Recovery of the 20Hz Rebound to Tactile and Proprioceptive Stimulation after Stroke

Sensorimotor integration is closely linked to changes in motor-cortical excitability, observable in the modulation of the 20 Hz rhythm. After somatosensory stimulation, the rhythm transiently increases as a rebound that reflects motor-cortex inhibition. Stroke-induced alterations in afferent input likely affect motor-cortex excitability and motor recovery. To study the role of somatosensory afferents in motor-cortex excitability after stroke, we employed magnetoencephalographic recordings (MEG) at 1-7 days, one month, and 12 months in 23 patients with stroke in the middle cerebral artery territory and 22 healthy controls. The modulation of the 20 Hz motor-cortical rhythm was evaluated to two different somatosensory stimuli, tactile stimulation, and passive movement of the index fingers. The rebound strengths to both stimuli were diminished in the acute phase compared to the controls and increased significantly during the first month after stroke. However, only the rebound amplitudes to tactile stimuli fully recovered within the follow-up period. The rebound strengths in the affected hemisphere to both stimuli correlated strongly with the clinical scores across the follow-up. The results show that changes in the 20 Hz rebound to both stimuli behave similarly and occur predominantly during the first month. The 20 Hz rebound is a potential marker for predicting motor recovery after stroke.Peer reviewe

