Effects of Long-Term Paired Associative Stimulation on Strength of Leg Muscles and Walking in Chronic Tetraplegia : A Proof-of-Concept Pilot Study

Recovery of lower-limb function after spinal cord injury (SCI) is dependent on the extent of remaining neural transmission in the corticospinal pathway. The aim of this proof-of-concept pilot study was to explore the effects of long-term paired associative stimulation (PAS) on leg muscle strength and walking in people with SCI. Five individuals with traumatic incomplete chronic tetraplegia (>34 months post-injury, motor incomplete, 3 females, mean age 60 years) with no contraindications to transcranial magnetic stimulation (TMS) received PAS to one or both legs for 2 months (28 sessions in total, 5 times a week for the first 2 weeks and 3 times a week thereafter). The participants were evaluated with the Manual Muscle Test (MMT), AIS motor and sensory examination, Modified Asworth Scale (MAS), and the Spinal Cord Independence Measure (SCIM) prior to the intervention, after 1 and 2 months of PAS, and after a 1-month follow-up. The study was registered at (NCT03459885). During the intervention, MMT scores and AIS motor scores increased significantly (p = 0.014 and p = 0.033, respectively). Improvements were stable in follow-up. AIS sensory scores, MAS, and SCIM were not modified significantly. MMT score prior to intervention was a good predictor of changes in walking speed (Radj2 = 0.962). The results of this proof-of-concept pilot study justify a larger trial on the effect of long-term PAS on leg muscle strength and walking in people with chronic incomplete SCI.Peer reviewe

Restoration of hand function with long-term paired associative stimulation after chronic incomplete tetraplegia: a case study

INTRODUCTION: This case study explores the gains in hand function in an individual with a chronic spinal cord injury (SCI). The intervention was long-term paired associative simulation (PAS). We aimed to provide PAS until full recovery of hand muscle strength occurred, or until improvements ceased. CASE PRESENTATION: A 46-year-old man with traumatic C7 AIS B tetraplegia was administered PAS three times per week. After 24 weeks, PAS was combined with concomitant motor training of the remaining weak hand muscles. Outcome measures included the manual muscle test (MMT), motor-evoked potentials (MEPs), F-responses, hand functional tests, and the spinal cord independence measure (SCIM). DISCUSSION: After 47 weeks of PAS the subject had improved self-care and indoor mobility and was able to perform complex motor tasks (SCIM score improved from 40 to 56). His left hand regained maximum MMT score (total 75; increase of score from baseline condition 19); the effect remained stable in the 32-week follow up. In the right-hand muscles, MMT scores of 4-5 were observed in follow up (total 71; increase from baseline 48). Improved values were also observed in other outcomes. This is the first demonstration of long-term PAS restoring muscle strength corresponding to MMT scores of 4-5 in an individual with chronic SCI. The effect persisted for several months, indicating that PAS induces stable plastic changes in the corticospinal pathway.Peer reviewe

Effect of long-term paired associative stimulation on the modulation of cortical sensorimotor oscillations after spinal cord injury

Study design A prospective interventional case series. Objectives To explore changes in the modulation of cortical sensorimotor oscillations after long-term paired associative stimulation (PAS) in participants with spinal cord injury (SCI). Setting BioMag Laboratory, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Methods Five patients with chronic incomplete SCI received unilateral spinal PAS to upper limb for 16-22 days. Changes in the modulation of sensorimotor oscillations in response to tactile stimulus and active and imaginary hand movements were assessed with magnetoencephalography recorded before and after the intervention. Results PAS restored the modulation of sensorimotor oscillations in response to active hand movement in four patients, whereas the modulation following tactile stimulation remained unaltered. The observed change was larger in the hemisphere that received PAS and preceded the clinical effect of the intervention. Conclusions Long-term spinal PAS treatment, which enhances the motor functions of SCI patients, also restores the modulation of cortical sensorimotor oscillations.Peer reviewe

Clinical use of fungal PCR from deep tissue samples in the diagnosis of invasive fungal diseases : a retrospective observational study

Objectives: To assess the clinical use of panfungal PCR for diagnosis of invasive fungal diseases (IFDs). We focused on the deep tissue samples. Methods: We first described the design of panfungal PCR, which is in clinical use at Helsinki University Hospital. Next we retrospectively evaluated the results of 307 fungal PCR tests performed from 2013 to 2015. Samples were taken from normally sterile tissues and fluids. The patient population was nonselected. We classified the likelihood of IFD according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG), comparing the fungal PCR results to the likelihood of IFD along with culture and microscopy results. Results: There were 48 positive (16%) and 259 negative (84%) PCR results. The sensitivity and specificity of PCR for diagnosing IFDs were 60.5% and 91.7%, respectively, while the negative predictive value and positive predictive value were 93.4% and 54.2%, respectively. The concordance between the PCR and the culture results was 86% and 87% between PCR and microscopy, respectively. Of the 48 patients with positive PCR results, 23 had a proven or probable IFD. Conclusions: Fungal PCR can be useful for diagnosing IFDs in deep tissue samples. It is beneficial to combine fungal PCR with culture and microscopy. M. Ala-Houhala, Clin Microbiol Infect 2018;24:301 (C) 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand

