Transcranial magnetic stimulation for individual identification of the best electrode position for a motor imagery-based brain-computer interface

Background: For the translation of noninvasive motor imagery (MI)-based brain-computer interfaces (BCIs) from the lab environment to end users at their homes, their handling must be improved. As a key component, the number of electroencephalogram (EEG)-recording electrodes has to be kept at a minimum. However, due to inter-individual anatomical and physiological variations, reducing the number of electrodes bares the risk of electrode misplacement, which will directly translate into a limited BCI performance of end users. The aim of the study is to evaluate the use of focal transcranial magnetic stimulation (TMS) as an easy tool to individually optimize electrode positioning for a MI-based BCI. For this, the area of MI-induced mu-rhythm modulation was compared with the motor hand representation area in respect to their localization and to the control performance of a MI-based BCI. Methods: Focal TMS was applied to map the motor hand areas and a 48-channel high-resolution EEG was used to localize MI-induced mu-rhythm modulations in 11 able-bodied, right-handed subjects (5 male, age: 23–31). The online BCI performances of the study participants were assessed with a single next-neighbor Laplace channel consecutively placed over the motor hand area and over the area of the strongest mu-modulation. Results: For most subjects, a consistent deviation between the position of the mu-modulation center and the corresponding motor hand areas well above the localization error could be observed in mediolateral and to a lesser degree in anterior-posterior direction. On an individual level, the MI-induced mu-rhythm modulation was at average found 1.6 cm (standard deviation (SD) = 1.30 cm) lateral and 0.31 cm anterior (SD = 1.39 cm) to the motor hand area and enabled a significantly better online BCI performance than the motor hand areas. Conclusion: On an individual level a trend towards a consistent average spatial distance between motor hand area and mu-rhythm modulation center was found indicating that TMS may be used as a simple tool for quick individual optimization of EEG-recording electrode positions of MI-based BCIs. The study results indicate that motor hand areas of the primary motor cortex determined by TMS are not the main generators of the cortical mu-rhythm

Depolarization and electrical stimulation enhance in vitro and in vivo sensory axon growth after spinal cord injury

Activity dependent plasticity is a key mechanism for the central nervous system (CNS) to adapt to its environment. Whether neuronal activity also influences axonal regeneration in the injured CNS, and whether electrical stimulation (ES) can activate regenerative programs in the injured CNS remains incompletely understood. Using KCl-induced depolarization, in vivo ES followed by ex-vivo neurite growth assays and ES after spinal cord lesions and cell grafting, we aimed to identify parameters important for ES-enhanced neurite growth and axonal regeneration. Using cultures of sensory neurons, neurite growth was analyzed after KCl-induced depolarization for 1-72h. Increased neurite growth was detected after short-term stimulation and after longer stimulation if a sufficient delay between stimulation and growth measurements was provided. After in vivo ES (20Hz, 2× motor threshold, 0.2ms, 1h) of the intact sciatic nerve in adult Fischer344 rats, sensory neurons showed a 2-fold increase in in vitro neurite length one week later compared to sham animals, an effect not observed one day after ES. Longer ES (7h) and repeated ES (7days, 1h each) also increased growth by 56-67% one week later, but provided no additional benefit. In vivo growth of dorsal column sensory axons into a graft of bone marrow stromal cells 4weeks after a cervical spinal cord lesion was also enhanced with a single post-injury 1h ES of the intact sciatic nerve and was also observed after repeated ES without inducing pain-like behavior. While ES did not result in sensory functional recovery, our data indicate that ES has time-dependent influences on the regenerative capacity of sensory neurons and might further enhance axonal regeneration in combinatorial approaches after SCI

