Repetitive transcranial magnetic stimulation in bipolar depression: Another puzzle of manic switch?

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Neurophysiological evaluation of patients with degenerative diseases of the cervical spine

Bacground/Aim. Diagnostic protocol for patients with degenerative diseases of the cervical spine demands, in parallel with neuroimaging methods, functional evaluation through neurophysiological methods (somatosensitive and motor evoked potentials and electromyoneurography) aiming to evaluate possible subclinical affection of spinal medula resulting in neurological signs of long tract abnormalities. Considering diversities of clinical outcomes for these patients, complex diagnostic evaluation provides a prognosis of the disease progression. Methods. The study included 21 patients (48.24 ± 11.01 years of age) with clinical presentation of cervical spondylarthropathy, without neuroradiological signs of myelopathy. For each patient, in addition to conventional neurophysiological tests (somatisensory evoked potentials - SSEP, motor evoked potentials - MEP, electromyoneurography - EMG, nerve conduction studies), we calculated central motor conduction time (CMCTF), as well the same parameter in relation to a different position of the head (maximal anteflexion and retroflexion), so-called dynamic tests. Results. Abnormalities of the peripheral motor neurone by conventional EMNeG was established in 2/3 of the patients, correponding to the findings of root condution time. Prolonged conventional CVMPF were found in 29% of the patients, comparing to 43% CVMPF abnormalities found with the dynamic tests. In addition, the SSEP findings were abnormal in 38% of the patients with degenerative diseases of the cervical spine. Conclusion. An extended neurophysiological protocol of testing corticospinal functions, including dynamic tests of central and periheral motor neurons are relevant for detection of subclinical forms of cervical spondylothic myelopathy, even at early stages. In addition to the conventional neurophysiological tests, we found usefull to include the dynamic motor tests and root conduction time measurement in diagnostic evaluation

Homeostatic Modulation of Stimulation-Dependent Plasticity in Human Motor Cortex

Since recently, it is possible, using noninvasive cortical stimulation, such as the protocol of paired associative stimulation (PAS), to induce the plastic changes in the motor cortex, in humans that mimic Hebb's model of learning. Application of TMS conjugated with peripheral electrical stimulation at strictly coherent temporal manner lead to convergence of inputs in the sensory-motor cortex, with the consequent synaptic potentiation or weakening, if applied repetitively. However, when optimal interstimulus interval (ISI) for induction of LTP-like effects is applied as a single pair, Motor evoked potential (MEP) amplitude inhibition is observed, the paradigm known as short-latency afferent inhibition (SLAI). Aiming to resolve this paradox, PAS protocols were applied, with 200 repetitions of TMS pulses paired with median nerve electrical stimulation, at ISI equal to individual latencies of evoked response of somatosensory cortex (N-20) (PASLTP), and at ISI of N-20 shortened for 5 msec (PASLTD) protocols that mimic LTP-like changes in the human motor cortex. MEP amplitudes before, during and after interventions were measured as an indicator based on output signals originating from the motor system. Post-intervention MEP amplitudes following the TMS protocols of PASLTP and PASLTD were facilitated and depressed, respectively, contrary to MEP amplitudes during intervention. During PASLTP MEP amplitudes were significantly decreased in case of PASLTP, while in the case of PASLTD an upward trend was observed. In conclusions, a possible explanation for the seemingly paradoxical effect of PAS can be found in the mechanism of homeostatic modulation of plasticity. Those findings indicate the existence of complex relationships in the development of plasticity induced by stimulation, depending on the level of the previous motor cortex excitability

Neuspeh sprečavanja razvoja intermedijernog sindroma kod akutnog trovanja organofosfornim insekticidima primenom oksima i atropina

