afferent activation. Histological measurements were performed to assess the infarct size and to confirm the location of the recording electrodes into the VPL. Behavioral results indicated that MCAO induced disorders of both mechanical sensibility and motor coordination of paretic forepaw during 7 days. Moreover, injured animals exhibited an absence of somatic reflex inhibition from the group III/IV afferents at D1, without affecting the response of both these afferents and the VPL. Finally, the regulation of the central motor drive by group III/IV afferents was modified at spinal level during the acute phase of cerebral ischemia and it might contribute to the observed behavioral disturbances.

Feasibility of imaging evoked activity throughout the rat brain using electrical impedance tomography

Electrical Impedance Tomography (EIT) is an emerging technique which has been used to image evoked activity during whisker displacement in the cortex of an anaesthetised rat with a spatiotemporal resolution of 200 μm and 2 ms. The aim of this work was to extend EIT to image not only from the cortex but also from deeper structures active in somatosensory processing, specifically the ventral posterolateral (VPL) nucleus of the thalamus. The direct response in the cortex and VPL following 2 Hz forepaw stimulation were quantified using a 57-channel epicortical electrode array and a 16-channel depth electrode. Impedance changes of −0.16 ± 0.08% at 12.9 ± 1.4 ms and −0.41 ± 0.14% at 8.8±1.9 ms were recorded from the cortex and VPL respectively. For imaging purposes, two 57-channel epicortical electrode arrays were used with one placed on each hemisphere of the rat brain. Despite using parameters optimised toward measuring thalamic activity and undertaking extensive averaging, reconstructed activity was constrained to the cortical somatosensory forepaw region and no significant activity at a depth greater than 1.6 mm below the surface of the cortex could be reconstructed. An evaluation of the depth sensitivity of EIT was investigated in simulations using estimates of the conductivity change and noise levels derived from experiments. These indicate that EIT imaging with epicortical electrodes is limited to activity occurring 2.5 mm below the surface of the cortex. This depth includes the hippocampus and so EIT has the potential to image activity, such as epilepsy, originating from this structure. To image deeper activity, however, alternative methods such as the additional implementation of depth electrodes will be required to gain the necessary depth resolution.

S117. Intraoperative detection of posterior circulation transient ischemic attack: Single case study

Introduction Intraoperative Neuromonitoring (IONM) has been utilized to aid in the prevention of iatrogenic injury. Studies have described the role IONM may play in predicting post procedural neurological deficits (PPNDs). Here we discuss a unique case study of a patient who underwent stent-assisted embolization of a large basilar tip aneurysm with very specific localizing changes observed by analysis of somatosensory evoked potentials (SSEPs), electroencephalography (EEG), and brainstem auditory evoked potentials (BAEPs). Methods A 66 year old female with past medical history of hypertension and hyperlipidemia presented to the emergency department (ED) with photophobia and a left dilated pupil. MR angiography revealed a large basilar tip aneurysm. Aspirin and Plavix were administered and a stent-assisted coil embolization was performed with complete resolution of symptoms. Follow-up elective repair of the aneurysm was scheduled. Prior to the follow-up elective repair, the patient presented to the ED once again with a new onset headache and anisocoria. MR angiogram was performed which revealed no acute changes. The patient was admitted and underwent further embolization of the aneurysm from the left P1 into the basilar apex. The initial stent was deployed with no complications. During advancement of a second stent, abrupt cortical amplitude decreases of 76% and 79% in the left upper and lower extremity traces, respectively, were observed. All other traces remained stable. Catheter placement was inspected and noted as normal. Signals began to improve and returned to baseline in less than 10 min as the procedure was completed without placement of an additional stent. Results Six days post-operatively, the patient presented to an outside ED complaining of posterior headache and left-sided paresthesia in the trigeminal nerve distribution. She was transferred to the University of Michigan for further evaluation. MR imaging was unremarkable but further workup revealed sub-therapeutic Plavix levels so her dose was increased. Her symptoms resolved within 24 h. Conclusion We hypothesize that both intraoperative electrophysiological changes and PPNDs reflect a specific ischemic event in the P1/P2 deep perforator distribution affecting the right ventral posterolateral and posteromedial nuclei of the thalamus, respectively. This case highlights the potential anatomic specificity of multimodal IONM by the changes seen at the time of manipulation of the perforating branches of the posterior circulation, correlating with subsequent TIA and symptoms attributable to the same vascular distribution. This interpretation must be taken with caution as this does not establish a direct correlation of IONM changes with subsequent TIA. Potential correlation should be studied in a larger population undergoing endovascular intervention in the posterior circulation.

