8 research outputs found

    Mechanisms of inhibition in the somatosensory system and perceptual threshold calculation

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    Die Verarbeitung sensorischer Informationen wird aufsteigend durch die Eigenschaften der Reize und absteigend durch individuelle Erfahrungen und Erwartungen gesteuert. Neuronale Schaltkreise regulieren die reiz- und aufgabenabhÀngige Informationsverarbeitung durch Hemmung neuronaler Verarbeitungsprozesse. Die Hemmung kann die auf- und absteigende Kontrolle kortikaler Regionen verÀndern und die Integration oder Segregation neuronaler AktivitÀt beeinflussen. In dieser Arbeit werde ich eine neuropharmakologisch-neurobildgebende Studie vorstellen, in der die Wahrnehmungsprozesse im somatosensorischen Kortex untersucht werden und die sich speziell mit den inhibitorischen Mechanismen auf der Ebene von SI (primÀrer somatosensorischer Kortex) und SII (sekundÀrer somatosensorischer Kortex) befasst. Durch die Verabreichung verschiedener GABA- Agonisten (Gamma-AminobuttersÀure) - dem wichtigsten inhibitorischen Neurotransmitter im Gehirn - konnte in der vorliegenden Arbeit die primÀre Bedeutung eines schnellen GABAA-Agonisten gezeigt und ein Modell der Hemmungsausbreitung von SI zum SII erstellt werden. Das Paradigma implizierte die taktile Stimulation auf dem Niveau der individuellen Wahrnehmungsschwelle, wobei das Reizniveau an die sensorischen Wahrnehmungsleistung der Teilnehmer kontinuierlich angepasst wurde. Diese adaptive Strategie wirft verschiedene Fragen hinsichtlich der Optimierung der Methode zur SchwellenschÀtzung auf. Der Schwellenwert wird indirekt aus den Reaktionen des Probanden auf die einzelnen Stimuli berechnet. Er hÀngt daher nicht nur von der Empfindlichkeit des sensorischen Systems, sondern auch von den EntscheidungsvorgÀngen und von dem Reaktionsverhalten der Versuchsperson ab. Insbesondere subjektive Tendenzen (englisch Bias) der Ebene der Entscheidungsfindung oder auf der Ebene des Antwortverhaltens könnte den Schwellwert beeinflussen. In Anbetracht der Bedeutung einer prÀzisen SchÀtzung des Schwellwertes bei Experimenten, in denen im Bereich der Schwelle stimuliert wird, konzentrierte sich die zweite Studie auf die Entwicklung einer Schwellenbestimmungsmethode die eventuelle Entscheidungs- und Antworttendenzen korrigiert. In der vorliegenden Arbeit wurde ein neues adaptives Verfahren entwickelt und evaluiert. Die Implementierung, Vorteile und Grenzen dieses Verfahrens wurden auf der Grundlage von Simulationen untersucht und beschrieben

    Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

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    Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.LÀÀketieteellisen teknologian kehitys on vasta viime vuosina mahdollistanut lasten aivotoiminnan tarkan, objektiivisen tutkimuksen. NĂ€in ollen esimerkiksi aistiĂ€rsykkeiden aivoprosessoinnista vastasyntyneillĂ€ tiedetÀÀn varsin vĂ€hĂ€n, samoin kuin monien aivotoimintojen kehittymisestĂ€ lapsen kasvaessa. Myös ymmĂ€rrys erilaisten aivovaurioiden vaikutuksesta kehittyviin aivoihin on puutteellista. Magnetoenkefalografialla (MEG) tutkitaan aivohermosolujen toimintaa mittaamalla niissĂ€ syntyvien sĂ€hkövirtojen tuottamia magneettikenttiĂ€ pÀÀn ulkopuolelta. VĂ€itöskirjassa MEG:n avulla tutkittiin tuntoaivokuoren toimintaa vastasyntyneillĂ€ ja tĂ€mĂ€n toiminnan kehitystĂ€ ensimmĂ€isten elinvuosien aikana. LisĂ€ksi tuntoaivokuoren toimintaa tarkasteltiin pikkukeskosena syntyneillĂ€ vauvoilla sekĂ€ nuorilla, joilla on varhaisen aivovaurion aiheuttama toispuoleinen CP-vamma. Jo vastasyntyneellĂ€ useat aivoalueet aktivoituivat kĂ€den alueen kosketusĂ€rsykkeen jĂ€lkeen. Tuntoaivokuoren aktiivisuus poikkesi kuitenkin oleellisesti aikuisesta: tietyt aikuistyyppiset aivovasteet puuttuivat vastasyntyneiltĂ€ tĂ€ysin heijastaen vastasyntyneen vauvan hermoston keskenerĂ€istĂ€ kehitysvaihetta. Tuntoaivovasteet kehittyivĂ€t iĂ€n myötĂ€ jĂ€rjestelmĂ€llisesti siten, ettĂ€ kaksivuotiailla ne alkoivat morfologisesti muistuttaa aikuisten vasteita. Pikkukeskosten primaarisen tuntoaivokuoren vaste oli lasketussa ajassa heikompi kuin terveillĂ€ tĂ€ysaikaisilla vauvoilla, mikĂ€ voi johtua pienemmĂ€stĂ€ aktivoituneesta hermosolujoukosta tai aktivaation epĂ€synkroniasta. Sekundaarisen tuntoaivokuoren vasteen puuttuminen liittyi poikkeaviin ultraÀÀni- ja magneettikuvauslöydöksiin. TĂ€mĂ€n havainnon ennusteellista merkitystĂ€ selvitetÀÀn parhaillaan seurantatutkimuksella. CP-vammaisilla nuorilla tuntoaivovasteissa havaittiin verrokkeihin nĂ€hden useita poikkeavuuksia, jotka olivat osin laaja-alaisempia kuin oli pÀÀteltĂ€vissĂ€ kliinisistĂ€ oireista tai aivojen rakenteellisesta vauriosta. Esimerkiksi potilailla, joiden sairauden taustalla oli subkortikaalinen aivovaurio, etu- ja pikkusormien edustusalueet tuntoaivokuorella olivat verrokkeihin nĂ€hden lĂ€hempĂ€nĂ€ toisiaan sekĂ€ vaurion puoleisessa ettĂ€ vastakkaisessa aivopuoliskossa. Aivojen erilaisten rakenteellisten vaurioiden aiheuttamien toiminnallisten muutosten tarkempi ymmĂ€rtĂ€minen voi osoittautua merkittĂ€vĂ€ksi CP-potilaiden kuntoutuksen ja hoidon yksilöllisessĂ€ rÀÀtĂ€löinnissĂ€

    Repetitive Passive Finger Movement Modulates Primary Somatosensory Cortex Excitability

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    Somatosensory inputs induced by repetitive passive movement (RPM) modulate primary motor cortex (M1) excitability; however, it is unclear whether RPM affects primary somatosensory cortex (S1) excitability. In this study, we investigated whether RPM affects somatosensory evoked potentials (SEPs) and resting state brain oscillation, including alpha and beta bands, depend on RPM frequency. Nineteen healthy subjects participated in this study, and SEPs elicited by peripheral nerve electrical stimulation were recorded from the C3’ area in order to assess S1 excitability (Exp. 1: n = 15). We focused on prominent SEP components such as N20, P25 and P45-reflecting S1 activities. In addition, resting electroencephalograms (EEGs) were recorded from C3’ area to assess the internal state of the brain network at rest (Exp. 2: n = 15). Passive abduction/adduction of the right index finger was applied for 10 min at frequencies of 0.5, 1.0, 3.0, and 5.0 Hz in Exp. 1, and 1.0, 3.0, and 5.0 Hz in Exp. 2. No changes in N20 or P25 components were observed following RPM. The 3.0 Hz-RPM decreased the P45 component for 20 min (p < 0.05), but otherwise did not affect the P45 component. There was no difference in the alpha and beta bands before and after any RPM; however, a negative correlation was observed between the rate of change of beta power and P45 component at 3.0 Hz-RPM. Our findings indicated that the P45 component changes depending on the RPM frequency, suggesting that somatosensory inputs induced by RPM influences S1 excitability. Additionally, beta power enhancement appears to contribute to the P45 component depression in 3.0 Hz-RPM