Aivoinfarktin aiheuttamat aktivaatiomuutokset ihmisen liikeaivokuorella

Despite advances in acute treatment of stroke, over third of the patients suffer from a disability, most often upper-limb paresis, still five years after stroke. To improve rehabil- itation, further understanding of stroke-induced plasticity is required. During the plastic period, cortical excitability increases, likely promoting cortical reorganization. Afferent input modulates the rolandic 20-Hz rhythm. The modulation, reflecting motor- cortex excitability, is observable as the activation-associated suppression and inhibition- associated rebound of the 20-Hz rhythm. In this Thesis, motor-cortex excitability was monitored by applying two different afferent inputs while recording the 20-Hz rhythm with magnetoencephalography (MEG), first in healthy controls and then in stroke patients in a one-year longitudinal study. Study I, comprising 22 healthy controls, focused on the modulation of the 20-Hz rhythm to tactile stimulation and passive movement as proprioceptive stimulation. The suppres- sion of the rhythm was similar to both stimuli whereas the rebound was stronger to pas- sive movement. Thus, passive movement could better serve in studying motor-cortex excitability changes. In Studies II and III, modulation of the 20-Hz rhythm to afferent input was measured in 23 patients having their first-ever stroke in the territory of the middle cerebral artery and related upper-limb paresis. Passive movement of the index finger (Study II) and tactile stimulation (Study III) were applied during MEG recordings in the acute (T 0 ; 1–7 days), subacute (T 1 ; one month) and chronic (T 2 ; 12 months) phases after stroke onset in conjunction with clinical testing of hand motor performance. The results showed that in the acute phase, the rebound was strongly diminished to both stimuli compared to the controls and increased significantly during the first month. During the follow-up period, the rebound strengths to both stimuli correlated with motor performance of the impaired hand. The bilateral weakness of the rebounds in the acute phase indicate hyperexcitability of both hemispheres after stroke. The subsequent increase in the rebound strength during the first month, reflecting an increase in motor-cortex inhibition, is in line with earlier studies in animals and humans suggesting a sensitive and motor-recovery-related plastic period immediately after stroke. The rebound strength to impaired-hand stimulation correlatedwith hand motor performance across the follow-up indicating that adequate integration of afferent input with motor functions is important for motor recovery. During the follow- up, the 20-Hz rebound to both tactile and passive-movement stimuli increased similarly. However, the rebounds to tactile stimuli recovered to the level of the controls whereas those to proprioceptive stimuli did not. This might indicate that proprioception did not recover fully in our patients. It would be most important to be able to predict and evaluate the progress of an individual patient during recovery from stroke to intensify and tailor rehabilitation for individual needs. Though, the efficacy of rehabilitation may be evaluated with different neuroimag- ing methods and clinical tests in a group level, so far there are no objective biomarkers to evaluate rehabilitation in an individual level. The results of this Thesis indicate that the 20-Hz rebound magnitude strongly reflects motor-cortex excitability and thus could serve as a robust noninvasive marker of stroke-induced neurophysiological processes that are relevant for motor recovery. Such a biomarker may enable to assess the efficacy of new therapeutical methods in stroke rehabilitation in both group and individual levels.Aivoinfarktin akuuttihoidon kehittymisestä huolimatta yli kolmannes potilaista kärsii ai- voinfarktin aiheuttamista vammoista, yleisimmin yläraajahalvauksesta, vielä viisi vuot- ta infarktin jälkeen. Kuntoutuksen tehostamiseksi aivoinfarktin jälkeistä aivojen muo- vautumiskykyä eli plastisiteettia tulisi ymmärtää nykyistä paremmin. Plastisen ajanjak- son aikana aivokuoren aktivaatiotila on lisääntynyt, mikä todennäköisesti mahdollistaa aivokuoren uudelleenjärjestäytymisen. Aistiärsykkeet moduloivat liikeaivokuoren rolandisen alueen 20 hertsin rytmiä. Rytmin modulaatio kuvastaa liikeaivokuoren aktivaatiotilaa, mikä voidaan havaita aktivaatioon liittyvänä rytmin vaimenemisena sekä inhibitioon liittyvänä rytmin elpymisenä ns. purs- keena. Tässä väitöskirjatutkimuksessa liikeaivokuoren aktivaatiotilaa tutkittiin rekisteröi- mällä magnetoenkefalografiamenetelmällä (MEG) 20 hertsin rytmiä käyttäen kahta eri- laista aistiärsykettä ensin terveillä verrokeilla ja sen jälkeen potilailla vuoden kestävässä pitkittäistutkimuksessa. Osatutkimuksessa I mittasimme 20 hertsin rytmin muutoksia 22 terveellä verrokilla käyt- täen kosketusärsykettä ja proprioseptisena ärsykkeenä passiiviliikettä. Rytmin vaimene- minen oli samankaltaista kummankin ärsykkeen vaikutuksesta, kun taas passiiviliike ai- heutti voimakkaamman rytmin purskeen kuin kosketusärsyke. Siten passiiviliike voisi toimia paremmin tutkittaessa liikeaivokuoren aktivaatiotilan muutoksia. Osatöissä II ja III mittasimme 20 hertsin rytmin modulaatiota 23 potilaalla, jotka olivat sairastuneet elämänsä ensimmäiseen aivoinfarktiin keskimmäisen aivovaltimon verisuonit- tamalla alueella ja siihen liittyen yläraajan halvaukseen. Aistiärsykkeinä käytimme etu- sormen passiiviliikettä (osatutkimus II) sekä kosketusärsykettä (osatutkimus III) MEG- mittauksen aikana akuutissa (1–7 päivää), subakuutissa (yksi kuukausi) ja kroonisessa (12 kuukautta) vaiheessa infarktiin sairastumisen jälkeen. Lisäksi kunkin mittauksen yhtey- dessä arvioitiin käden motorinen toiminta kliinisin testein. Tulokset osoittavat, että stimu- laation jälkeinen rytmin purske oli akuutissa vaiheessa voimakkaasti heikentynyt molem- mille ärsykkeille verrattuna verrokkien arvoihin, mutta ensimmäisen kuukauden aikana purske voimistui merkittävästi. Rytmin purskeen voimakkuus korreloi sairaan käden mo- torisen suorituksen kanssa koko seurantatutkimuksen ajan. Rytmin purskeen heikkous akuuttivaihessa viittaa molempien aivopuoliskojen liikeai-vokuorien hyperaktiivisuuteen. Purskeen voimistuminen ensimmäisen kuukauden aikana kuvastaa lisääntynyttä liikeaivokuoren inhibitiota, jota on havaittu aiemmissa aivoinfark- tin jälkeistä herkkää ja lyhyttä sekä motoriseen toipumiseen liittyvää plastisiteettijaksoa osoittavissa eläin- ja ihmistutkimuksissa. Rytmin purskeen voimakkuus korreloi sairaan käden motorisen toiminnan parantumisen kanssa koko seurantajakson ajan viitaten sii- hen, että tuntoaistin ja proprioseptiivisen informaation integraatio motorisen aivokuoren toimintaan ovat tärkeitä motoriselle toipumiselle. Seurantajakson aikana 20 hertsin rytmi voimistui samankaltaisesti kummankin aistiärsykkeen, niin kosketusärsykkeen kuin pro- prioseptiivisen ärsykkeen vaikutuksesta. Purskeen voimakkuus kosketusärsykkeen vaiku- tuksesta kuitenkin saavutti terveiden verrokkien tason, kun taas proprioseptiiviselle ärsyk- keelle se ei toipunut samalle tasolle kuin verrokeilla. Tämä saattaisi viitata siihen, että potilaidemme proprioseptiikka ei toipunut täysin. Olisi tärkeää pystyä ennustamaan potilaan yksilöllistä toipumista aivoinfarktin jälkeen, jotta kuntoutusta voitaisiin tehostaa ja räätälöidä kunkin potilaan tarpeiden mukaan. Vaik- ka erilaisilla kuvantamistutkimuksilla ja kliinisillä mittareilla voidaankin arvioida kun- touksen edistymistä ryhmätasolla, toistaiseksi objektiivista yksilöllistä mittaria ei ole ole- massa. Tämän väitöskirjatutkimuksen tulokset viittaavat siihen, että 20 hertsin rytmin purskeen suuruus kuvastaa voimakkaasti liikeaivokuoren aktiviteettimuutoksia ja voisi siten toimia luotettavana kajoamattomana mittarina tutkittaessa aivoinfarktin aiheuttamia ja motoriselle toipumiselle tarpeellisia liikeaivokuoren neurofysiologisisa muutoksia. Täl- lainen biomarkkeri mahdollistaisi uusien aivoinfarktin jälkeisten kuntoutusmenetelmien tehon arvioimisen sekä ryhmä- että yksilötasolla