Viral‐genetic Mapping of Neural Circuit Organization of Nociceptive Neurons in the Thalamus

There is a critical need to determine the location, connections and neurochemical identities of neurons participating in the transmission and modulation of pain in the CNS so that these circuits can be precisely targeted for pain intervention. Without such knowledge the development of effective, low side‐effect pain treatments will be difficult. In this talk I will report our progress using recent technological advancements to determine detailed neural activation patterns and synaptic circuit organization of neurons related to pain sensation and modulation in the thalamus. We have identified and visualized thalamic nociceptive neurons activated by chronic pain, using a strategy of genetic capture of active neurons on the basis of activity dependent c‐fos gene expression. Specifically, pain‐activated neurons are captured using Fos‐CreER mice with tamoxifen‐dependent recombinase CreERT2 under the promoter of the immediate early gene c‐fos. These mice are crossed with Cre reporter Ai9 mice to express tdTomato fluorescent proteins. A noxious stimulus is evoked by injection of complete Freund's adjuvant (CFA) into the hind paw; only neurons that are functionally active within a limited time window of 4‐OHT administration are genetically labeled. Then we build on this technical development to combine the Fos‐CreER based strategy with new viral tracing of circuit connections to nociceptive neurons in the ventral posterolateral (VPL) nucleus. Genetically modified rabies is used to trace global direct synaptic connections to pain activated neurons in VPL. These studies allow us to map molecular and neurochemical identities (e.g., excitatory versus inhibitory) of whole brain‐wide presynaptic neurons that are directly connected to thalamic nociceptive neurons. We foresee that this new research can address the critical barrier in the field and will advance our understanding of thalamic nociceptive neuron circuits and pain modulating processes.Support or Funding InformationStart‐up funds from Texas A&M UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Selective downregulation of vesicular glutamate transporter2 in ventral posterolateral nucleus of thalamus attenuates neuropathic mechanical allodynia in mice

Vesicular glutamate transporters (VGLUTs) transport glutamate into synaptic vesicles prior to exocytotic release. The expression pattern of VGLUT2 and studies of genetically modified mice have revealed that VGLUT2 contributes to neuropathic pain. We previously showed that VGLUT2 is upregulated in supraspinal regions including the thalamus in mice following spared nerve injury (SNI), and blocking VGLUTs using the VGLUT inhibitor CSB6B attenuated mechanical allodynia. To further evaluate the role of VGLUT2 in neuropathic pain, in this study, we developed a lentiviral vector expressing small hairpin RNAs (shRNAs) against mouse VGLUT2, which was injected into the ventral posterolateral (VPL) nucleus of the thalamus in the presence or absence of SNI. The administration of VGLUT2 shRNAs result in downregulation of VGLUT2 mRNA and protein expression, and decreased extracellular glutamate release in primary cultured neurons. We also showed that VGLUT2 shRNAs attenuated SNI-induced mechanical allodynia, in accordance with knockdown of VGLUT2 in the VPL nucleus in mice. Accordingly, our study supports the essential role of supraspinal VGLUT2 in neuropathic pain in adult mice and, thereby, validates VGLUT2 as a potential target for neuropathic pain therapy.

Characterising the frequency response of impedance changes during evoked physiological activity in the rat brain

Objective: Electrical impedance tomography (EIT) can image impedance changes associated with evoked physiological activity in the cerebral cortex using an array of epicortical electrodes. An impedance change is observed as the externally applied current, normally confined to the extracellular space is admitted into the conducting intracellular space during neuronal depolarisation. The response is largest at DC and decreases at higher frequencies due to capacitative transfer of current across the membrane. Biophysical modelling has shown that this effect becomes significant above 100 Hz. Recordings at DC, however, are contaminated by physiological endogenous evoked potentials. By moving to 1.7 kHz, images of somatosensory evoked responses have been produced down to 2 mm with a resolution of 2 ms and 200 μm. Hardware limitations have so far restricted impedance measurements to frequencies <2 kHz. The purpose of this work was to establish the optimal frequency for extending EIT to image throughout the brain and to characterise the response at frequencies >2 kHz using improved hardware. Approach: Impedance changes were recorded during forepaw somatosensory stimulation in both cerebral cortex and the VPL nucleus of the thalamus in anaesthetised rats using applied currents of 1 kHz to 10 kHz. Main results: In the cortex, impedance changed by –0.04 ± 0.02 % at 1 kHz, reached a peak of –0.13 ± 0.05 % at 1475 Hz and decreased to –0.05 ± 0.02 % at 10 kHz. At these frequencies, changes in the thalamus were –0.26 ± 0.1%, –0.4 ± 0.15 % and –0.08 ± 0.03 % respectively. The signal-to-noise ratio was also highest at 1475 Hz with values of –29.5 ± 8 and –31.6 ±10 recorded from the cortex and thalamus respectively. Signficance: This indicates that the optimal frequency for imaging cortical and thalamic evoked activity using fast neural EIT is 1475 Hz.

