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

ABSTRACT: 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 clinicaltrials.gov (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.

SUBMITTER: Rodionov A

PROVIDER: S-EPMC7251052 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Rodionov Andrei A Savolainen Sarianna S Kirveskari Erika E Mäkelä Jyrki P JP Shulga Anastasia A

Frontiers in neurology 20200520

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 trans ...[more]

PMID: 32508738

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Project description:OBJECTIVE:To determine whether neurophysiological mechanisms indicating cortical excitability, long-term potentiation (LTP)-like plasticity, GABAergic and glutamatergic function are altered in patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response. METHODS:Neurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender-matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation-derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP-like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging. RESULTS:PAS-induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor-evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS-induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = -0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow-up assessments were available in six patients and demonstrated parallel improvement of PAS-induced plasticity and mRS. INTERPRETATION:Assessment of PAS-induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well-tolerated "electrophysiological biomarker" to monitor therapy response in the future. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov: Identifier: NCT01865578.

Project description:BackgroundPeople with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain-computer interface (iBCI).MethodsWe recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041.FindingsThe intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant).InterpretationTo our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis.FundingNational Institutes of Health, Department of Veterans Affairs.

Project description:Advances in our understanding of neural plasticity have prompted the emergence of neuromodulatory interventions, which modulate corticomotor excitability (CME) and hold potential for accelerating stroke recovery. Endogenous paired associative stimulation (ePAS) involves the repeated pairing of a single pulse of peripheral electrical stimulation (PES) with endogenous movement-related cortical potentials (MRCPs), which are derived from electroencephalography. However, little is known about the optimal parameters for its delivery. A factorial design with repeated measures delivered four different versions of ePAS, in which PES intensities and movement type were manipulated. Linear mixed models were employed to assess interaction effects between PES intensity (suprathreshold (Hi) and motor threshold (Lo)) and movement type (Voluntary and Imagined) on CME. ePAS interventions significantly increased CME compared to control interventions, except in the case of Lo-Voluntary ePAS. There was an overall main effect for the Hi-Voluntary ePAS intervention immediately post-intervention (p = 0.002), with a sub-additive interaction effect at 30 min' post-intervention (p = 0.042). Hi-Imagined and Lo-Imagined ePAS significantly increased CME for 30 min post-intervention (p = 0.038 and p = 0.043 respectively). The effects of the two PES intensities were not significantly different. CME was significantly greater after performing imagined movements, compared to voluntary movements, with motor threshold PES (Lo) 15 min post-intervention (p = 0.012). This study supports previous research investigating Lo-Imagined ePAS and extends those findings by illustrating that ePAS interventions that deliver suprathreshold intensities during voluntary or imagined movements (Hi-Voluntary and Hi-Imagined) also increase CME. Importantly, our findings indicate that stimulation intensity and movement type interact in ePAS interventions. Factorial designs are an efficient way to explore the effects of manipulating the parameters of neuromodulatory interventions. Further research is required to ensure that these parameters are appropriately refined to maximise intervention efficacy for people with stroke and to support translation into clinical practice.

Project description:Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cognition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China (approval No. TJ-A20151102) on July 11, 2015.

Dataset Information

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

Publications

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

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