Modulation of the similar to 20-Hz motor-cortex rhythm to passive movement and tactile stimulation

Background: Integration of afferent somatosensory input with motor-cortex output is essential for accurate movements. Prior studies have shown that tactile input modulates motor-cortex excitability, which is reflected in the reactivity of the similar to 20-Hz motor-cortex rhythm. similar to 20-Hz rebound is connected to inhibition or deactivation of motor cortex whereas suppression has been associated with increased motor cortex activity. Although tactile sense carries important information for controlling voluntary actions, proprioception likely provides the most essential feedback for motor control. Methods: To clarify how passive movement modulates motor-cortex excitability, we studied with magnetoencephalography (MEG) the amplitudes and peak latencies of suppression and rebound of the similar to 20-Hz rhythm elicited by tactile stimulation and passive movement of right and left index fingers in 22 healthy volunteers. Results: Passive movement elicited a stronger and more robust similar to 20-Hz rebound than tactile stimulation. In contrast, the suppression amplitudes did not differ between the two stimulus types. Conclusion: Our findings suggest that suppression and rebound represent activity of two functionally distinct neuronal populations. The similar to 20-Hz rebound to passive movement could be a suitable tool to study the functional state of the motor cortex both in healthy subjects and in patients with motor disorders.Peer reviewe

Alumiinin osuus (eräissä) keskushermostosairauksissa ja subkroonisen alumiinialtistuksen vaikutus rotan isojen aivojen entsyymien aktiivisuuteen.