    Postnatal maturation of the opioid and endocannabinoid signalling systems within the descending pain pathway of the rat

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    Significant opioid- and endocannabinoid-dependent changes occur within the periaqueductal grey (PAG), rostroventral medulla (RVM) and spinal cord (DH) during postnatal development of the rat (Sprague Dawley). These changes are involved in the differential descending control of spinal excitability between young and mature rats. Microinjection of the ”-opioid receptor (MOR) agonist DAMGO (30ng) into the PAG of rats increased spinal excitability and lowered mechanical threshold to noxious stimuli in postnatal day (P)21 rats, but had inhibitory effects in adults and lacked efficacy in P10 pups. A tonic opioidergic tone within the PAG was revealed in adult rats by intra-PAG microinjection of CTOP (120ng, MOR antagonist) which lowered mechanical thresholds and increased spinal reflex excitability. Spinal adminstration of DAMGO inhibited spinal excitability in all ages yet the magnitude of this was greater in younger animals than in adults. The expression of MOR and related peptides were also investigated using TaqMan RT-PCR and immunohistochemistry. Proopiomelanocortin (POMC) peaked at P21 in the ventral-PAG, and MOR increased significantly in the DH as the animals aged. CB1/CB2 receptor activation by WIN55212 (4”g, CB1/CB2 agonist) and HU210 (4”g, CB1/CB2 receptor agonist) in the PAG, RVM and DH was anti-nociceptive in both young (P10, P21) and adult rats, but GPR55 receptor activation by LPI (12”g, endogenous GPR55 agonist) and AM251 (2.77”g, CB1 antagonist, GPR55 agonist) was exclusively inhibitory in young rats. Micro-injection of LPI into the adult RVM facilitated spinal reflex excitability, suggesting that GPR55 receptor activation in mature animals is pro-nociceptive. The expression of cannabinoid receptors and endocannabinoid-synthesising enzymes was investigated with immunohistochemical and TaqMan RT-PCR techniques. Overall the expression of CB1 receptors and the anandamide synthesising enzyme NAPE-phospholipase D (NAPE-PLD) increased within the descending pain pathway with age, whereas the expression of the 2-AG synthesising enzyme Diacylglycerol lipase α (DAGLα) decreased. These results illustrate that profound differences in the endogenous-opioidergic and endocannabinoid signalling systems occur within the descending pain pathway throughout postnatal development

    Postnatal maturation of the opioid and endocannabinoid signalling systems within the descending pain pathway of the rat

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    Significant opioid- and endocannabinoid-dependent changes occur within the periaqueductal grey (PAG), rostroventral medulla (RVM) and spinal cord (DH) during postnatal development of the rat (Sprague Dawley). These changes are involved in the differential descending control of spinal excitability between young and mature rats. Microinjection of the ”-opioid receptor (MOR) agonist DAMGO (30ng) into the PAG of rats increased spinal excitability and lowered mechanical threshold to noxious stimuli in postnatal day (P)21 rats, but had inhibitory effects in adults and lacked efficacy in P10 pups. A tonic opioidergic tone within the PAG was revealed in adult rats by intra-PAG microinjection of CTOP (120ng, MOR antagonist) which lowered mechanical thresholds and increased spinal reflex excitability. Spinal adminstration of DAMGO inhibited spinal excitability in all ages yet the magnitude of this was greater in younger animals than in adults. The expression of MOR and related peptides were also investigated using TaqMan RT-PCR and immunohistochemistry. Proopiomelanocortin (POMC) peaked at P21 in the ventral-PAG, and MOR increased significantly in the DH as the animals aged. CB1/CB2 receptor activation by WIN55212 (4”g, CB1/CB2 agonist) and HU210 (4”g, CB1/CB2 receptor agonist) in the PAG, RVM and DH was anti-nociceptive in both young (P10, P21) and adult rats, but GPR55 receptor activation by LPI (12”g, endogenous GPR55 agonist) and AM251 (2.77”g, CB1 antagonist, GPR55 agonist) was exclusively inhibitory in young rats. Micro-injection of LPI into the adult RVM facilitated spinal reflex excitability, suggesting that GPR55 receptor activation in mature animals is pro-nociceptive. The expression of cannabinoid receptors and endocannabinoid-synthesising enzymes was investigated with immunohistochemical and TaqMan RT-PCR techniques. Overall the expression of CB1 receptors and the anandamide synthesising enzyme NAPE-phospholipase D (NAPE-PLD) increased within the descending pain pathway with age, whereas the expression of the 2-AG synthesising enzyme Diacylglycerol lipase α (DAGLα) decreased. These results illustrate that profound differences in the endogenous-opioidergic and endocannabinoid signalling systems occur within the descending pain pathway throughout postnatal development

