Exploring the Link between Hydrodynamic Size and Immunoglobulins of Circulating Immune Complexes in Rheumatoid Arthritis Patients.

The function of immune complexes in rheumatoid arthritis (RA) is related to their composition and size. Using dynamic light scattering (DLS), we investigated the link between the RA circulating immune complex (CIC) particles' size and the CIC immunoglobulin level. In this study, 30 RA patients and 30 healthy individuals were included. IgA, IgG, and IgM were found in all analyzed CICs, but more IgA and IgG were found in RA than in control CICs. In both control and RA CICs, DLS detected 50 particles that differed in size and clustered around two size groups: with a 7.5-164 nm radius and with a 342-1718 nm radius. An increased level of IgA in RA CICs, compared to control ones, was associated with more than 50% of CIC particles. In RA, compared to the control, a higher number of CICs with 28.2 nm, 531 nm, 712 nm, and 1718 nm particles and a lower number of CICs with 78.8 nm particles were detected. This particle distribution pattern did not reflect the changes in the CIC immunoglobulin level. Thus, RA elevated CIC IgA was linked with all these particles (except the 1718 nm particle), the IgM increase was linked with 43.8 nm and 712 nm particles, and the IgG increase was linked with the 712 nm particle only. This study provides the very first data on the association between CIC particles' size, CIC immunoglobulin level, and RA. It opens the possibility that the size of CICs determined by DLS can be used as a criterion in RA diagnosis or monitoring after a large-scale study confirmation.

Natural Substances vs. Approved Drugs in the Treatment of Main Cardiovascular Disorders-Is There a Breakthrough?

Cardiovascular diseases (CVDs) are a group of diseases with a very high rate of morbidity and mortality. The clinical presentation of CVDs can vary from asymptomatic to classic symptoms such as chest pain in patients with myocardial infarction. Current therapeutics for CVDs mainly target disease symptoms. The most common CVDs are coronary artery disease, acute myocardial infarction, atrial fibrillation, chronic heart failure, arterial hypertension, and valvular heart disease. In their treatment, conventional therapies and pharmacological therapies are used. However, the use of herbal medicines in the therapy of these diseases has also been reported in the literature, resulting in a need for critical evaluation of advances related to their use. Therefore, we carried out a narrative review of pharmacological and herbal therapeutic effects reported for these diseases. Data for this comprehensive review were obtained from electronic databases such as MedLine, PubMed, Web of Science, Scopus, and Google Scholar. Conventional therapy requires an individual approach to the patients, as when patients do not respond well, this often causes allergic effects or various other unwanted effects. Nowadays, medicinal plants as therapeutics are frequently used in different parts of the world. Preclinical/clinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common CVDs. The natural products analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in CVDs pharmacotherapy, and some of them have already been approved by the FDA. There are insufficient clinical studies to compare the effectiveness of natural products compared to approved therapeutics for the treatment of CVDs. Further long-term studies are needed to accelerate the potential of using natural products for these diseases. Despite this undoubted beneficence on CVDs, there are no strong breakthroughs supporting the implementation of natural products in clinical practice. Nevertheless, they are promising agents in the supplementation and co-therapy of CVDs.

Resveratrol improved kidney function and structure in malignantly hypertensive rats by restoration of antioxidant capacity and nitric oxide bioavailability.

BACKGROUND: The main cause of death among patients with malignant hypertension is a kidney failure. The promising field in essential and malignant hypertension therapy could be centered on the amelioration of oxidative stress using antioxidant molecules like resveratrol. Resveratrol is a potent antioxidative agent naturally occurred in many plants that possess health-promoting properties. METHODS: In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with anti-oxidative activity, in NG-L-Arginine Methyl Ester (L-NAME) treated spontaneously hypertensive rats (SHR) - malignantly hypertensive rats (MHR). RESULTS: Resveratrol significantly improves oxidative damages by modulation of antioxidant enzymes and suppression of prooxidant factors in the kidney tissue of MHR. Enhanced antioxidant defense in the kidney improves renal function and ameliorates the morphological changes in this target organ. Besides, protective properties of resveratrol are followed by the restoration of the nitrogen oxide (NO) pathway. 4) Conclusion: Antioxidant therapy with resveratrol could represent promising therapeutical approach in hypertension, especially malignant, against kidney damage.

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.

Resveratrol Protects Cardiac Tissue in Experimental Malignant Hypertension Due to Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Properties.

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-ß and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

Sport-Specific Warm-Up Attenuates Static Stretching- Induced Negative Effects on Vertical Jump But Not Neuromuscular Excitability in Basketball Players.