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Post-stroke cognitive impairment is frequent after infra-tentorial infarct

Background and purpose: Post-stroke cognitive impairment is a common and well-known consequence of supra-tentorial infarct, but its prevalence and severity after infra-tentorial infarct is unclear. We compared the frequencies and prognostic value of domain-specific cognitive deficits after supra-tentorial and infra-tentorial infarct. Methods: In a consecutive cohort of patients with first-ever stroke (N = 244) admitted to Helsinki University Hospital, 37 patients had an infra-tentorial infarct. Patients were assessed with a comprehensive neuropsychological examination 3 months post-stroke covering 9 cognitive domains and functional disability was assessed at 15 months with the modified Rankin Scale. Results: There were no statistically significant differences between the frequencies of cognitive deficits in patients with infra-tentorial vs supra-tentorial infarct. Altogether 73% of patients with infra-tentorial infarct and 82% of patients with supra-tentorial infarct had impairment in at least one cognitive domain. Further 42% of patients with infra-tentorial infarct and 47% of those with supra-tentorial infarct had deficits in 3 or more cognitive domains. In patients with infra-tentorial infarct, visuo-constructional deficits were significantly associated with functional disability at 15 months (OR 9.0, 95%CI 1.3-62.5, p = 0.027). In patients with supratentorial infarct, executive deficits (OR 2.9, 95%CI 1.5-5.8, p = 0.002) and visuo-constructional deficits (OR 2.9, 95%CI 1.5-5.7, p = 0.001) showed associations with functional disability at 15 months. Conclusion: Cognitive deficits are as common in patients with infra-tentorial infarct as in those with supra-tentorial infarct, and it is important to recognize them to meet the needs of rehabilitation.Peer reviewe

Author's personal copy Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

a b s t r a c t Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). b 2 -Adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective b 2 -agonist salbutamol. Isolated human peripheral blood eosinophils were cultured in the absence or presence of a b 2 -agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding. Salbutamol prolonged survival of human eosinophils and it was inhibited by a b-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl-and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC 50 for the salbutamol effect was 13.6 AE 4.0 and 8.1 AE 3.1 nM in the absence and presence of rolipram, respectively; p ¼ 0.0142, n ¼ 10). In contrast, inhibition of Ca 2þ -activated K þ -channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival. Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical b 2 -receptor-adenylyl cyclase ecAMP-protein kinase A pathway. Ó 2011 Elsevier Ltd. All rights reserved. Abbreviations: Apamin, Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-Ala-Arg-Arg-Cys-Gln-Gln-His-NH 2 [disulfide bridges: 1e11, 3e15]; cAMP, cyclic adenosine-3 0 , 5 0 -monophosphate; Charybdotoxin, pGlu-Phe-Thr-Asn-Val-Ser-Cys-Thr-Thr-Ser-Lys-Glu-Cys-Trp-Ser-Val-Cys-Gln-Arg-Leu-His-Asn-Thr-Ser-Arg-Gly-Lys-Cys-Met-Asn-LysLys-Cys-Arg-Cys-Tyr-Ser [disulfide bridges: 7e28, 13e33, 17e35]; COPD, chronic obstructive pulmonary disease; Iberiotoxin, pGlu-Phe-Thr-Asp-Val-Asp-Cys-Ser-Val-Ser-LysGlu-Cys-Trp-Ser-Val-Cys-Lys-Asp-Leu-Phe-Gly-Val-Asp-Arg-Gly-Lys-Cys-Met-Gly-Lys-Lys-Cys-Arg-Cys-Tyr-Gln [disulfide bridges: 7e28, 13e33, 17e35]; NS-1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; paxilline, (2R,4bS,6aS,12bS,12cR,14aS)-5,6,6a,7,12,12b,12c,13,14,14a- 2':6,7]indeno[1,2-b]indol-3(4bH)-one; PDE, phosphodiesterase; PI, propidium iodide; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; adenosine-3 0 ,5'-cyclic monophosphorothioate, Rp-isomer; SQ-22,536, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine