The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760]

BACKGROUND: Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions. RESULTS: We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels. CONCLUSION: We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation

Mapping the cortical representation of the lumbar paravertebral muscles

Objective: The aim of this study was to map the cortical representation of the lumbar spine paravertebral (LP) muscles in healthy subjects. Methods: Transcranial magnetic stimulation (TMS) was employed to map the cortical representations of the LP muscles at two sites. Stimuli were applied to points on a grid representing scalp positions. The amplitude of motor evoked potentials (n = 6) was averaged for each position. Results: The optimal site for evoking responses in the contralateral LP muscles was situated 1 cm anterior and 4 cm lateral to the vertex. Ipsilateral responses were evoked from sites lateral to the optimal site for evoking contralateral responses. Contralateral responses were also obtained from areas anterior to the optimal site. Conclusions: Maps of these muscles can be produced. The results suggest discrete contra- and ipsilateral cortical projections. Anterior sites at which excitation can be evoked may indicate projections arising in the SMA are involved. Significance: This study provides normative data regarding the cortical representation of the paravertebral muscles and provides a technique for evaluating cortical motor plasticity in patients presenting with spinal pathologies

Polarity-Specific Cortical Effects of Transcranial Direct Current Stimulation in Primary Somatosensory Cortex of Healthy Humans

Transcranial direct current stimulation (tDCS) is a noninvasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1). We measured paired-pulse suppression (PPS) of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by paired-pulse suppression. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS

Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the relationship between chronic neuropathic pain after incomplete peripheral nerve lesion, chronic nociceptive pain due to osteoarthritis, and the excitability of the motor cortex assessed by transcranial magnetic stimulation (TMS). Hence in 26 patients with neuropathic pain resulting from an isolated incomplete lesion of the median or ulnar nerve (neuralgia), 20 patients with painful osteoarthritis of the hand, and 14 healthy control subjects, the excitability of the motor cortex was tested using paired-pulse TMS to assess intracortical inhibition and facilitation. These excitability parameters were compared between groups, and the relationship between excitability parameters and clinical parameters was examined.</p> <p>Results</p> <p>We found a significant reduction of intracortical inhibition in the hemisphere contralateral to the lesioned nerve in the neuralgia patients. Intracortical inhibition in the ipsilateral hemisphere of neuralgia patients and in both hemispheres of osteoarthritis patients did not significantly differ from the control group. Disinhibition was significantly more pronounced in neuralgia patients with moderate/severe pain intensity than in patients with mild pain intensity, whereas the relative compound motor action potential as a parameter of nerve injury severity did not correlate with the amount of disinhibition.</p> <p>Conclusions</p> <p>Our results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry.</p

Motor cortex excitability and BDNF levels in chronic musculoskeletal pain according to structural pathology

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19-65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0-10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0-10) during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inteThis research was supported by grants and materials support from the following Brazilian agencies: (grants to; AD, JAD-S, FC) and material support. National Council for Scientific and Technological Development-CNPq (grants to ILdST, WC). Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul (material support). International Cooperation Program-CAPES-PGI-project (023-11). CAPES 129/2013 material support and grant for FP as visiting professor (AD, WC, PP). Postgraduate Research Group at the Hospital de Clinicas de Porto Alegre-PIPE HCPA (material support). Foundation for Support of Research at Rio Grande do Sul (FAPERGS) (material support). Brazilian Innovation Agency (FINEP) process number-1245/13 (ILdST, WC). Research grant: National Council for Scientific and Technological Development-CNPq (ILdS 302345/2011-6 and WC-301256/2013-6)

A Randomized and Controlled Crossover Study Investigating the Improvement of Walking and Posture Functions in Chronic Stroke Patients Using HAL Exoskeleton – The HALESTRO Study (HAL-Exoskeleton STROke Study)

Background: The exoskeleton HAL (hybrid assistive limb) has proven to improve walking functions in spinal cord injury and chronic stroke patients when using it for body-weight supported treadmill training (BWSTT). Compared with other robotic devices, it offers the possibility to initiate movements actively. Previous studies on stroke patients did not compare HAL-BWSTT with conventional physiotherapy (CPT). Therefore, we performed a crossover clinical trial comparing CPT and HAL-BWSTT in chronic stroke patients with hemiparesis, the HALESTRO study. Our hypothesis was that HAL-training would have greater effects on walking and posture functions compared to a mixed-approach CPT.Methods: A total of 18 chronic stroke patients participated in this study. Treatment consisted of 30 CPT sessions and of 30 sessions of BWSTT with a double leg type HAL exoskeleton successively in a randomized, crossover study design. Primary outcome parameters were walking time and speed in 10-meter walk test (10MWT), time in timed-up-and-go test (TUG) and distance in 6-min walk test (6MWT). Secondary outcome parameters were the functional ambulatory categories (FAC) and the Berg-Balance Scale (BBS). Data were assessed at baseline, at crossover and at the end of the study, all without using and wearing HAL.Results: Our study demonstrate neither a significant difference in walking parameters nor in functional and balance parameters. When HAL-BWSTT was applied to naïve patients, it led to an improvement in walking parameters and in balance abilities. Pooling all data, we could show a significant effect in 10MWT, 6MWT, FAC and BBS, both therapies sequentially applied over 12 weeks. Thereby, FAC improve from dependent to independent category (3 to 4). One patient dropped out of the study due to intensive fatigue after each training session.Conclusion: HAL-BWSTT and mixed-approach CPT were effective therapies in chronic stroke patients. However, compared with CPT, HAL training with 30 sessions over 6 weeks was not more effective. The combination of both therapies led to an improvement of walking and balance functions. Robotic rehabilitation of walking disorders alone still lacks the proof of superiority in chronic stroke. Robotic treatment therapies and classical CPT rehabilitation concepts should be applied in an individualized therapy program