A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38-68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0-5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 +/- 0.17 points (p <0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 +/- 29%, p = 0.046, n = 5 patients). Longterm PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.Peer reviewe

Association between CMD signs and symptoms, oral parafunctions, race and sex, in 4–6-year-old African-American and Caucasian children

The associations between oral parafunctions, signs and symptoms of craniomandibular disorders (CMD), race, and sex were analysed in recordings from 203 4-6-year-old African-American and Caucasian children. Significant correlations were found between bruxism, nail biting, thumb sucking and most of the CMD signs and symptoms. There were also significant associations between most of the signs and symptoms and race, while significant association with sex was found only regarding headache, TMJ sounds and chewing pain. Significant associations were found between most CMD signs and TMJ sounds supporting the view that joint sound recordings have diagnostic value. There were also significant associations between the pain variables recorded by questionnaire and those recorded by palpation, which indicates that reliable data can be obtained by interviewing children as young as five. The results of this study support the concept that oral parafunctions have a significant role in the aetiology of CMD. The results also show that race and sex need to be considered when analysing the possible aetiological role of oral parafunctions in CMD. Longitudinal studies, beginning with low age groups are needed to better determine the role of childhood oral parafunctions in CMD aetiology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75673/1/j.1365-2842.1995.tb00241.x.pd

The use of electronic coil location control for focal magnetic stimulation at the cervical level

Background Accurate re-positioning of the coil is challenging in magnetic stimulation at the cervical spinal level. The applicability of coil location control for this type of stimulation is unexplored. New method Utilizing a figure-of-eight coil and anatomy-specific models of the magnetic stimulation system, we developed a novel technique that enables probing corticospinal excitability at the cervical spinal level. Magnetic stimulation was performed in 9 healthy subjects at C2-C6 spinal levels using a figure-of-eight coil and a coil tracking system. MEPs were recorded from the abductor digiti minimi muscle. The functioning of the coil tracking system was tested with an estimated electric field maximum (eEFM) above the C1 cervical level (group 1) and below (group 2). Motor-evoked potential (MEP) reproducibility was assessed with intra-class correlation coefficient (ICC). Results The use of coil location control in cervical level focal magnetic stimulation enabled the recording of highly reproducible MEPs. Within one co-registration, the ICC 95% confidence interval (CI) in group 1 was 0.89-0.99 and in group 2 was 0.24-0.85. Comparison with existing methods and conclusions This method can be used for accurate maintenance and retrieval of the focal coil position at the cervical level with low spatial variability during stimulation. Existing methodologies employ determination of the coil location based on external landmarks, which makes the procedure cumbersome. This technique can optimize existing stimulation protocols and facilitate development of navigated spinal stimulation.Peer reviewe

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain : A Pilot Trial

Objectives Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. Materials and Methods This prospective, randomized, double-blind, Sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations, and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. Results We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of >= 30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or Sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. Conclusions S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.Peer reviewe

Paired associative stimulation improves hand function after nontraumatic spinal cord injury: a case series

Objectives Long-term paired associative stimulation (PAS) is a non-invasive combination of transcranial magnetic stimulation and peripheral nerve stimulation and leads to improved hand motor function in individuals with incomplete traumatic tetraplegia. Spinal cord injuries (SCIs) can also be induced by neurological diseases. We tested a similar long-term PAS approach in patients with nontraumatic neurological SCI. Methods In this case series five patients with nontraumatic tetraplegia received PAS to the weaker upper limb 3 to 5 times per week for 6 weeks. Patients were evaluated with manual muscle testing (MMT) before and immediately after therapy and at the 1- and 6-month follow ups. Patients were also evaluated for spasticity, hand mechanical and digital dynamometry, pinch, and Box and Blocks tests. Results All patients had improved MMT values at all post-PAS evaluations. The mean±standard error MMT increase was 1.44±0.37 points (p=0.043) immediately after PAS, 1.57±0.4 points (p=0.043) at the 1-month follow-up, and 1.71±0.47 points (p=0.043) at the 6-month follow up. The pinch, digital dynamometry values, and Box and Blocks test results also improved in all patients. Conclusions Long-term PAS may be a safe and effective treatment for improving hand function in patients with nontraumatic tetraplegia. Significance This is the first report demonstrating the therapeutic potential of PAS for neurological SCI.Peer reviewe