An Inducible Tyrosine Kinase Receptor for Axonal Regeneration

The prevention or reduction of neuronal degeneration remains a challenge in neurotrophins therapy. An inducible trkA (ItrkA) system has been shown to regulate embryonic dorsal root ganglion (DRG) neuronal survival and neurite outgrowth in vitro. A new ItrkA plasmid ItrkA-membrane (ItrkAmemb) with one adenine at 3’ terminal was established by correcting the sequence of the original plasmid ItrkA-cytosol (ItrkAcyto). Adult DRGs were dissected from adult Fischer 344 rats (8-14 weeks) for the treatment with AP20187 (membrane-permeable small-molecule ligand), vehicle or NGF (Nerve Growth Factor). Neurite outgrowth assessments were done by manually tracing the longest neurite of each neuron. Cell diameters were also measured and averaged for each well. Protein expression after ItrkAmemb transfection and trkA downstream signaling were investigated by Western-blotting. Neurite length of ItrkAmemb transfected DRGs was not influenced by AP20187 or NGF but cells displayed shorter neurites compared to GFP control groups. While ItrkAcyto transfected DRGs cultured with AP20187 had the longest neurite growth compared to ItrkAmemb transfected neurons and ItrkAcyto transfected cells treated with vehicle or NGF, no significant difference to GFP controls was detected. Quantification of the mean diameter of transfected DRGs demonstrated that ItrkAmemb electroporation significantly increased cell diameter, while the diameter of ItrkAcyto transfected neurons and GFP controls were almost the same as naïve neurons. In contrast to electroporated adult DRG neurons, ItrkAmemb virus transfection did not affect the diameter of infected adult DRG Neurons. No obvious difference was observed between the ItrkAmemb and GFP electroporated cells, and only cells transduced with ItrkAmemb treated with AP20187 seemed to show higher phosphorylation both of Akt and Erk1/2. The effect of adult DRG neurons after ItrkA transfection differs, which depends on the change of cell soma size and/or neurite growth, gene delivery technique, expression level and the localization of ItrkA

Recovery of erectile function comparing autologous nerve grafts, unseeded conduits, Schwann-cell-seeded guidance tubes and GDNF-overexpressing Schwann cell grafts

Dissection of the cavernous nerves during radical prostatectomy for prostate cancer eliminates spontaneous erections. Using the rat as an experimental model, we compared the regenerative capacity of autologous nerve grafts and Schwann-cell-seeded nerve guides. After bilateral excision of cavernous nerve segments, cavernous nerves were reconstructed using unseeded silicon tubes, nerve autografts and silicon tubes seeded with either Glial-cell-line-derived (GDNF)-overexpressing or green fluorescent protein (GFP)-expressing Schwann cells (SCs) (16 study nerves per group). Control groups underwent either a sham operation or bilateral excision of cavernous nerve segments without repair. After 12 weeks erectile function was assessed by neurostimulation and intracavernous pressure (ICP) measurement. The reconstructed nerve segments were excised and histologically analyzed. We demonstrated an intact erectile response upon neurostimulation in 25%(4/16) of autologous nerve grafts, in 50% (8/16) of unseeded tubes, in 75% (12/16) of the Schwann-cell-GFP group and in 93.75% (15/16) of the GDNF group. ICP was significantly increased when comparing the Schwann-cell-GFP group with nerve autografts, unseeded conduits and negative controls (P < 0.005). In conclusion, Schwann-cell-seeded scaffolds combined with neurotrophic factors are superior to unseeded tubes and autologous nerve grafts. They present a promising therapeutic approach for the repair of erectile nerve gaps

Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats

Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI

Mesenchymal Stem Cells Promote Oligodendroglial Differentiation in Hippocampal Slice Cultures

We have previously shown that soluble factors derived from mesenchymal stem cells (MSCs) induce oligodendrogenic fate and differentiation in adult rat neural progenitors (NPCs) in vitro. Here, we investigated if this pro-oligodendrogenic effect is maintained after cells have been transplanted onto rat hippocampal slice cultures, a CNS-organotypic environment. We first tested whether NPCs, that were pre-differentiated in vitro by MSC-derived conditioned medium, would generate oligodendrocytes after transplantation. This approach resulted in the loss of grafted NPCs, suggesting that oligodendroglial pre-differentiated cells could not integrate in the tissue and therefore did not survive grafting. However, when NPCs together with MSCs were transplanted in situ into hippocampal slice cultures, the grafted NPCs survived and the majority of them differentiated into oligodendrocytes. In contrast to the prevalent oligodendroglial differentiation in case of the NPC/MSC co-transplantation, naive NPCs transplanted in the absence of MSCs differentiated predominantly into astrocytes. In summary, the pro-oligodendrogenic activity of MSCs was maintained only after co-transplantation into hippocampal slice cultures. Therefore, in the otherwise astrogenic milieu, MSCs established an oligodendrogenic niche for transplanted NPCs, and thus, co-transplantation of MSCs with NPCs might provide an attractive approach to re-myelinate the various regions of the diseased CNS. Copyright (C) 2009 S. Karger AG, Base

Trainer in a pocket - proof-of-concept of mobile, real-time, foot kinematics feedback for gait pattern normalization in individuals after stroke, incomplete spinal cord injury and elderly patients

