Insular Cortex: Functional Mapping and Allodynic Behavior in the Rat

The insular cortex is the often forgotten 5th lobe of the brain, and examination of its functional anatomy as well as its role in behavior is still in its infancy. To elucidate these unknown details a complete mapping of the functional anatomy of the caudal granular insular cortex (CGIC), as well as its relative position to other somatosensory maps was undertaken revealing its mislabeling as the parietal ventral region (PV). Using this unprecedented localization of CGIC, targeted lesions revealed its role in the maintenance of long-term allodynia in the chronic constriction injury (CCI) model of neuropathic pain. In addition the efferent outputs were examined using neuroanatomical tract tracing techniques. Using this knowledge as an anatomical blueprint, a possible spinal-cortico-spinal loop was uncovered using laminar multi-unit analysis of the lumbar dorsal horn combined with evoked stimulation and inhibition of sciatic, CGIC, and primary somatosensory cortex (SI). Further, an electrophysiological signature of disinhibition was seen in CGIC two weeks post CCI, which was verified with laminar multi-unit analysis and protein analysis. Acute disinhibition of CGIC mimicked cold allodynia behavior in an operant two-plate temperature discrimination task. These data suggest that disinhibition of CGIC plays a critical role in the maintenance of allodynia following CCI in the rat

Intensity-dependent modulation of cortical somatosensory processing during external, low-frequency peripheral nerve stimulation in humans.

External low-frequency peripheral nerve stimulation (LFS) has been proposed as a novel method for neuropathic pain relief. Previous studies have reported that LFS elicits long-term depression-like effects on human pain perception when delivered at noxious intensities, while lower intensities are ineffective. To shed light on cortical regions mediating the effects of LFS, we investigated changes in somatosensory-evoked potentials (SEPs) during four LFS intensities. LFS was applied to the radial nerve (600 pulses, 1 Hz) of twenty-four healthy participants at perception (1×), low (5×), medium (10×) and high intensities (15× detection threshold). SEPs were recorded during LFS, and averaged SEPs in 10 consecutive one-minute epochs of LFS were analysed using source dipole modelling. Changes in resting electroencephalography (EEG) were investigated after each LFS block. Source activity in the midcingulate cortex (MCC) decreased linearly during LFS, with greater attenuation at stronger LFS intensities, and in the ipsilateral operculo-insular cortex during the two lowest LFS stimulus intensities. Increased LFS intensities resulted in greater augmentation of contralateral primary sensorimotor cortex (SI/MI) activity. Stronger LFS intensities were followed by increased alpha (9-11 Hz) band power in SI/MI and decreased theta (3-5 Hz) band power in MCC. Intensity-dependent attenuation of MCC activity with LFS is consistent with a state of long-term depression. Sustained increases in contralateral SI/MI activity suggests that effects of LFS on somatosensory processing may also be dependent on satiation of SI/MI. Further research could clarify if the activation of SI/MI during LFS competes with nociceptive processing in neuropathic pain

Suitability of the dorsal column nuclei for a neural prosthesis: functional considerations

The brainstem dorsal column nuclei (DCN) may be an ideal target for a future neural prosthesis to restore somatosensation in tetraplegic patients. We aimed to investigate the functional and structural characteristics of the DCN, with the overarching goal of determining their suitability as a somatosensory neural prosthetic target. First, we review the neuroanatomy of the DCN and surrounding nuclei, including the cuneate, gracile, external cuneate, X, and Z nuclei, which together comprise the DCN-complex. We reveal that the DCN are not organised to only process and relay tactile information, as is commonly thought, but instead are a complex sensorimotor integration and distribution hub, with diverse projection targets throughout the hindbrain and midbrain. Next, we sought to show that somatosensory signals arriving in the DCN are reproducible, and that they carry decodable information about the location and quality of somatosensory stimuli, which we propose are necessary conditions for a potential somatosensory neural prosthetic target. We record somatosensory-evoked signals from various locations across the surface of the DCN in 8-week-old anaesthetised male Wistar rats. We characterised somatosensory-evoked DCN surface signals and demonstrated that they have robust and reproducible high-frequency and low-frequency features within and across animals. Using a machine-learning approach, we developed a metric for evaluating the relevance of machine-learning inputs to target outputs, which we coined feature-learnability. Using feature-learnability allowed us to determine the DCN signal features that were most relevant to peripheral somatosensory events, which facilitated very high accuracy prediction of the location and quality of somatosensory events, from small numbers of features. This thesis supports the DCN as a potential somatosensory neural prosthetic target by: i) showing DCN connectivity with sensorimotor targets essential for movement modulation in conscious and non-conscious neural pathways; ii) determining DCN signal features that are most relevant to peripheral tactile and proprioceptive events. New knowledge about the most relevant DCN signal features may inform the development of biomimetic stimulus patterns designed to artificially activate the DCN in future neural prosthetic devices for restoring somatosensory feedback