    Epileptiform Activity in Isolated Cortex and Hippocampal Preparations, and Its Modulation by Purinergic Compounds

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    1. This dissertation addresses both the physical requirements (in terms of the minimal mass of tissue needed) for the generation and propagation of epileptiform activity, and the purinergic modulation of this epileptiform activity in the cerebral cortex. Studies on the minimal mass were performed in rat somatosensory cortex in vivo, using subpial transsections based on a recently developed neurosurgical approach to the treatment of drug-resistant epilepsy (Morrell et al 1989: "Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy"), in conjunction with the iontophoretic application of the convulsant penicillin. For a detailed analysis of the structural requirements for epileptiform activity and the rapid application and wash-out of drugs of known concentration, a novel in vitro model of the isolated neocortical column was developed which allowed the manipulation of radial intracortical pathways via pressure ejection of drugs at various cortical depths, and the isolation of specific layers by subsectioning the tissue. It therefore provided a unique way of studying the intrinsic pathways of individual cortical layers. The epileptiform potentials in rat and mouse neocortical cylinders were recorded with standard extracellular recording techniques in an attempt to elucidate some of the aspects of the ongoing debate on whether the so-called 'cortical columns' are hardwired information processing units, or functional groups of co-active neurones whose configuration varies with the task performed. 2. After preliminary findings in rat neocortex in vivo had indicated that the minimal mass, i.e. the smallest block of cortical brain tissue able to generate epileptiform spiking, was small enough to be investigated in vitro, work on the subsequently developed in vitro model of the cortical column clearly showed that the minimal diameter was below that of the postulated columns defined by the so-called 'barrel' structures found in layer IV of the rat somatosensory cortex. Furthermore, blocks of brain tissue (containing an estimated 1500 neurones) which excluded layer IV displayed epileptiform activity which was indistinguishable from that observed in preparations containing all neocortical layers, or indeed from records obtained by other groups in chronically isolated neocortex in situ. It is concluded that the minimal mass problem is, to a certain extent, merely a question of the degree of connectivity; from the results of the present study, no horizontal boundaries corresponding to the postulated 'cortical modules' were found to exist with respect to the generation of paroxysmal discharges. Similarly, the importance of layer IV in the generation of epileptiform discharges appears to pertain only to the specialised case of discharges induced by GABA receptor blockade, as exclusion of this layer did not affect the ability of the tissue to display the spikes/afterdischarges commonly observed in intact cortical slices in vitro, and in cortical subpial isolations in vivo. 3. In Part Two, the purinergic modulation of this epileptiform activity was studied in mouse neocortical cylinders and in rat hippocampal slices. The inhibitory effects of adenosine (a metabolite of nucleotide hydrolysis which may act as an 'endogenous anticonvulsant') on low-magnesium ACSF-induced epileptiform activity are described, followed by an analysis of the factors contributing to the proconvulsant effects caused by selective adenosine A1 receptor blockade in vitro. The main compound used was l,3-dipropyl-8-cyclopentyl-xanthine (DPCPX), a highly selective A1 antagonist which in previous in vitro studies had been reported to induce persistent epileptiform activity by an unknown mechanism after transient application; these prolonged epileptogenic effects are not usually observed after the application of less selective adenosine antagonists. 4. Despite the marked proconvulsant effects reported for DPCPX in vitro, the drug does not induce seizures when administered in vivo. A similar effect was observed in the present study in vitro', on the basis of these findings, it is suggested that the main physiological role of adenosine in the brain is to exert an activity-dependent negative feedback control which limits the effects of calcium influx through voltage-activated Ca++ channels, rather than the 'inhibitory purinergic tone' proposed by some authors
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