Introduction. Intermediate syndrome (IMS) was described a few decades ago, however, there is still a controversy regarding its exact etiology, risk factors, diagnostic parameters and required therapy. Considering that acute poisonings are treated in different types of medical institutions this serious complication of organophosphate insecticide (OPI) poisoning is frequently overlooked. The aim of this paper was to present a case of IMS in organophosphate poisoning, which, we believe, provides additional data on the use of oxime or atropine. Case report. After a well-resolved cholinergic crisis, the patient developed clinical presentation of IMS within the first 72 h from deliberate malathion ingestion. The signs of IMS were weakness of proximal limb muscles and muscles innervated by motor cranial nerves, followed by the weakness of respiratory muscles and serious respiratory insufficiency. Malathion and its active metabolite were confirmed by analytical procedure (liquid chromatography-mass spectrometry). Pralidoxime methylsulphate, adiministered as a continuous infusion until day 8 (total dose 38.4 g), and atropine until the day 10 (total dose 922 mg) did not prevent the development of IMS, hence the mechanical ventilation that was stopped after 27 h had to be continued until the day 10. Conclusion. Continuous pralidoxime methylsulphate infusion with atropine did not prevent the development of IMS, most likely due to the delayed treatment and insufficient oxime dose but also because of chemical structure and lipophilicity of ingested OPI. A prolonged intensive care monitoring and respiratory care are the key management for the intermediate syndrome.Uvod. Intermedijerni sindrom (IMS) opisan je pre nekoliko decenija, međutim i dalje postoje kontroverze u vezi sa njegovom etiologijom, faktorima rizika, dijagnostičkim parametrima i potrebnom terapijom. S obzirom na to da se akutna trovanja leče u medicinskim ustanovama različitog tipa, ova teška komplikacija akutnih trovanja organofosfornim insekticidima (OFI) često se ne prepoznaje. Cilj rada bio je da se prikaže slučaj akutnog trovanja organofosfornim insekticidom koji će dati dodatne podatke o upotrebi oksima i atropina. Prikaz bolesnika. Nakon kupirane holinergičke krize kod bolesnika, 72 h od namerne ingestije malationa, došlo je do razvoja kliničke slike IMS. Znaci IMS su uključivali slabost mišića gornjih ekstremiteta i mišića inervisanih motornim kranijalnim nervima, što je bilo praćeno slabošću respiratorne muskulature i teškom respiratornom insuficijencijom. Malation i njegov aktivni metabolit potvrđeni su analitičkom procedurom (tečna hromatografijamasena spektrometrija). Kontinuiranom infuzijom pralidoksim metilsulfata do osmog dana (ukupno 38,4 g) i atropina do desetog dana (ukupna doza 922 mg), nije sprečen razvoj IMS, te je mehanička ventilacija, koja je prekinuta nakon 27 h, morala biti nastavljena do desetog dana. Zaključak. Kontinuiranom infuzijom pralidoksim-metilsulfata i atropina nije sprečen razvoj IMS, najverovatnije zbog odloženog početka lečenja i nedovoljne doze primenjenog oksima, ali i hemijske strukture i lipofilnosti ingestiranog OFI. Istaknut je značaj produžene opservacije u jedinici intenzivne nege i respiratorne podrške u lečenju intermedijernog sindroma

Kompleksna modulacija sila tokom preciznog hvata šake primenom ponavljane transkranijalne magnetne stimulacije pražnjenjima u teta frekvenciji iznad dorzalnog premotornog korteksa