Catecholaminergic Modulation of Sensory Processing in functionally distinct Primary Sensory and Association Cortex

The vertebrate sensory system is enabled to differentiate between a vast variety of sensory information under different behavioral and environmental conditions. The required flexibility is provided by complex brain functions including neuromodulation. Specific structures contributing in neuromodulation of sensory processing are the noradrenergic nucleus locus coeruleus and the dopaminergic ventral tegmental area (VTA), combined referred to as catecholaminergic system. However, how catecholaminergic neuromodulation affects sensory processing in functionally different brain regions is not well discovered. To approach this question, experiments in anesthetized rats were conducted in order to examine qualitative differences of noradrenergic modulation of sensory processing between the functionally distinct primary somatosensory cortex (S1) and the associative medial prefrontal cortex (mPFC). These experiments confirmed the already reported function of noradrenaline (NE) in activation of the cortical state and increase of the signal-to-noise ratio (SNR) of sensory-evoked responses, however only for S1. In mPFC, reorganization of neuronal activity, orchestrated by NE, is suggested in order to adequately evaluate the biological relevance of the stimulus and integrate sensory and non-sensory information. Further results show that NE improves noxious somatosensory processing within the VTA to induce the observed reorganization of local networks in mPFC in synergy with dopamine (DA). A possible outcome includes enhanced sensory gating by suppression of irrelevant and accentuation of relevant network information. This prefrontal cortical function was finally specifically explored in awake rats. Target specific manipulation of DA release revealed that prefrontal DA is essential to ensure adequate prefronto-accumbal interactions which, in turn, are necessary for sensory gating. Together, this work demonstrated that catecholamines are needed to improve sensory processing in functionally distinct cortical and subcortical brain regions. Thereby, classical improvement of SNR is not the only mechanism but also the catecholaminergic modulation of complex local network dynamics contributes to processing of relevant or irrelevant sensory information

Restored laser evoked potential and decreased gamma band activity in chronic-neuropathic pain patients under dorsal root ganglion stimulation treatment