Neuromodulation with single-element transcranial focused ultrasound in human thalamus.

Transcranial focused ultrasound (tFUS) has proven capable of stimulating cortical tissue in humans. tFUS confers high spatial resolutions with deep focal lengths and as such, has the potential to noninvasively modulate neural targets deep to the cortex in humans. We test the ability of single-element tFUS to noninvasively modulate unilateral thalamus in humans. Participants (N = 40) underwent either tFUS or sham neuromodulation targeted at the unilateral sensory thalamus that contains the ventro-posterior lateral (VPL) nucleus of thalamus. Somatosensory evoked potentials (SEPs) were recorded from scalp electrodes contralateral to median nerve stimulation. Activity of the unilateral sensory thalamus was indexed by the P14 SEP generated in the VPL nucleus and cortical somatosensory activity by subsequent inflexions of the SEP and through time/frequency analysis. Participants also under went tactile behavioral assessment during either the tFUS or sham condition in a separate experiment. A detailed acoustic model using computed tomography (CT) and magnetic resonance imaging (MRI) is also presented to assess the effect of individual skull morphology for single-element deep brain neuromodulation in humans. tFUS targeted at unilateral sensory thalamus inhibited the amplitude of the P14 SEP as compared to sham. There is evidence of translation of this effect to time windows of the EEG commensurate with SI and SII activities. These results were accompanied by alpha and beta power attenuation as well as time-locked gamma power inhibition. Furthermore, participants performed significantly worse than chance on a discrimination task during tFUS stimulation.

Thalamo-cortical projections to the macaque superior parietal lobule areas PEc and PE.

The exposed surface of the superior parietal lobule in macaque brain contains two architectonically defined areas named PEc and PE. The aim of the present study is the characterization of thalamic afferents of these two areas. For this purpose, retrograde neuronal tracers were injected, or placed in crystal form, in areas PEc and PE. We found that the two areas show a similar pattern of thalamic inputs, mainly originating from Lateral Posterior (LP), Pulvinar (Pul), Ventral Posterior Lateral (VPL), and Ventral Lateral (VL) nuclei, all structures known to be involved in visual, somatosensory, and/or sensorimotor processing. Minor afferents were observed from the Centromedian/Parafascicular complex (CM/PF), Central Lateral (CL), Ventral Anterior (VA), and Medial Dorsal (MD) nuclei. LP and VL were more strongly connected to PEc than to PE, while the other main thalamic inputs to the two areas showed slight differences in strength. The part of the Pul mostly connected with areas PEc and PE was the Medial Pul. No labeled cells were found in the retinotopically organized Lateral and Inferior Pul. In the somatotopically organized VPL and VL nuclei, labeled neurons were mainly found in regions likely to correspond to the trunk and limb representations (in particular the legs). These findings are in line with the sensory-motor nature of areas PEc and PE, and with their putative functional roles, being them suggested to be involved in the preparation and control of limb interaction with the environment, and in locomotion.

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype - a placebo controlled fMRI study.

BackgroundKetamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI.MethodsFifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840).ResultsA significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers.ConclusionsWe demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression.

Axons of Individual Dorsal Horn Neurons Bifurcated to Project in Both the Anterolateral and the Postsynaptic Dorsal Column Systems

Sensory information stimulates receptors of somatosensory system neurons generating a signal that codifies the characteristics of peripheral stimulation. This information reaches the spinal cord and is relayed to supra-spinal structures through two main systems: the postsynaptic dorsal column-medial lemniscal (DC-ML) and the anterolateral (AL) systems. From the classical point of view, the DC-ML has an ipsilateral ascending pathway to the Gracilis (GRA) or Cuneate (CUN) nuclei and the AL has a contralateral ascending pathway to the ventral posterolateral (VPL) thalamic nucleus. These two systems have been the subject of multiple studies that established their independence and interactions. To analyze the ascending projections of L1–L5 spinal dorsal horn neurons in the rat, two retrograde neuronal tracers were injected into the GRA and the VPL. Additionally, an electrophysiological study was performed by applying electrical stimulation at the GRA or VPL and recording antidromic evoked activity in single unit spinal cord cells. Importantly, a subset of spinal dorsal horn neurons exhibited double staining, indicating that these neurons projected to both the GRA and the VPL. These double-stained neurons were located on both sides of the dorsal horn of the spinal cord. The spinal dorsal horn neurons exhibited antidromic and collision activities in response to both GRA and VPL electrical activation. These results show spinal cord neurons with bifurcated bilateral projections to both the DC-ML and AL systems. Based on these results, we named these neurons bilateral and bifurcated cells.

Cytoarchitecture and Myeloarchitecture of the Pulvinar.

In this chapter, we discuss the different ways in which the primate pulvinar has been subdivided, based on cytoarchitectural and myeloarchitectural criteria. One original criterion, based on cytoarchitecture, subdivided the pulvinar into nucleus pulvinaris medialis (PM), nucleus pulvinaris lateralis (PL), and nucleus pulvinaris inferior (PI). Later, the anterior limits of the pulvinar were extended and a subdivision was added to this nucleus, named pulvinar oralis (PO). PO occupies the anterior portion of the pulvinar and appears between the nucleus centrum medianum (CM) and the nucleus ventralis posterior lateralis (VPL).

Altered Expression of Reorganized Inputs as They Ascend From the Cuneate Nucleus to Cortical Area 3b in Monkeys With Long-Term Spinal Cord Injuries.

Chronic deafferentations in adult mammals result in reorganization of the brain. Lesions of the dorsal columns of the spinal cord at cervical levels in monkeys result in expansion of the intact chin inputs into the deafferented hand representation in area 3b, second somatosensory (S2) and parietal ventral (PV) areas of the somatosensory cortex, ventroposterior lateral nucleus (VPL) of the thalamus, and cuneate nucleus of the brainstem. Here, we describe the extent and nature of reorganization of the cuneate and gracile nuclei of adult macaque monkeys with chronic unilateral lesions of the dorsal columns, and compare it with the reorganization of area 3b in the same monkeys. In both, area 3b and the cuneate nucleus chin inputs expand to reactivate the deafferented neurons. However, unlike area 3b, neurons in the cuneate nucleus also acquire receptive fields on the shoulder, neck, and occiput. A comparison with the previously published results shows that reorganization in the cuneate nucleus is similar to that in VPL. Thus, the emergent topography following deafferentations by spinal cord injuries undergoes transformation as the reorganized inputs ascend from subcortical nuclei to area 3b. The results help us understand mechanisms of the brain plasticity following spinal cord injuries.

Differential effect of motor cortex stimulation on unit activities in the ventral posterior lateral thalamus in cats.

Although motor cortex stimulation (MCS) is being increasingly used to treat chronic refractory neuropathic pain in humans, its mechanisms of action remain elusive. Studies in animals have suggested the involvement of subcortical structures, in particular, the thalamus. Most of these studies have been performed in rats, a species presenting significant differences in thalamic anatomy and function relative to primates, in particular, a very limited number of thalamic GABA interneurons. The aim of this study was to investigate the effects of MCS on single-unit activities of the thalamic ventral posterior lateral (VPL) nucleus in cats, which contains substantial numbers of GABA interneurons. Spontaneous and evoked activities of VPL units were studied before and after MCS. Motor cortex stimulation induced significant depression of the wide-dynamic-range (WDR) cells' firing rate, concomitant with activity enhancement of nonnociceptive (NN) units. More than half of WDR cells showed a significant decrease in the firing rate, while a similar proportion of NN units exhibited the opposite after-effect. Maximal firing attenuation of WDR cells occurred when the MCS location matched somatotopically their receptive field. Repetition of MCS runs led to an accentuation of WDR depression. After peripheral stimulation, evoked activity in each cell showed MCS effects similar to those observed in spontaneous activity. These data demonstrate a selective top-down inhibition by MCS of nonspecific nociceptive (WDR) cells, enhanced by somatotopic concordance and stimulation repetition, in parallel to facilitation of NN cells. These 2 outcomes may play a role in the complex analgesic effect of MCS observed in neuropathic pain conditions.