The purpose of this study was to examine the acute effects of static stretching (SS) and dynamic stretching (DS), alone and in combination with specific basketball warm-up (SBWU), on the neuromuscular excitability and vertical jump height in basketball players. Twelve healthy young male basketball players participated in the study (18 ± 0.42 years; 17.4 - 18.6 age range; 188 ± 9 cm; 76.5 ± 9 kg). All participants completed two different stretching treatments (static and dynamic), performed on different days at least seven days apart, in the same period of training microcycle, in a counterbalanced order. Each session consisted of a self-paced jogging warm-up, followed by a 10-minute testing period (T0), which involved eliciting H reflex and M waves, followed by three trials of a vertical jump test. Participants then performed one of the treatment protocols. After another test (T1), participants conducted 8-minute specific basketball warm-up and then one more test (T2). Combined 3 (time) x 2 (stretching protocol) analysis of variance with repeated measures on both factors revealed that SS significantly decreased spinal excitability (H/M ratio) (p = 0.015, d = -0.38, percentage of change = -20.55%) and vertical jump height (p = 0.007, d = -1.91, percentage of change = -2.6%), but after SBWU, vertical jump height increased (p = 0.006, d = 1.13, percentage of change = 3.01%), while H/M ratio continued decreasing (p = 0.019, d = -0.45, percentage of change = -30.23%). Acute effects of DS, alone and in combination with SBWU were not significant. It seems that SBWU attenuates negative acute effects of SS on vertical jump performance in young basketball players, while DS appears to cause no significant acute effect for this population.

Transcranial direct current stimulation (tDCS) over parietal cortex improves associative memory.

Associative memory plays a key role in everyday functioning, but it declines with normal ageing as well as due to various pathological states and conditions, thus impairing quality of life. Associative memory enhancement via neurostimulation over frontal areas resulted in limited success, while posterior stimulation sites seemed to be more promising. We hypothesized that anodal transcranial direct current stimulation (tDCS) of parietal areas would lead to higher performance in associative memory due to high connectivity between posterior parietal cortex (PPC) and hippocampus. Forty-two healthy adults participated in two sham-controlled cross-over experiments. Anodal electrode (20 min, 1.5 mA) was placed over P3 in Experiment 1 and over P4 in Experiment 2. During tDCS participants played a simple computer game. After each stimulation session, participants completed parallel forms of an associative memory task (Experiment 1: face-word memory; Experiment 2: object-location memory) and a control task (verbal fluency). In both experiments, associative memory was improved after anodal stimulation compared to sham stimulation, while no differences were observed in the control task. Additionally, memory performance was higher in the second than in the first trial, but the increase in performance between the two trials did not differ between stimulation conditions. It can be concluded that a single-session anodal tDCS over posterior parietal cortex can improve associative memory performance. The specificity, robustness, and reproducibility of the effect suggest that PPC is a promising target for brain stimulation aiming to enhance memory functions.

Changes in cortical excitability during paired associative stimulation in Parkinson's disease patients and healthy subjects.

Paired associative stimulation (PAS) combines repetitive peripheral nerve stimulation with motor cortex (M1) transcranial magnetic stimulation (TMS), to induce plastic-like changes of cortical excitability. While much attention has been dedicated to post-PAS effects little is known about processes during PAS. We compared the time-course of changes in M1 excitability during standard facilitatory PAS intervention among patients with Parkinson's disease (PD), known to have diminished post-PAS response, and healthy subjects. Compared to baseline pre-PAS MEPs, conditioned MEPs during PAS decreased significantly in both groups. The decrease was significantly larger in healthy subjects than in PD patients, regardless whether patients were drug-naïve or not. Although post-PAS excitability increase was also larger in healthy subjects than in PD patients, there was no significant correlation between the two phenomena, i.e. the extent of MEP decrease during PAS and the extent of the post-PAS excitability increase. The results highlight an apparent physiological paradox that repetitive application of an inhibitory stimulation pattern leads to subsequent prolonged facilitation, thus broadening the understanding of the phenomenology of PAS response. Results also suggest that in PD cortical circuits involved in conveying inhibition during PAS, are impaired at the clinical onset of the disease and are not influenced by subsequent PD treatment.

Bilateral sequential motor cortex stimulation and skilled task performance with non-dominant hand.