Background: Walking disabilities negatively affect inclusion in society and quality of life and increase the risk for secondary complications. It has been shown that external feedback applied by therapists and/or robotic training devices enables individuals with gait abnormalities to consciously normalize their gait pattern. However, little is known about the effects of a technically-assisted over ground feedback therapy. The aim of this study was to assess whether automatic real-time feedback provided by a shoe-mounted inertial-sensor-based gait therapy system is feasible in individuals with gait impairments after incomplete spinal cord injury (iSCI), stroke and in the elderly. Methods: In a non-controlled proof-of-concept study, feedback by tablet computer-generated verbalized instructions was given to individuals with iSCI, stroke and old age for normalization of an individually selected gait parameter (stride length, stance or swing duration, or foot-to-ground angle). The training phase consisted of 3 consecutive visits. Four weeks post training a follow-up visit was performed. Visits started with an initial gait analysis (iGA) without feedback, followed by 5 feedback training sessions of 2–3 min and a gait analysis at the end. A universal evaluation and FB scheme based on equidistant levels of deviations from the mean normal value (1 level = 1 standard deviation (SD) of the physiological reference for the feedback parameter) was used for assessment of gait quality as well as for automated adaptation of training difficulty. Overall changes in level over iGAs were detected using a Friedman’s Test. Post-hoc testing was achieved with paired Wilcoxon Tests. The users’ satisfaction was assessed by a customized questionnaire. Results: Fifteen individuals with iSCI, 11 after stroke and 15 elderly completed the training. The average level at iGA significantly decreased over the visits in all groups (Friedman’s test, p &lt; 0.0001), with the biggest decrease between the first and second training visit (4.78 ± 2.84 to 3.02 ± 2.43, p &lt; 0.0001, paired Wilcoxon test). Overall, users rated the system’s usability and its therapeutic effect as positive. Conclusions: Mobile, real-time, verbalized feedback is feasible and results in a normalization of the feedback gait parameter. The results form a first basis for using real-time feedback in task-specific motor rehabilitation programs. Trial registration: DRKS00011853 , retrospectively registered on 2017/03/23

Magnetic nanoparticle-gel materials for development of joint phantoms for MPI and MRI

To evaluate the performance of commercial as well as custom-made scanners, dedicated phantoms with defined magnetic nanoparticle (MNP) distributions are required. Prerequisite for the development of such phantoms is the establishment of suitable MNP-matrix combinations. In this study, two different gel types were investigated as potential matrix materials: water-based biopolymers and synthetic polymers. These materials exhibit similar imaging behaviour to body tissue in MRI and MPI. Aqueous suspensions of MNP coated with different types of functionalized dextranes were used for embedding particles into the biopolymers, and organic fluids with oleic acid coated MNP for synthetic polymers, respectively. The obtained MNP-matrix combinations were tested for their shape stability. The homogeneity of MNP distribution and immobilization within the matrix was determined by optical investigation of the samples with a microscope, and the magnetic properties of the composite materials measured by vibrating sample magnetometry. From the tested combinations of MNP and matrix material, oleic acid coated MNP embedded in Permagel was found to be the most suitable for the construction of MPI phantoms. This was based on the reliable and homogeneous fixation of the MNP within the matrix without agglomeration of the particles

Feasibility of visual instrumented movement feedback therapy in individuals with motor incomplete spinal cord injury walking on a treadmill

Background: Incomplete spinal cord injury (iSCI) leads to motor and sensory deficits. Even in ambulatory persons with good motor function an impaired proprioception may result in an insecure gait. Limited internal afferent feedback (FB) can be compensated by provision of external FB by therapists or technical systems. Progress in computational power of motion analysis systems allows for implementation of instrumented real-time FB. The aim of this study was to test if individuals with iSCI can normalize their gait kinematics during FB and more importantly maintain an improvement after therapy. Methods: Individuals with chronic iSCI had to complete 6 days (one day per week) of treadmill-based FB training with a 2 weeks pause after 3 days of training. Each day consists of an initial gait analysis followed by 2 blocks with FB/no-FB. During FB the deviation of the mean knee angle during swing from a speed matched reference (norm distance, ND) is visualized as a number. The task consists of lowering the ND, which was updated after every stride. Prior to the tests in patients the in-house developed FB implementation was tested in healthy subjects with an artificial movement task. Results: 4 of 5 study participants benefited from FB in the short and medium term. Decrease of mean ND was highest during the first 3 sessions (from 3.93±1.54 to 2.18±1.04). After the pause mean ND stayed in the same range than before. In the last 3 sessions the mean ND decreased slower (2.40±1.18 to 2.20±0.90). Direct influences of FB ranged from 60% to 15% of reduction in mean ND compared to initial gait analysis and from 20% to 1% compared to no-FB sessions. Conclusions: Instrumented kinematic real-time FB may serve as an effective adjunct to established gait therapies in normalizing the gait pattern after incomplete spinal cord injury. Further studies with larger patient groups need to prove long term learning and the successful transfer of newly acquired skills to activities of daily living