P 170 A potential signature for ongoing pain in mice

Chronic pain is a major health care problem nowadays with no convincing treatment yet ( Apkarian et al., 2009 ). One challenge of research and treatment of pain is that it cannot be objectively quantified. Only indirect measurements like the Visual Analogue Scale for humans and responses to mechanical or thermal stimuli for animals are used. Electrophysiological changes in brain activity are a possible candidate for a direct measurement of pain and could be easily obtained by EEG recordings. However most of the studies with this scope are focused on evoked potentials of short lasting pain stimuli (ms to s) ( Zhang et al., 2012 ) and only few studies have been conducted on longer lasting pain ( Leblanc et al., 2014 ). Therefore we analyzed Local Field Potential (LFP) recordings in mice after injection of capsaicin in order to find a signature of ongoing pain. LFP was recorded in freely moving and head-restrained mice before, during and after ongoing pain induced by capsaicin injection into the hindpaw. As a control, NaCl was injected into the same hindpaw one day earlier. Implantation sites were the Primary Somatosensory Cortex - Hindlimb Region (S1HL), the Cingulate Cortex (ACC), the Ventro Posterolateral Thalamic Nucleus (VPL) and the Insular Cortex (Ins) both ipsi- and contralateral to the injection site respectively, as well as the Parietal Cortex and the Olfactory Bulb (left side only). For analysis the signal 15 min before injection of NaCl and immediately after injection (up to 5 min) was taken. To avoid muscle artefacts, phases in which the mouse did not move were extracted and concatenated until a 30 s window was reached. The mean power was then computed in six different frequency bands (1–4 Hz, 4–12 Hz,12–30 Hz, 30–80 Hz, 80–120 Hz, 120–160 Hz) using the MATLAB pwelch function (Hamming window 4s, 50% overlap). These values were normalized using the following formula (Power post Injection − Power pre Injection) /(Power post Injection + Power pre Injection) . A logistic regression model was fitted for each channel trying to predict whether capsaicin was administered based on the normalized power values across all frequencies. From these values a receiver operating characteristic (ROC) curve was computed and the area under the curve was taken as the probability of prediction whether capsaicin was injected. A p -value was computed using the wilcoxon signed rank test ( Table 1 ). To control for multiple testing the Benjamin-Hochberg procedure was used. We conclude that LFP recordings could be a measurement to infer whether an animal is experiencing acute pain and thus might be used as a signature of pain. However, a larger sample size is needed to determine the details of those changes in LFP activity and the most relevant frequency bands.

Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain

Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. Immunohistochemistry revealed that microglial and astrocytic activation in the perilesional areas lasted at least 3 months after injection. The present model reproduced the symptoms of patients suffering from CPSP, in which both mechanical allodynia and thermal hyperalgesia often develop several weeks after cerebrovascular accident. Further, the long-lasting glial activation revealed here may be characteristic of primate brains following injury. The present model will be useful not only for examining the neurological changes underlying CPSP, but also for testing therapeutic interventions for CPSP.

Can local-community-paradigm and epitopological learning enhance our understanding of how local brain connectivity is able to process, learn and memorize chronic pain?

The mystery behind the origin of the pain and the difficulty to propose methodologies for its quantitative characterization fascinated philosophers (and then scientists) from the dawn of our modern society. Nowadays, studying patterns of information flow in mesoscale activity of brain networks is a valuable strategy to offer answers in computational neuroscience. In this paper, complex network analysis was performed on the time-varying brain functional connectomes of a rat model of persistent peripheral neuropathic pain, obtained by means of local field potential and spike train analysis. A wide range of topological network measures (14 in total, the code is publicly released at: https://github.com/biomedical-cybernetics/topological_measures_wide_analysis) was employed to quantitatively investigate the rewiring mechanisms of the brain regions responsible for development and upkeep of pain along time, from three hours to 16 days after nerve injury. The time trend (across the days) of each network measure was correlated with a behavioural test for rat pain, and surprisingly we found that the rewiring mechanisms associated with two local topological measure, the local-community-paradigm and the power-lawness, showed very high statistical correlations (higher than 0.9, being the maximum value 1) with the behavioural test. We also disclosed clear functional connectivity patterns that emerged in association with chronic pain in the primary somatosensory cortex (S1) and ventral posterolateral (VPL) nuclei of thalamus. This study represents a pioneering attempt to exploit network science models in order to elucidate the mechanisms of brain region re-wiring and engram formations that are associated with chronic pain in mammalians. We conclude that the local-community-paradigm is a model of complex network organization that triggers a local learning rule, which seems associated to processing, learning and memorization of chronic pain in the brain functional connectivity. This rule is based exclusively on the network topology, hence was named epitopological learning.