OBJECTIVE: To check whether bilateral sequential stimulation (BSS) of M1 with theta burst stimulation (TBS), using facilitatory protocol over non-dominant M1 followed by inhibitory one over dominant M1, can improve skilled task performance with non-dominant hand more than either of the unilateral stimulations do. Both, direct motor cortex (M1) facilitatory non-invasive brain stimulation (NIBS) and contralateral M1 inhibitory NIBS were shown to improve motor learning. METHODS: Forty right-handed healthy subjects were divided into 4 matched groups which received either ipsilateral facilitatory (intermittent TBS [iTBS] over non-dominant M1), contralateral inhibitory (continuous TBS [cTBS] over dominant M1), bilateral sequential (contralateral cTBS followed by ipsilateral iTBS), or placebo stimulation. Performance was evaluated by Purdue peg-board test (PPT), before (T0), immediately after (T1), and 30min after (T2) an intervention. RESULTS: In all groups and for both hands, the PPT scores increased at T1 and T2 in comparison to T0, showing clear learning effect. However, for the target non-dominant hand only, immediately after BSS (at T1) the PPT scores improved significantly more than after either of unilateral interventions or placebo. CONCLUSION: M1 BSS TBS is an effective intervention for improving motor performance. SIGNIFICANCE: M1 BSS TBS seems as a promising tool for motor learning improvement with potential uses in neurorehabilitation.

Effects of anodal tDCS and occupational therapy on fine motor skill deficits in patients with chronic stroke.

BACKGROUND: A growing body of evidence supports the effectiveness of using transcranial direct current stimulation (tDCS) in patients with chronic hand motor impairment resulting from stroke. OBJECTIVE: In this study, we investigate and compare the combined effects of anodal tDCS and occupational therapy (OT) to sham stimulation with OT (control) on fine motor skill deficits of chronic stroke patients. METHODS: A total of 26 stroke patients (at ≥ 9 months) were randomly assigned to an active treatment or a control group in a double-blinded, sham-controlled, parallel design study. Each group received OT for 45 min/day (10 sessions for 2 weeks). Treatment was preceded by either 20 minutes of 2 mA anodal tDCS over ipsilesional M1 or sham tDCS. A modified Jebsen-Taylor Hand Function Test (mJTHFT) was administered as primary outcome measure, and handgrip dynamometer and upper limb Fugl-Meyer (ULFM) assessments were performed as secondary outcomes. The assessment was done at baseline (T0), after the interventions on day 1(T1), day 10 (T2) and day 40 (T3). RESULTS: We observed a statistically significant effect in the tDCS group when the results were compared to the sham group. The mJTHFT times were significantly shorter immediately after treatment and at day 40. The intervention had no effect on handgrip strength or ULFM score. CONCLUSION: Fine motor skill deficits in chronic stroke survivors can be improved when intensive OT is primed with anodal tDCS over the ipsilesional hemisphere.

Transcranial theta-burst stimulation alters GLT-1 and vGluT1 expression in rat cerebellar cortex.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in activity of excitatory and inhibitory systems as well as redox homeostasis. Our aim was to investigate the effect of single (SS) and repeated session (RS) of intermittent and continuous theta-burst stimulation (iTBS; cTBS) on the expression of vesicular and plasmatic glutamate transporters 1 (vGluT1 and GLT-1), glial fibrillary acidic protein (GFAP) and influence on oxidative status in rats cerebellar tissue and plasma. Redox state parameters in cerebellar tissue and plasma were assessed 24 h after single and 48 h after the last TBS session. Molecular changes were examined by immunofluorescence. Stimulation significantly increased thiol groups (SH) in tissue of SS iTBS group, and decreased in iTBS RS. Activity of glucose-6-phosphate-dehydrogenase (G6PD) was increased markedly in cTBS RS. Immunoreactivity of vGluT1 in cTBS RS decreased, while GLT-1 increased in cTBS SS and cTBS RS, compared to control. Present study gives insight in molecular and biochemical mechanisms by which iTBS and cTBS exerts its effects on rats cerebellar cortex.

Sex and age differences and outcomes in acute coronary syndromes.

BACKGROUND: There is conflicting information about sex differences in presentation, treatment, and outcome after acute coronary syndromes (ACS) in the era of reperfusion therapy and percutaneous coronary intervention. The aim of this study was to examine presentation, acute therapy, and outcomes of men and women with ACS with special emphasis on their relationship with younger age (≤65years). METHODS: From January 2010 to June 2015, we enrolled 5140 patients from 3 primary PCI capable hospitals. Patients were registered according to the International Survey of Acute Coronary Syndrome in Transitional Countries (ISACS-TC) registry protocol (ClinicalTrials.gov: NCT01218776). The primary outcome was the incidence of in-hospital mortality. RESULTS: The study population was constituted by 2876 patients younger than 65years and 2294 patients older. Women were older than men in both the young (56.2±6.6 vs. 54.1±7.4) and old (74.9±6.4 vs. 73.6±6.0) age groups. There were 3421 (66.2%) patients with ST elevation ACS (STE-ACS) and 1719 (33.8%) patients without ST elevation ACS (NSTE-ACS). In STE-ACS, the percentage of patients who failed to receive reperfusion was higher in women than in men either in the young (21.7% vs. 15.8%) than in the elderly (35.2% vs. 29.6%). There was a significant higher mortality in women in the younger age group (age-adjusted OR 1.52, 95% CI: 1.01-2.29), but there was no sex difference in the older group (age-adjusted OR 1.10, 95% CI: 0.87-1.41). Significantly sex differences in mortality were not seen in NSTE-ACS patients. CONCLUSIONS: In-hospital mortality from ACS is not different between older men and women. A higher short-term mortality can be seen only in women with STEMI and age of 65 or less.