Background/Aim. Adaptive control and fingertip force synchronization of precise grasp stability during unimanual manipulation of small objects represents an illustrative example of highly fractionated movements that are foundation of fine motor control. It is assumed that this process is controlled by several motor areas of the frontal lobe, particularly applicable to the primary motor (M-1) and dorsal premotor cortex (PMd). Aiming to examine the role of PMd during fine coordination of fingertip forces we applied theta burst repetitive magnetic stimulation (TBS) to disrupt neural processing in that cortical area. Methods. Using a single-blind, randomized, crossover design, 10 healthy subjects (29 ± 3.9 years) received single sessions of continuous TBS (cTBS600), intermittent TBS (iTBS600), or sham stimulation, separate from one another at least one week, over the PMd region of dominant hemisphere. Precision grasp and lift were assessed by instrumented device, recording grip (G) and load (L) forces, during three manipulation tasks (ramp-and-hold, oscillation force producing and simple lifting tasks), with each hand separately, before and after interventions. Results. We observed the improvement of task performance related to constant error (CE) in oscillation task with the dominant hand (DH) after the iTBS (p = 0.009). On the contrary, the cTBS reduced variable error (VE) for non-dominant hand (NH), p = 0.005. Considering force coordination we found that iTBS worsened variables for NH (G/L ratio, p = 0.017; cross-correlation of the G and L, p = 0.047; Gain, p = 0.047). Conclusion. These results demonstrate the ability of TBS to modulate fingertip forces during precision grasping and lifting, when applied over PMd. These findings support the role of PMd in human motor control and forces generation required to hold small objects stable in our hands.Uvod/Cilj. Adaptivna kontrola i sinhronizacija sila prstiju šake tokom preciznog hvata pri manipulisanju malim predmetima jednom rukom predstavlja ilustrativni primer visoko frakcionisanih pokreta koji predstavljaju temelj motorne kontrole preciznih pokreta. Pretpostavlja se da ovim procesom upravlja nekoliko motornih oblasti frontalnog režnja, i to prvenstveno primarni motorni (M-1) i dorzalni premotorni korteks (PMd). Cilj istraživanja bio je ispitivanje uloge PMd-a tokom vršenja pokreta koji zahtevaju finu koordinaciju sila prstiju šake. U istraživanju smo primenili ponavljanu magnetnu stimulaciju pražnjenjima u teta frekvenciji, kako bi ometali neuralno procesiranje u toj oblasti moždane kore. Metode. Primenom jednostrano slepe studije, uz nasumičnu raspodelu i ukršteni dizajn, 10 zdravih ispitanika (29 ± 3,9 godina) bilo je izloženo pojedinačnim sesijama kontinuirane magnetne stimulacije (cTBS600), ili intermitentne ponavljane magnetne stimulacije (iTBS600), pražnjenjima u teta frekvenciji kao i prividnoj stimulaciji iznad PMd regiona dominantne hemisfere, odvojenih međusobno, najkraće nedelju dana. Precizanost hvata šake i podizanja procenjivani su uređajem koji je registrovao silu stiska (G) i silu podizanja (L) prilikom izvođenja tri zadatka (zadatak sa zadatim profilom L, zadatak sa oscilatornim variranjem nivoa L i zadatak sa podizanjem), koji su izvođeni sa obe ruke odvojeno, i to pre i nakon svake intervencije. Rezultati. Nakon primene iTBS protokola zabeleženo je poboljšanje izvođenja iskazano konstantnom greškom (CE) u zadatku sa oscilatornim variranjem nivoa L, kada je izvođen dominantnom rukom (DH), p = 0.009. Suprotno tome, primena cTBS protokola dovela je do smanjenja promenjive greške (VE) za nedominantnu ruku (NH), p = 0.005. Sa aspekta koordinacije sila utvrđeno je da je iTBS protokol doveo do pogoršanja rezultata praćenih pokazatelja za nedominantnu ruku (G/L odnos, p = 0.017; korelacija G i L, p = 0.047; prirast sile p = 0.047). Zaključak. Rezultati našeg istraživanja ukazuju na mogućnost modulacije sila prstiju šake tokom preciznog hvata i podizanja, ukoliko se TBS primeni iznad PMd-a. Dobijeni nalazi podržavaju ulogu PMd u motornoj kontroli i generisanju sila neophodnih za stabilno držanje malih predmeta kod ljudi

Poređenje dijagnostičkih kriterijuma kod bolesnika sa amiotrofičnom lateralnom sklerozom - doprinos elektromiografskih nalaza

