Neurophysiological Predictors of Response to Medication in Parkinson's Disease

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking. Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects. Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined. Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration. Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD

Promene ekscitabilnosti motorne kore udružene sa zamorom mišića kod obolelih od Parkinsonove bolesti

Background/Aim. Transcranial magnetic stimulation (TMS) is a standard technique for noninvasive assessment of changes in central nervous system excitability. The aim of this study was to examine changes in responses to TMS in patients suffering from Parkinson's disease (PD) during sustained submaximal isometric voluntary contraction [60% of maximal voluntary contraction (MVC)] of the adductor pollicis muscle, as well as during a subsequent recovery period. Methods. Cortical excitability was tested by single TMS pulses of twice of the motor threshold intensity applied over the vertex. Testing was carried out during the sustained contraction phase every 10 s before and every 5 s after the endurance point, as well as at rest and during brief 60% MVC contractions before (control), immediately after the sustained contraction, and at 5 min intervals during the recovery period. Results. Although the PD patients could sustain the contraction at the required level for as long period of time as the healthy subjects (though contraction level subsided more rapidly after the endurance point), effects of muscle fatigue on the responses to TMS were different. In contrast to the findings observed in the healthy people where motor evoked potentials (MEP) and EMG silent period (SP) in fatigued muscle gradually diminished during contraction up to the endurance point, and increased thereafter, in the majority of patients no changes occurred in MEP size (peak and area) of the adductor pollicis muscle, either before or after the endurance point. On the other hand, changes in the SP of this muscle differed among the subjects, showing a gradual increase, a decrease or no changes in duration. The trends of changes in both MEP size and SP duration in the musculus brachioradialis varied among the tested PD patients, without any consistent pattern, which was in contrast with the findings in the healthy people where both measures showed a gradual increase from the beginning of the sustained contraction. A complete dissociation between changes in MEP and SP during fatigue was also of note, which differed sharply from the findings in the healthy people in who fatigue induced changes in these measures followed identical patterns. Conclusion. These results in the PD patients suggest the presence of impairment and/or compensatory changes in mechanisms responsible for adaptation of voluntary drive as well as for matching between cortical excitation and inhibition which become manifest in demanding motor tasks such as those imposed by muscle fatigue.Uvod/Cilj. Transkranijalna magnetna stimulacija (TMS) je standardna tehnika za neinvazivnu procenu promena ekscitabilnosti centralnog nervnog sistema. Cilj rada je bio da se prikažu promene odgovora na TMS kod obolelih od Parkinsonove bolesti (PB) za vreme trajanja submaksimalne voljne izometrijske kontrakcije [60% maksimalne voljne kontrakcije (MVK)] mišića adductor pollicis, kao i tokom perioda oporavka. Metode. Kortikalna ekscitabilnost testirana je TMS pulsevima dvostruko većeg intenziteta od motornog praga. Testiranje je vršeno za vreme održavanja kontrakcije na svakih 10 s do tačke izdržljivosti i na svakih 5 s posle toga, a, takođe, u miru kao i za vreme kratkotrajnih 60% MVK u periodu pre (kontrola), neposredno posle održavanja kontrakcije, i u intervalima od pet minuta za vreme perioda oporavka. Rezultati. Iako su bolesnici sa PB mogli da održavaju zahtevani nivo kontrakcije jednako dugo kao i zdravi ispitanici (mada je nivo opadao brže nakon tačke izdržljivosti), efekti mišićnog zamora na odgovor izazvan TMS-om bili su različiti. Za razliku od zdravih ispitanika kod kojih se motorni evocirani potencijali (MEP) i trajanje perioda EMG tišine (PT) u zamaranom mišiću postepeno smanjuju tokom kontrakcije do tačke izdržljivosti, a zatim rastu, kod većine bolesnika nije došlo do promena veličine (maksimalna amplituda i površina) MEP mišića adductor pollicis, bilo pre ili posle tačke izdržljivosti. S druge strane, promene PT ovog mišića su se razlikovale među ispitanicima, pokazujući bilo postepeno povećanje, smanjenje ili odsustvo promena. Promene kako amplitude MEP tako i trajanje PT u EMG mišića brahioradialisa varirale su među bolesnicima sa PB, bez nekog dominantnog obrasca, po čemu su se, takođe, razlikovale od promena nađenih kod zdravih ispitanika, kod kojih su se oba parametra postepeno povećavala od početka održavanja tonične kontrakcije. Upadljiva je, takođe, i potpuna disocijacija između promena MEP i PT tokom zamora, što je u oštroj suprotnosti sa nalazom kod zdravih ispitanika gde su promene ovih parametara pratile identičan obrazac. Zaključak. Rezultati kod bolesnika sa PB ukazuju na postojanje oštećenja i/ili kompenzatornih promena mehanizmima odgovornih za adaptaciju voljne pobude i usklađivanja kortikalne eksitacije i inhibicije, koji se manifestuju tokom mišićnog zamora i u drugim zahtevnim motornim zadacima

Reptiles in Serbia: Distribution and diversity patterns

In this paper we present confirmed and potential distribution ranges of all native Serbian reptile species. The information provided herein presents the combination of the newly collected faunistic data and previously published records. The centres of reptilian diversity in Serbia were evaluated, in order to focus future conservation efforts on the regions of particular importance for the protection of this understudied group of animals. We found four main centres of species richness: three in Metohija and one in Šumadija, with 17-21 species per 50 × 50 km square. Analysis of the similarity of species composition in different regions of Serbia showed that South-eastern Serbia is the most distinct from other regions of Serbia, due to high number of Mediterranean species, with two being found exclusively in that region (E. quatuorlineata and P. najadum). Metohija is also very distinct, due to the highest number of species and significant number of specific (Mediterranean) faunal elements. The remaining geographic regions are grouped into three clusters, with Kosovo-Southern Serbia cluster being especially distinct in the terms of species richness and the presence of Mediterranean species. We also compared Serbian herpetofauna with those in other Balkan countries, considering species' numbers and zoogeographic herpetofaunistic elements. Serbian herpetofauna is closest to the Romanian. Zoogeographic analysis showed that reptilian fauna of Serbia consists of eight chorotypes, with the Eastern-Mediterranean (nine species) and Southern-European (five species) as the most dominant ones.U ovom radu predstavljeni su potvrđeni i potencijalni areali svih autohtonih gmizavaca Srbije. Korišćeni su do sada neobjavljeni podaci terenskih istraživanja, kao i informacije objavljene u literaturi. Ocenjeni su pretpostavljeni centri diverziteta gmizavaca u Srbiji, sa ciljem da se skrene pažnja na konzervacione mere neophodne za zaštitu pojedinih regiona od značaja za diverzitet gmizavaca u našoj zemlji. Utvrđeno je postojanje četiri centra diverziteta: tri u Metohiji i jednog u Šumadiji, sa prisustvom od 17 do 21 vrste na površini od 50 × 50 km. Analiza regiona Srbije po pitanju sličnosti sastava faune gmizavaca pokazala je da se region jugoistočne Srbije najviše odvaja od svih ostalih zbog ekskluzivnog prisustva dve mediteranske vrste gmizavaca (Elaphe quatuorlineata i Platyceps najadum). Metohija se odvaja po najvećem diverzitetu kao i prisustvu velikog broja mediteranskih vrsta gmizavaca. Ostali regioni formiraju tri grupe, pri čemu se klaster koga čine Kosovo i južna Srbija odvaja po prisustvu mediteranskih vrsta gmizavaca. Kada su na sličan način upoređene faune gmizavaca svih država Balkanskog poluostrva ispostavilo se da je fauna gmizavaca Srbije najsličnija onoj u Rumuniji. Zoogeografska analiza je pokazala da gmizavci Srbije spadaju u osam horotipova, pri čemu su po broju vrsta najzastupljeniji istočnomediteranski (sa devet vrsta) i južnoevropski (sa pet vrsta) horotipovi.nul

Reptiles in Serbia: Distribution and diversity patterns

In this paper we present confirmed and potential distribution ranges of all native Serbian reptile species. The information provided herein presents the combination of the newly collected faunistic data and previously published records. The centres of reptilian diversity in Serbia were evaluated, in order to focus future conservation efforts on the regions of particular importance for the protection of this understudied group of animals. We found four main centres of species richness: three in Metohija and one in Šumadija, with 17-21 species per 50 × 50 km square. Analysis of the similarity of species composition in different regions of Serbia showed that South-eastern Serbia is the most distinct from other regions of Serbia, due to high number of Mediterranean species, with two being found exclusively in that region (E. quatuorlineata and P. najadum). Metohija is also very distinct, due to the highest number of species and significant number of specific (Mediterranean) faunal elements. The remaining geographic regions are grouped into three clusters, with Kosovo-Southern Serbia cluster being especially distinct in the terms of species richness and the presence of Mediterranean species. We also compared Serbian herpetofauna with those in other Balkan countries, considering species' numbers and zoogeographic herpetofaunistic elements. Serbian herpetofauna is closest to the Romanian. Zoogeographic analysis showed that reptilian fauna of Serbia consists of eight chorotypes, with the Eastern-Mediterranean (nine species) and Southern-European (five species) as the most dominant ones.U ovom radu predstavljeni su potvrđeni i potencijalni areali svih autohtonih gmizavaca Srbije. Korišćeni su do sada neobjavljeni podaci terenskih istraživanja, kao i informacije objavljene u literaturi. Ocenjeni su pretpostavljeni centri diverziteta gmizavaca u Srbiji, sa ciljem da se skrene pažnja na konzervacione mere neophodne za zaštitu pojedinih regiona od značaja za diverzitet gmizavaca u našoj zemlji. Utvrđeno je postojanje četiri centra diverziteta: tri u Metohiji i jednog u Šumadiji, sa prisustvom od 17 do 21 vrste na površini od 50 × 50 km. Analiza regiona Srbije po pitanju sličnosti sastava faune gmizavaca pokazala je da se region jugoistočne Srbije najviše odvaja od svih ostalih zbog ekskluzivnog prisustva dve mediteranske vrste gmizavaca (Elaphe quatuorlineata i Platyceps najadum). Metohija se odvaja po najvećem diverzitetu kao i prisustvu velikog broja mediteranskih vrsta gmizavaca. Ostali regioni formiraju tri grupe, pri čemu se klaster koga čine Kosovo i južna Srbija odvaja po prisustvu mediteranskih vrsta gmizavaca. Kada su na sličan način upoređene faune gmizavaca svih država Balkanskog poluostrva ispostavilo se da je fauna gmizavaca Srbije najsličnija onoj u Rumuniji. Zoogeografska analiza je pokazala da gmizavci Srbije spadaju u osam horotipova, pri čemu su po broju vrsta najzastupljeniji istočnomediteranski (sa devet vrsta) i južnoevropski (sa pet vrsta) horotipovi.nul

Spectroscopic study of the laser-induced indium plasma

We report experimental research of the laser-produced indium plasma in hydrogen, argon and residual atmospheric ambient conditions. Note on general plasma behavior and morphology is presented. On the basis of intensity ratio of the two intense neutral resonance spectral lines (In I 410.2 nm and 451.1 nm), self-absorption was found to be almost negligible in case of argon environment at a pressure of 6650 Pa. Under these conditions, the first Stark widths (W) and shifts (d) measurements were performed as well. The resulting synthetic Lorentz profiles, based on the hyperfine structure of these two lines and corresponded W values, were calculated in order to reproduce measured Wm in case of particular electron temperature (T) and number density (N). These results should be of interest to the upcoming theoretical calculations concerning neutral indium spectral lines and also for various diagnostic applications

Transcranial Magnetic Stimulation of Degenerating Brain: A Comparison of Normal Aging, Alzheimer's, Parkinson's and Huntington's Disease

Although the brain's ability to change constantly in response to external and internal inputs is now well recognized the mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding, transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the cortical neurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whether repetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer's and Parkinson's disease. The results of these studies in normal aging and neurodegeneration have emerged reasonably coherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodological variability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known about TMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structures with disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormal brain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiology and neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurements of cortical excitability and plasticity in physiological aging, Alzheimer's, Parkinson's, and Huntington's, disease. The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologic aging from neurodegeneration and its potential as a method of therapeutic intervention

Detecting long-range correlations in time series of dorsal horn neuron discharges

We have studied the discharge dynamics of dorsal horn neurons by applying the detrended fluctuation analysis and the wavelet transform technique. We have adopted that the neuronal discharge dynamics is manifested by the random time series of interspike intervals. In all cases studied, we found two different power-law type behaviors across interspike intervals enumeration scale, that are separated by crossover regions (which implies existence of two different types of neuronal noise). Our results reveal that complex neuronal dynamics may change in the presence of external stimulation, manifested by changing of the noise characteristics that appear before crossover

Detrended fluctuation analysis of time series of a firing fusimotor neuron

We study the interspike intervals (ISI) time series of the spontaneous fusimotor neuron activity by applying the detrended fluctuation analysis that is a modification of the random walk model analysis. Thus, we have found evidence for the white noise characteristics of the ISI time series, which means that the fusimotor activity does not possess temporal correlations. We conclude that such an activity represents the requisite noisy component for occurrence of the stochastic resonance mechanism in the neural coordination of muscle spindles

Wavelet analysis of discharge dynamics of fusimotor neurons

We study the interspike intervals (ISI) time series of the spontaneous fusimotor neuron activity by applying the wavelet transform analysis and confirm the existence of the white noise characteristics of the ISI time series. This means that the neuron activity may serve as the requisite noisy component for occurrence of the stochastic resonance mechanism in the neural coordination of muscle spindles. Besides, we apply the multifractal formalism adapted for the wavelet transform time series analysis. Thus, we have established the multifractality of the ISI data and achieved an additional insight into fusimotor discharge dynamics