Differential effects of facilitatory and inhibitory theta burst stimulation of the primary motor cortex on motor learning.

OBJECTIVE: To evaluate the differential effects on motor learning of two types of theta burst stimulation (TBS), the excitatory intermittent TBS (iTBS) and inhibitory continuous TBS (cTBS), if TBS is applied in an early stage of learning process. METHODS: Thirty right handed healthy people were randomly allocated into one of the three groups according to the intervention applied, iTBS, cTBS or placebo. The interventions and measurements targeted the non-dominant side. The reaction time task (RTT) and Purdue pegboard task (PPT) were used. Measurements and motor tasks were carried out at baseline (T0), immediately after the intervention (T1), and 30 min later (T2). RESULTS: Compared to placebo, following cTBS M1 excitability went down and PPT learning was slowed. Following iTBS M1 excitability increased temporarily and PPT learning pattern changed, but learning was not improved. The MEP and PPT changes induced during the T0-T1 time interval correlated significantly. CONCLUSIONS: The early consolidation of the learned material was much more influenced by the TBS induced promotion/suppression of the M1 functional plasticity reserves than by the absolute level of the M1 activation. SIGNIFICANCE: The results may help to better define the use of TBS in promotion of motor learning in neurorehabilitation and cognitive enhancement.

Improvement of language functions in a chronic non-fluent post-stroke aphasic patient following bilateral sequential theta burst magnetic stimulation.

In chronic non-fluent aphasia patients, inhibition of the intact right hemisphere (RH), by transcranial magnetic stimulation (TMS) or similar methods, can induce improvement in language functions. The supposed mechanism behind this improvement is a release of preserved left hemisphere (LH) language networks from RH transcallosal inhibition. Direct stimulation of the damaged LH can sometimes bring similar results too. Therefore, we developed a novel treatment approach that combined direct LH (Broca's area (BA)) stimulation, by intermittent theta burst stimulation (TBS), with homologue RH area's inhibition, by continuous TBS. We present the results of application of 15 daily sessions of the described treatment approach in a right-handed patient with chronic post-stroke non-fluent aphasia. The intervention appeared to improve several language functions, but most notably propositional speech, semantic fluency, short-term verbal memory, and verbal learning. Bilateral TBS modulation of activation of the language-related areas of both hemispheres seems to be a feasible and promising way to induce recovery in chronic aphasic patients. Due to potentially cumulative physiological effects of bilateral stimulation, the improvements may be even greater than following unilateral interventions.

Transcranial application of near-infrared low-level laser can modulate cortical excitability.

BACKGROUND AND OBJECTIVE: Near-infrared low-level laser (NIR-LLL) irradiation penetrates scalp and skull and can reach superficial layers of the cerebral cortex. It was shown to improve the outcome of acute stroke in both animal and human studies. In this study we evaluated whether transcranial laser stimulation (TLS) with NIR-LLL can modulate the excitability of the motor cortex (M1) as measured by transcranial magnetic stimulation (TMS). METHODS: TLS was applied for 5 minutes over the representation of the right first dorsal interosseal muscle (FDI) in left primary motor cortex (M1), in 14 healthy subjects. Motor evoked potentials (MEPs) from the FDI, elicited by single-pulse TMS, were measured at baseline and up to 30 minutes after the TLS. RESULTS: The average MEP size was significantly reduced during the first 20 minutes following the TLS. The pattern was present in 10 (71.5%) of the participants. The MEP size reduction correlated negatively with the motor threshold at rest. CONCLUSIONS: TLS with NIR-LLL induced transitory reduction of the excitability of the stimulated cortex. These findings give further insights into the mechanisms of TLS effects in the human cerebral cortex, paving the way for potential applications of TLS in treatment of stroke and in other clinical settings.

Transcranial magnetic stimulation has no placebo effect on motor learning.