Diagnosis of amyotrophic lateral sclerosis (ALS) is based on combination of clinical signs and electrophysiological correlates of pathological process which takes place in general. New electrophysiological criteria Awaji-Shima (AS) additionally qualify the complex fasciculations and neurogenically modified potentials of motor units as signs of active lesions of peripheral motor neuron, contrary to previously valid revised El Escorial criteria (rEE). The objective of this research was to determine the clinical significance and advantages of using the AS criteria in patients with ALS. Methods. Thirty patients (59.2 ± 10.9 years, 57% of them with spinal form of the disease) with clinically suspected ALS were monitored from the time of diagnosis until reaching the category of definitive diagnosis or death. The clinical evaluation and electromyographic (EMG) examinations were carried out at 3-month intervals. Results. By applying the AS criteria, the category of probable or definite diagnosis was achieved in all patients with ALS, except in one (96.6%), as contrary to the rEE (33.3%), after 6 months of the follow-up period. The subclinical affection in more than two body regions has been defined through detection of denervation potentials (80% of the patients by using the AS, or 67% by the rEE criteria). The complex fasciculations were registered particularly often in small muscles of the feet (37- 40%). Conclusion. Application of the AS criteria improve the achievment of category of probable or definite diagnosis of ALS by 2.7 months earlier compared to the rEE. This outcome is particularly affected by a higher frequency of positive EMG findings, when the AS criteria were employed. Early determination of diagnosis provides the better perspective and more frequent participation of the ALS patients in pharmacotherapy studies intended to establish new therapeutic options.Dijagnoza amiotrofične lateralne skleroze (LS) zasniva se na kombinaciji kliničkih znakova i elektrofizioloških korelata patološkog procesa koji se odvija u osnovi. Novi elektrofiziološki kriterijumi, Awaji-Shima (AS), dodatno kvalifikuju kompleksne fascikulacije i neurogeno izmenjene potencijale motornih jedinica kao znakove aktivnih lezija perifernog motornog neurona, nasuprot ranije važećim revidiranim El Escorial kriterijumima (rEE). Cilj ovog istraživanja bio je da se utvrdi klinički značaj i prednosti primene AS kriterijuma, kod obolelih od ALS. Metode. 30 bolesnika (59,2 ± 10,9 godina, od kojih 57% sa spinalnom formom bolesti) sa klinički suspektnom ALS, praćeno je od vremena postavljanja dijagnoze do postizanja kategorije definitivne dijagnoze ili smrtnog ishoda. Kod bolesnika su obavljane klinička evaluacija i elektromiografski (EMG) pregledi u tromesečnim intervalima. Rezultati. Primjenom AS kriterijuma, nakon 6 meseci praćenja, kategorija verovatne ili pouzdane dijagnoze postignuta je kod svih bolesnika sa ALS, izuzev jednog (96,6%), nasuprot rEE kriterijuma (33.3%). EMG nalazi bili su pozitivni u ≥ 2 telesna regiona kod 80% bolesnika primenom AS, odnosno 67% primenom rEE. Kompleksne fascikulacije zabeležene su posebno učestalo u malim mišićima stopala (37-40%). Zaključak. Primenom AS kriterijuma kategorija vjerovatne ili pouzdane dijagnoze ALS postiže se za 2,7 meseca ranije, u poređenju sa rEE, na šta posebno utiče veća učestalost pozitivnih EMG nalaza. Ranije utvrđivanje dijagnoze donosi perspektivu veće zastupljenosti obolelih u farmakoterapijskim studijama sa novim terapeutskim agensima

Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD

Antioksidativni status i kliničko-patološki parametri kod obolelih od Parkinsonove bolesti

Backgroun / Aim. Constant production of free radicals and antioxidants (AO) in the cell is a part of normal cellular function. Their imbalance might take a part in pathophysiology of many diseases, including Parkinson’s disease (PD). Evaluation of the disease status, prooxidant-antioxidant balance (PAB) and antioxidants are being widely estimated. The aim of this study was to examine potential interaction between several AO variables (GSH, SOD, CAT and PAB) and clinicopathological features of patients with PD, particularly Hoehn and Yahr (H&Y) stage. Methods. A multivariate analysis of variance (MANOVA) was conducted to test the hypothesis of the mean differences between clinicopathological characteristics (gender, age at examination, duration of the disease, and H&Y stage) and AO variables, compared with age/sex matched healthy controls. The study included 91 patients with idiopatic PD patients and 20 healthy controls. Results. The multivariate effect size was estimated at 0.269, p <0.001, implying that 27.0% of the variance of the dependent variables was accounted for H&Y stage. Univariate tests showed that there were significant differences (p <0.001) across the H&Y stage on all AO variables. The H&Y stage remained significant predictor after controlling for the second variable, the disease duration (p <0.001, η2 = 0.249), and there were still significant differences across the H&Y stage on all variables, with effect size ( η2) ranging from 0.132, p =0.011 (lnGSH) to the still high values of 0.535 (lnPAB), 0.627 (lnSOD) and 0.964 (lnCAT). Conclusion. The results indicate that higher level of oxidative stress in blood of PD patients is possibly related to PD stage. Along with reduction of SOD and GSH level, CAT activity was elevated in comparison to healthy subjects. Furthermore, Pwas shifted toward oxidative stress

Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model—experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A2AR/A1R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1β and NF- κB-ir and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment

Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits. © 2023 by the authors