Neuropathische Schmerzen sind schwierig zu behandeln und stellen häufig ein großes Problem dar. Etwa 10% der Menschen sind weltweit davon betroffen (Colloca et al., 2017). Die Erkrankung nimmt dabei meist einen chronischen Verlauf und schränkt die Lebensqualität der Betroffenen häufig stark ein. Versicherungsträger und die Gesellschaft aber auch die Betroffenen und die Angehörigen sind durch dieses Schmerzsysndrom gleichermaßen massiv beeinträchtigt. Shealy hat (Shealy et al., 1967) 1967 erstmals die Rückenmarkstimulation in die klinische Behandlung für chronische neuropathische Schmerzen eingeführt (Loeser & Treede, 2008; Moore, 2009) und damit gute Ergebnisse erzielt. Die Dorsalganlienstimulation ist eine neue neuromodulative Stimulationsform, die insbesondere chronische neuropathische Schmerzen in diskreten Schmerzarealen gezielt zu reduzieren vermag. Sie stellt damit eine wichtige Ergänzung zu den bereist bestehenden Stimulationsformen dar (Deer et al., 2013; Sapunar et al., 2012). Laser evozierte Potenziale (LEP) sind derzeit die effektivste Methode um die Integrität der nozizeptiven Bahnen zu untersuchen und gelten aktuell als Goldstandard um neuropathische Schmerzen zu diagnostizieren. In früheren Untersuchungen konnten wir zeigen, dass sich die LEPs bei Patienten mit lokalen chronischen neuropathischen Schmerzen unter DRGS wieder erholten. Das Gammaband kann zur Beurteilung von Prozessen in der Schmerzverarbeitung genutzt werden (Wang et al., 2016). Es wurde berichtet, dass die Gammabandaktivität bei Patienten mit neuropathischen Schmerzen im Vergleich zu gesunden Probanden signifikant erhöht ist (Lim et al., 2016). Wir haben diese Studie durchgeführt um speziell auch Veränderungen der Gammabandaktivität bei Patienten mit neuropathischen Schmerzen unter DRGs-Behandlungen zu untersuchen. In der vorliegenden Studie haben wir bei Patienten mit chronischen neuropathischen Schmerzen an drei verschiedenen aufeinanderfolgenden Zeitpunkten LEP- und Gammabanduntersuchungen durchgeführt. Wir konnten zeigen, dass das LEP von neuropathischen Schmerzpatienten innerhalb von 7 Tagen wiederhergestellt werden konnte. Der NRS-Wert der Patienten war im Vergleich zu präoperativ ebenfalls verringert. Gleichzeitig hat die Leistung des unteren Gammabandes (30-45 Hz) und des höheren Gammabandes (55-95 Hz) nach 7 Tagen DRGS-Behandlung ebenfalls abgenommen. Der NRS-Wert korrelierte dabei positiv mit einer niedrigeren bzw. einer höheren Gammabandleistung. Diese Ergebnisse zeigen, dass die Stimulation des Dorsalganglions auch bei der zentralen Verarbeitung chronischer neuropathischer Schmerzen beteiligt sein kann. Das wiederhergestellte LEP und die verringerte Gammabandleistung bei der DRGS-Therapie können einen wertvolleren und objektiveren neurophysiologischen Beweis für die Schmerzlinderung liefern als nur die bloße subjektive Schmerzlinderung, gemessen anhand der NRS-Schmerzskala. Daher könnten diese Parameter möglicherweise als neurophysiologische Marker für die Beurteilung der Wirksamkeit einer neuromodulativen Behandlung von Patienten mit chronischen neuropathischen Schmerzen genutzt werden. Weitere Studien mit einem größeren Patientenkollektiv sind jedoch notwendig, um diese Ergebnisse zu bestätigen

Lycium barbarum (wolfberry) polysaccharide facilitates ejaculatory behaviour in male rats

Poster Session AOBJECTIVE: Lycium barbarum (wolfberry) is a traditional Chinese medicine, which has been considered to have therapeutic effect on male infertility. However, there is a lack of studies support the claims. We thus investigated the effect of Lycium barbarum polysaccharide (LBP), a major component of wolfberry, on male rat copulatory behavior. METHOD: Sprague-Dawley rats were divided into two groups (n=8 for each group). The first group received oral feeding of LBP at dosage of 1mg/kg daily. The control group received vehicle (0.01M phosphate-buffered saline, served as control) feeding daily for 21 days. Copulatory tests were conducted at 7, 14 and 21 days after initiation of treatment. RESULTS: Compared to control animals, animals fed with 1mg/kg LBP showed improved copulatory behavior in terms of: 1. Higher copulatory efficiency (i.e. higher frequency to show intromission rather than mounting during the test), 2. higher ejaculation frequency and 3. Shorter ejaculation latency. The differences were found at all time points (Analyzed with two-tailed student’s t-test, p<0.05). There is no significant difference found between the two groups in terms of mount/intromission latency, which indicates no difference in time required for initiation of sexual activity. Additionally, no difference in mount frequency and intromission frequency was found. CONCLUSION: The present study provides scientific evidence for the traditional use of Lycium barbarum on male sexual behavior. The result provides basis for further study of wolfberry on sexual functioning and its use as an alternative treatment in reproductive medicine.postprintThe 30th Annual Meeting of the Australian Neuroscience Society, in conjunction with the 50th Anniversary Meeting of the Australian Physiological Society (ANS/AuPS 2010), Sydney, Australia, 31 January-3 February 2010. In Abstract Book of ANS/AuPS, 2010, p. 177, abstract no. POS-TUE-19

THE MANY WAYS OF WAKING UP FROM SLEEP - MOVING FORWARD THE ANALYSIS OF SLEEP MICROARCHITECTURE

One of the defining characteristics of sleep is that it is readily reversible towards wakefulness. This is exemplified in the common daily experience of waking up in the morning. My thesis studies sleep-wake transitions that are equally common and frequent, yet often not consciously perceived and neglected as random sleep perturbations of minor significance. Using mice as an experimental species, I find that healthy non-rapid-eye-movement sleep (NREMS), also named deep restorative sleep, is a dynamic brain state showing defined, periodically recurring moments of fragility. During these, diverse types of brief arousal-like events with various combinations of physiological correlates appear, including global or local cortical activation, muscle activity, and heart rate changes. Using a mice model of chronic neuropathic pain, I find that the rules I have identified in healthy sleep serve to identify previously unrecognized sleep disruptions that could contribute to sleep complaints of chronic pain patients. The experimental and analytical methods I have developed in these studies also helped in the identification of the neuronal basis of the fragility periods of NREM sleep. Together, my studies offer novel insights and analytical tools for the study of sleep-wake transitions and their perturbance in pathological conditions linked to sensory discomfort. More specifically, my work departed from recent findings that NREMS in mice is divided in recurring periods of sleep fragility at frequencies ~0.02 Hz, characterized by heightened arousability. Through analyzing the temporal distribution of brief arousal events termed microarousals, I hypothesized that these fragility periods could serve a time raster for the probing of spontaneous sleep perturbations. Motivated by the question of how sensory discomfort caused by pain affects sleep, I have used the spared nerve injury (SNI) model, which consists in the injury of two of the 3 branches of the sciatic nerve. I found that the role of fragility periods in timing spontaneous arousals is highly useful to identify sleep disruptions not commonly detected with standard polysomnographic measures. Thus, by scrutinizing the fragility periods of NREMS in the SNI mice, I discovered an overrepresentation of a novel form of local perturbation within the hindlimb primary somatosensory cortex (S1HL), accompanied by heart rate increases. In addition, I showed that SNI animals woke up more frequently facing external stimuli, using closed-loop methods targeting specifically the fragility or continuity periods. These findings led me to propose that chronic pain-related sleep complaints may arise primarily from a perturbed arousability. The closed-loop techniques to probe arousability could be transferred to interrogate neuronal mechanisms underlying NREMS fragility, leading to the recognition that intrusion of wake-related activity into NREMS is a previously underappreciated mechanism controlling sleep fragility and architecture. Overall, I present my thesis to advance the view on NREMS as a dynamic heterogeneous state of which insights into its neuronal mechanisms, and its physio- and pathophysiological manifestations in animal models should be key to formulate testable hypotheses aimed to cure the suffering of sleep disorder in human. -- Une des caractéristiques qui définit le sommeil, est que l’on peut rapidement retourner à un état d’éveil. De fait, nous l’expérimentons chaque matin au réveil. Ma thèse étudie les transitions sommeil-éveil qui, bien que fréquentes, sont souvent non consciemment perçues et traitées comme des perturbations sans importance et aléatoires du sommeil. En utilisant la souris comme modèle expérimental, je montre que le sommeil sans mouvements rapides des yeux (NREMS), également appelé le sommeil profond et réparateur, est un état cérébral dynamique composé de périodes discrètes et récurrentes de fragilité face à des stimuli externe. Pendant celles-ci, plusieurs types d’évènements associés à des éveils brefs apparaissent, combinant activation corticale, activité musculaire et/ou une hausse des battements cardiaques. Je démontre que la compréhension des transitions sommeil-éveil physiologiques s’avère utile pour étudier le sommeil de souris souffrant de douleurs neuropathiques chroniques. Ces souris présentent un nouveau type de perturbations locales lors du sommeil, qui pourraient possiblement expliquer une partie des plaintes de mauvais sommeil exprimées par les patients souffrant de douleurs chroniques. Les méthodes analytiques et expérimentales que j’ai développées dans ces études ont aussi aidé à l’identification des bases neuronales de la genèse des périodes de fragilités du sommeil NREM. En somme, mes études offrent des connaissances inédites et des méthodes d’analyses pour l’étude des transitions sommeil-éveil et de leurs perturbations en conditions pathologiques. Une étude récente du laboratoire a montré que le sommeil NREM est divisé en périodes de fragilité alternant avec des périodes de non-fragilité (continuité), environ toutes les 50 secondes ce qui donne une fréquence de 0.02 Hz. Les périodes de fragilité sont caractérisées par une hausse de « l’éveillabilité » ou propension à s’éveiller. Ma première observation est que les éveils brefs, couramment appelés micro-réveils, présentent une distribution temporelle hautement restreinte aux périodes de fragilité. Ainsi, j’ai émis l’hypothèse que ces périodes pourraient servir de moments spécialement choisis par le cerveau pour la mesure de potentielles perturbations spontanées. Motivé par la question de comment les douleurs chroniques perturbent le sommeil, je l’ai analysé chez un modèle de souris de douleurs neuropathique, le modèle de d’épargne du nerf sural (SNI). Le rôle des périodes de fragilité à restreindre les micro- réveils s’est avéré très utile pour détecter de nouvelles formes de réaction à des perturbations qui ne sont pas évidentes par des analyses classiques du sommeil. En effet, spécifiquement pendant ces périodes de fragilité, j’ai découvert une sur-représentation d’un nouveau type d’éveil local confiné au cortex somatosensoriel primaire et accompagné d’une hausse du rythme cardiaque. De plus, en utilisant de nouvelles méthodes basées sur des boucles-fermées, j’ai démontré que les souris SNI se réveillaient plus fréquemment que leurs contrôles en faisant face à des stimuli externes. Sur la base de ces découvertes, je propose que les plaintes de mauvais sommeil chez les patients souffrant de douleurs chroniques puissent prendre leur source dans une éveillabilité perturbée. Les méthodes de boucles-fermées pour analyser l’éveillabilité a aussi pu être transférée pour l’étude optogénétique des mécanismes neuronaux à la base de la fragilité du sommeil NREM. Cela a mené à la reconnaissance que l’intrusion d’activité normalement associée à l’éveil dans le sommeil est un mécanisme de contrôle de sa fragilité et de son architecture souvent ignoré dans le domaine. En somme, ma thèse permet une avancée de notre vision du sommeil NREM comme étant un état dynamique et hétérogène dont les mécanismes neuronaux sous-jacent, en conditions normales et pathogéniques, sont clefs pour la formulation d’hypothèses testables visant à la guérison des patients souffrant de troubles du sommeil