OBJECTIVE: Motor learning is the core cognitive function in neurorehabilitation and in various other skill-training activities (e.g. sport, music). Therefore, there is an increasing interest in the use of transcranial magnetic stimulation (TMS) methods for its enhancement. However, although usually assumed, a potential placebo effect of TMS methods on motor learning has never been systematically investigated. METHODS: Improvement of performance on the Purdue Pegboard Task over three test-blocks (T0, T1, and T2), separated by >20 min, was used to evaluate motor learning. In Experiment-1, two groups of 10 participants each were compared: one group immediately before T1 received a sham intermittent theta burst stimulation procedure (P-iTBS group), while another did not have any intervention at all (control - CON group). In Experiment-2, a third group of participants (six subjects) who received sham high-frequency repetitive TMS procedure before T1 (P-rTMS group) was compared with P-iTBS group. RESULTS: All three groups showed significant learning over time, but without any difference between them, either in Experiment-1 between P-iTBS and CON, or in Experiment-2 between P-rTMS and P-iTBS. CONCLUSION: The results suggest lack of any placebo effect of TMS on motor learning. SIGNIFICANCE: The results may help in designing further TMS-motor learning studies and in interpreting their results.

[Postmarketing study of efficacy and safety of losartan during the treatment of patients with mild and moderate hypertension: LOTAR (corrected) study].

INTRODUCTION: Losartan, the angiotensin type 1 receptor blocker (ARB) exercises its main antihypertensive effect by vasodilatation of peripheral arteries. OBJECTIVE: The aim of this study was to evaluate the antihypertensive effect and safety of losartan in patients with mild and moderate arterial hypertension (AH). METHODS: This was an open post-marketing study with losartan as monotherapy in previously treated or untreated patients with AH. Primary efficacy parameter was the percentage of patients that achieved target blood pressure after 8-week treatment with a single daily dose of losartan of 50-100 mg. Safety parameters were assessed according to the percentage of adverse events and metabolic effects of therapy. RESULTS: The study included 550 patients with AH (59% female and 41% male), mean age 56.8 +/-11.4 years, BMI = 27 +/- 4 kg/m2. Losartan was applied in 31% of untreated and 69% of previously treatment-resistant patients After 8 weeks target blood pressure was achieved in 67.8% (SBP) and in 81.1% (DBP) of patients, respectively. The mean decrease was 21.8% for SBP and 21.1% for DBP (p < 0.001). Out of all, 65% of patients achieved both target SBP and DBP values. Hydrochlorothiazide was added to the therapy in 11.6% of patients. There were no significant differences in drug efficacy between the entire group and subgroups of patients with diabetes mellitus and impaired renal function (p = ns). Adverse events were rare and metabolic effect was favorable. CONCLUSION: Monotherapy with losartan in a dosage of 50-100 mg applied during 8 weeks resulted in achieving target values of blood pressure in 65% of patient with mild and moderate hypertension, also including the patients with diabetes mellitus and impaired renal function. Losartan is a safe and metabolically neutral medication.

Changes in motor cortex excitability associated with muscle fatigue in patients with Parkinson's disease.

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.

The efficacy of two protocols for inducing motor cortex plasticity in healthy humans--TMS study.

Stimulation-induced plasticity represents an experimental model of motor cortex reorganization. It can be produced in awaked humans by combining the non-invasive electrical stimulation of somatosensory afferents via mixed peripheral nerves with the transcranial magnetic stimulation (TMS) of the motor cortex. Animal experiments indicate that an application of two converging inputs from various sources in a tightly coupled manner, following the so called Hebbian rule of learning, leads to an increase in motor cortical excitability. The aim of our study was to compare the effects of two plasticity-inducing protocols by quantifying the motor cortex changes using TMS. Plasticity was induced by combining peripheral nerve stimulation with TMS (paired associative stimulation - PAS) and by peripheral motor point stimulation of two adjacent hand muscles (dual associative stimulation - DAS). The protocols were randomly applied in 12 right-handed healthy volunteers. The amplitudes of TMS-induced motor-evoked potentials (MEPs) in the right abductor pollicis brevis muscle were recorded before, immediately after PAS or DAS stimulation, and 10, 20 and 30 min later. Both protocols led to significant and lasting changes in MEP amplitudes, however, a significantly larger increase in MEPs was observed after PAS than DAS. The results indicate that afferent input can differently affect cortical motor circuits and produce variable motor output. Thus, the efficacy of LTP-like mechanisms, presumably involved in Hebbian-like plasticity in humans, varies with the types/origin of the converging inputs. Our findings may be relevant when designing therapeutic interventions for improving motor function after neurological injury or disease.