218 Target Selection for Deep Brain Stimulation in Children with Secondary Dystonia Utilizing Temporary Depth Electrodes for Stimulation and Chronic Recording

Abstract INTRODUCTION The optimal target for deep brain stimulation (DBS) treatment in children with secondary dystonia is not known, and the target may vary depending on the etiology and anatomic distribution of injury in each child. We present a new technique for determining optimal neuro-anatomical targets in these patients. METHODS Up to ten depth electrodes are implanted in each child in multiple brain regions, including bilateral STN, GPi, and the VLa (Vo), VLp (Vim) and VPL nuclei of the thalamus. Each electrode had both high-impedance micro contacts to identify single unit firing and macro contacts for identifying local field potentials and for performing test stimulation. Children were monitored for up to one week with continuous recording from all electrodes and intermittent test stimulation at bilateral contact pairs. RESULTS &gt;No single consistent pattern of abnormality was found. Most often, single-unit recording showed high firing rates in GPi, and dystonic movement correlated with activity VLa or VLp. The optimal stimulation target varied between children, with rapid improvement of dystonic postures during stimulation in either VLa, VLp or VPL. Stimulation of STN caused resolution of spasms during sleep in one child. Stimulation in GPi did not produce an immediate effect during the recording period, consistent with known latency of treatment effect. All of the children were implanted with up to 4 permanent stimulation leads connected to implanted pulse generators. Preliminary clinical observations show significant beneficial effect in all children. CONCLUSION This new method of DBS targeting identified targets that varied between children. Early response to therapy suggests a beneficial effect that exceeds what would be expected for GPi stimulation alone. This technique may increase the effectiveness of DBS in secondary dystonia and may allow application to a broader range of conditions in children not previously known to respond to stimulation.

GS-KG9 ameliorates diabetic neuropathic pain induced by streptozotocin in rats

BackgroundDiabetic neuropathy is one of the most devastating ailments of the peripheral nervous system. Neuropathic pain develops in ∼30% of diabetics. Here, we examined the suppressive effect of GS-KG9 on neuropathic pain induced by streptozotocin (STZ). MethodsHyperglycemia was induced by intraperitoneal injection of STZ. Rats showing blood glucose level > 250 mg/dL were divided into five groups, and treatment groups received oral saline containing GS-KG9 (50 mg/kg, 150 mg/kg, or 300 mg/kg) twice daily for 4 wk. The effects of GS-KG9 on pain behavior, microglia activation in the lumbar spinal cord and ventral posterolateral (VPL) nucleus of the thalamus, and c-Fos expression in the dorsal horn of the lumbar spinal cord were examined. ResultsThe development of neuropathic pain began at Day 5 and peaked at Week 4 after STZ injection. Mechanical and thermal pains were both significantly attenuated in GS-KG9-treated groups from 10 d after STZ injection as compared to those in the STZ control. GS-KG9 also repressed microglia activation in L4 dorsal horn and VPL region of the thalamus. In addition, increase in c-Fos-positive cells within L4 dorsal horn lamina I and II of the STZ control group was markedly alleviated by GS-KG9. ConclusionThese results suggest that GS-KG9 effectively relieves STZ-induced neuropathic pain by inhibiting microglial activation in the spinal cord dorsal horn and VPL region of the thalamus.

Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters.

The facet joint is a common source of neck pain, particularly after excessive stretch of its capsular ligament. Peptidergic afferents have been shown to have an important role in the development and maintenance of mechanical hyperalgesia, dysregulated nociceptive signaling, and spinal hyperexcitability that develop after mechanical injury to the facet joint. However, the role of non-peptidergic isolectin-B4 (IB4) cells in mediating joint pain is unknown. Isolectin-B4 saporin (IB4-SAP) was injected into the facet joint to ablate non-peptidergic cells, and the facet joint later underwent a ligament stretch known to induce pain. Behavioral sensitivity, thalamic glutamate transporter expression, and thalamic hyperexcitability were evaluated up to and at day 7. Administering IB4-SAP prior to a painful injury prevented the development of mechanical hyperalgesia that is typically present. Intra-articular IB4-SAP also prevented the upregulation of the glutamate transporters GLT-1 and EAAC1 in the ventral posterolateral nucleus of the thalamus and reduced thalamic neuronal hyperexcitability at day 7. These findings suggest that a painful facet injury induces changes extending to supraspinal structures and that IB4-positive afferents in the facet joint may be critical for the development and maintenance of sensitization in the thalamus after a painful facet joint injury.