Feldenkrais method and movement education - An alternate therapy in musculoskeletal rehabilitation

Introduction Feldenkrais method (FM) is a movement education technique that emphasizes movement teaching based on sensory motor awareness and cognitive perception of the movement. Although this technique gained popularity in different parts of the world, it is still regarded as a non-conventional science. Aim Absence of in-depth review and high quality scientific studies in this technique necessitates the need for generation of knowledge and scientific review on this efficient method. Discussion This current review paper made an effort to provide conventional scientific explanation about this method that suits the medical paradigm. In this paper, a brief introduction followed by description of the technique is given with a clinical example toward its application. Furthermore, the neurophysiologic explanation and mechanical concepts are provided in the conventional scientific manner. Indications, contra indications and clinical implications were also discussed to accommodate the clinical practice in musculoskeletal rehabilitation. Conclusions Feldenkrais exercises can be used as an alternative therapy in musculoskeletal rehabilitation for movement education

Corticospinal excitability as a biomarker of myofascial pain syndrome

Abstract Introduction: Myofascial pain syndrome (MPS) is a common chronic pain disorder that lacks effective diagnostic criteria. To better understand neurophysiological changes in chronic pain, several trials exploring corticospinal excitability in different populations of patients with chronic pain have been performed. Objectives: In this systematic review, we aimed to investigate the current literature on MPS and intracortical disinhibition, by means of increased intracortical facilitation and decreased intracortical inhibition (ICI). Methods: We performed a search on PubMed to identify clinical trials on MPS and transcranial magnetic stimulation measurements. We then applied the Harford Hill criteria to the identified studies to assess the possible causal relationship between intracortical disinhibition measurements and MPS. Finally, we compared our findings on MPS with other chronic pain conditions. Results: Four studies assessing corticospinal excitability in patients with MPS were found. Although the amount of trials available is limited, all the reported studies indicated an increased intracortical disinhibition in patients with MPS. Importantly, these measurements were also correlated with psychological factors, such as pain catastrophism, or anxiety. However, based on the Harford Hill criteria, we could not assert a strong causal relationship between these markers and MPS. Although intracortical disinhibition has been consistently found in patients having MPS, this lack of cortical inhibition was not only observed in this specific chronic pain syndrome but also in fibromyalgia and neuropathic pain conditions. Conclusion: Intracortical disinhibition seems to be a marker that has been consistently observed in MPS. Future prospective cohort studies could provide new insights in the development of neoplastic and maladaptive changes occurring in chronic pain syndromes and help the development of new therapeutic options

Epoxidation of (E,E)-cinnamylideneacetophenones with hydrogen peroxide and iodosylbenzene with salen-mnIII as the catalyst

(E,E)-Cinnamylideneacetophenones 3a–j were epoxidized under mild conditions with Jacobsen’s catalyst 4 and hydrogen peroxide or iodosylbenzene as oxidants. γ,δ-Monoepoxides and a diastereomeric mixture of α,β:γ,δ-diepoxides were obtained in each case, and only the α,β-monoepoxide of 4- nitrocinnamylideneacetophenone (3d) was isolated. The presence of a methyl group in the vinylic moiety of substrates 3i,j allowed the formation of two γ,δ-monoepoxide diastereomers. The epoxidation of (E,E)-2 -hydroxycinnamylid- Introduction Salen MnIII complexes are efficient catalysts for the epoxidation of various olefinic compounds.[1–3] Since the pioneering work of Kochi et al.,[4] many contributors have reviewed a wide range of applications of these powerful and selective catalysts.[5–7] Several oxidants have been used as effective oxygen donors in these epoxidations, with iodosylbenzene[ 8–11] and sodium hypochlorite[12–14] being the most frequently reported. Among other common olefin oxidants hydrogen peroxide,[15–17] oxone®,[18] dimethyldioxirane (DMD),[19–23] m-chloroperbenzoic acid (MCPBA),[24] molecular oxygen[25] and more recently also tetrabutylammonium monosulfate[24,26,27] and tetrabutylammonium periodate[ 28] have been used. Alkene epoxidation can also be achieved with simple co-catalysts such as imidazoles, pyridines and tertiary amine N-oxides, which act as axial ligands and, in some cases, as phase-transfer catalysts.[29–31] [a] Department of Agro-Industries, Escola Superior Agrária de Bragança, 5301-855 Bragança, Portugal Fax: +351-273-325405 E-mail: [email protected] [b] Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Fax: +351-234-370084 E-mail: [email protected] [c] Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary Fax: +36-52-453836 E-mail: [email protected] Eur. J. Org. Chem. 2007, 2877–2887 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2877 eneacetophenones 3h,j led to the formation of the corresponding γ,δ-monoepoxides as well as (E)-2,3-trans-3-hydroxy- 2-styryl-4-chromanones, which originated from the in situ cyclisation of 2,3-epoxy-1-(2-hydroxyphenyl)-5-phenyl- 4-penten-1-ones. The structures of all new compounds and the stereochemistry of the mono- and diepoxide diastereomers were established by NMR studies