Respiratory Control: Central and Peripheral Mechanisms

Understanding of the respiratory control system has been greatly improved by technological and methodological advances. This volume integrates results from many perspectives, brings together diverse approaches to the investigations, and represents important additions to the field of neural control of breathing. Topics include membrane properties of respiratory neurons, in vitro studies of respiratory control, chemical neuroanatomy, central integration of respiratory afferents, modulation of respiratory pattern by peripheral afferents, respiratory chemoreception, development of respiratory control, behavioral control of breathing, and human ventilatory control. Forty-seven experts in the field report research and discuss novel issues facing future investigations in this collection of papers from an international conference of nearly two hundred leading scientists held in October 1990. This research is of vital importance to respiratory physiologists and those in neurosciences and neurobiology who work with integrative sensory and motor systems and is pertinent to both basic and clinical investigations. Respiratory Control is destined to be widely cited because of the strength of the contributors and the dearth of similar works. The four editors are affiliated with the University of Kentucky: Dexter F. Speck is associate professor of physiology and biophysics, Michael S. Dekin is assistant professor of biological sciences, W. Robert Revelette is research scientist of physiology and biophysics, and Donald T. Frazier is professor and chairman of physiology and biophysics. Experts in the field report current research and discuss novel issues facing future investigations. —SciTech Book Newshttps://uknowledge.uky.edu/upk_biology/1002/thumbnail.jp