Electrophysiological Correlates of Dentate Nucleus Deep Brain Stimulation for Poststroke Motor Recovery.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

Neurostimulation After Stroke.

Neural stimulation technology aids stroke survivors in regaining lost motor functions. This article explores its applications in upper and lower limb stroke rehabilitation. The authors review various methods to target the corticomotor system, including transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. In addition, the authors review the use of peripheral neuromuscular electrical stimulation for therapeutic and assistive purposes, including transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, and functional electrical stimulation. For each, the authors examine the potential benefits, limitations, safety considerations, and FDA status.

Contralaterally controlled functional electrical stimulation video game therapy for hand rehabilitation after stroke: a randomized controlled trial.

PURPOSE: To estimate the effect of integrating custom-designed hand therapy video games (HTVG) with contralaterally controlled functional electrical stimulation (CCFES) therapy. METHODS: Fifty-two stroke survivors with chronic (>6 months) upper limb hemiplegia were randomized to 12 weeks of CCFES or CCFES + HTVG. Treatment involved self-administration of technology-mediated therapy at home plus therapist-administered CCFES-assisted task practice in the lab. Pre- and post-treatment assessments were made of hand dexterity, upper limb impairment and activity limitation, and cognitive function. RESULTS: No significant between-group differences were found on any outcome measure, and the average magnitudes of improvement within both groups were small. The incidence of technical problems with study devices at home was greater for the CCFES + HTVG group. This negatively affected adherence and may partially explain the absence of effect of HTVG. At end-of-treatment, large majorities of both treatment groups had positive perceptions of treatment efficacy and expressed enthusiasm for the treatments. CONCLUSION: This study makes an important contribution to the research literature on the importance of environmental factors, concomitant impairments, and technology simplification when designing technology-based therapies intended to be self-administered at home. This study failed to show any added benefit of HTVG to CCFES therapy.Clinicaltrials.gov (NCT03058796).

Contralaterally controlled functional electrical stimulation (CCFES) is an emerging therapy for upper limb rehabilitation after stroke that is designed, in part, to be self-administered at home.While movement-soliciting video games have shown promise in rehabilitation, this study failed to show a significant added benefit of integrating CCFES with hand therapy video games.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of making every component of rehabilitation technology as user friendly and trouble-free as possible.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of assuring that the home environment is conducive to home-based therapy.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke.

Background: Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections. Objective: The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity. Methods: Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions. Results: Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants. Conclusions: Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants. Trial Registration: ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012.

Contralaterally Controlled Functional Electrical Stimulation Combined With Brain Stimulation for Severe Upper Limb Hemiplegia-Study Protocol for a Randomized Controlled Trial.

Background: Approximately two-thirds of stroke survivors experience chronic upper limb paresis, and of them, 50% experience severe paresis. Treatment options for severely impaired survivors are often limited. Rehabilitation involves intensively engaging the paretic upper limb, and disincentivizing use of the non-paretic upper limb, with the goal to increase excitability of the ipsilesional primary motor cortex (iM1) and suppress excitability of the undamaged (contralesional) motor cortices, presumed to have an inhibitory effect on iM1. Accordingly, brain stimulation approaches, such as repetitive transcranial magnetic stimulation (rTMS), are also given to excite iM1 and/or suppress contralesional motor cortices. But such approaches aimed at ultimately increasing iM1 excitability yield limited functional benefit in severely impaired survivors who lack sufficient ipsilesional substrate. Aim: Here, we test the premise that combining Contralaterally Controlled Functional Electrical Stimulation (CCFES), a rehabilitation technique that engages the non-paretic upper limb in delivery of neuromuscular electrical stimulation to the paretic upper limb, and a new rTMS approach that excites intact, contralesional higher motor cortices (cHMC), may have more favorable effect on paretic upper limb function in severely impaired survivors based on recruitment of spared, transcallosal and (alternate) ipsilateral substrate. Methods: In a prospective, double-blind, placebo-controlled RCT, 72 chronic stroke survivors with severe distal hand impairment receive CCFES plus cHMC rTMS, iM1 rTMS, or sham rTMS, 2X/wk for 12wks. Measures of upper limb motor impairment (Upper Extremity Fugl Meyer, UEFM), functional ability (Wolf Motor-Function Test, WMFT) and perceived disability are collected at 0, 6, 12 (end-of-treatment), 24, and 36 wks (follow-up). TMS is performed at 0, 12 (end-of-treatment), and 36 wks (follow-up) to evaluate inter-hemispheric and ipsilateral mechanisms. Influence of baseline severity is also characterized with imaging. Conclusions: Targeting of spared neural substrates and rehabilitation which engages the unimpaired limb in movement of the impaired limb may serve as a suitable combinatorial treatment option for severely impaired stroke survivors. ClinicalTrials No: NCT03870672.

Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial.

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target. CPMd can offer alternate, bi-hemispheric and ipsilateral connections in support of paretic limb movement. This pilot, randomized clinical trial seeks to investigate whether rTMS delivered to facilitate cPMd in conjunction with rehabilitation produces greater gains in motor function than conventional rTMS delivered to facilitate iM1 in conjunction with rehabilitation in severely impaired stroke survivors. Twenty-four chronic (≥6 months) stroke survivors with severe loss of ipsilesional substrate (defined by the absence of physiologic evidence of excitable residual pathways tested using TMS) will be included. Participants will be randomized to receive rTMS to facilitate cPMd or iM1 in conjunction with task-oriented upper limb rehabilitation given for 2 sessions/week for 6 weeks. Assessments of primary outcome related to motor impairment (upper extremity Fugl-Meyer [UEFM]), motor function, neurophysiology, and functional neuroimaging will be made at baseline and at 6-week end-of-treatment. An additional assessment of motor outcomes will be repeated at 3-month follow-up to evaluate retention. The primary endpoint is 6-week change in UEFM. This pilot trial will provide preliminary evidence on the effects and mechanisms associated with facilitating intact cPMd in chronic severe stroke survivors. The trial is registered on clinicaltrials.gov, NCT03868410.

The ß-encapsulation cage of rearrangement hotspot (Rhs) effectors is required for type VI secretion.

Bacteria deploy rearrangement hotspot (Rhs) proteins as toxic effectors against both prokaryotic and eukaryotic target cells. Rhs proteins are characterized by YD-peptide repeats, which fold into a large ß-cage structure that encapsulates the C-terminal toxin domain. Here, we show that Rhs effectors are essential for type VI secretion system (T6SS) activity in Enterobacter cloacae (ECL). ECL rhs- mutants do not kill Escherichia coli target bacteria and are defective for T6SS-dependent export of hemolysin-coregulated protein (Hcp). The RhsA and RhsB effectors of ECL both contain Pro-Ala-Ala-Arg (PAAR) repeat domains, which bind the ß-spike of trimeric valine-glycine repeat protein G (VgrG) and are important for T6SS activity in other bacteria. Truncated RhsA that retains the PAAR domain is capable of forming higher-order, thermostable complexes with VgrG, yet these assemblies fail to restore secretion activity to ∆rhsA ∆rhsB mutants. Full T6SS-1 activity requires Rhs that contains N-terminal transmembrane helices, the PAAR domain, and an intact ß-cage. Although ∆rhsA ∆rhsB mutants do not kill target bacteria, time-lapse microscopy reveals that they assemble and fire T6SS contractile sheaths at ∼6% of the frequency of rhs+ cells. Therefore, Rhs proteins are not strictly required for T6SS assembly, although they greatly increase secretion efficiency. We propose that PAAR and the ß-cage provide distinct structures that promote secretion. PAAR is clearly sufficient to stabilize trimeric VgrG, but efficient assembly of T6SS-1 also depends on an intact ß-cage. Together, these domains enforce a quality control checkpoint to ensure that VgrG is loaded with toxic cargo before assembling the secretion apparatus.

Stratifying chronic stroke patients based on the influence of contralesional motor cortices: An inter-hemispheric inhibition study.

OBJECTIVE: A recent "bimodal-balance recovery" model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. METHODS: Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21). RESULTS: Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40-46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction. CONCLUSIONS: A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. SIGNIFICANCE: The criterion may be used to stratify patients to design targeted, precision treatments.

Bilateral Contralaterally Controlled Functional Electrical Stimulation Reveals New Insights Into the Interhemispheric Competition Model in Chronic Stroke.

Background. Upper-limb chronic stroke hemiplegia was once thought to persist because of disproportionate amounts of inhibition imposed from the contralesional on the ipsilesional hemisphere. Thus, one rehabilitation strategy involves discouraging engagement of the contralesional hemisphere by only engaging the impaired upper limb with intensive unilateral activities. However, this premise has recently been debated and has been shown to be task specific and/or apply only to a subset of the stroke population. Bilateral rehabilitation, conversely, engages both hemispheres and has been shown to benefit motor recovery. To determine what neurophysiological strategies bilateral therapies may engage, we compared the effects of a bilateral and unilateral based therapy using transcranial magnetic stimulation. Methods. We adopted a peripheral electrical stimulation paradigm where participants received 1 session of bilateral contralaterally controlled functional electrical stimulation (CCFES) and 1 session of unilateral cyclic neuromuscular electrical stimulation (cNMES) in a repeated-measures design. In all, 15 chronic stroke participants with a wide range of motor impairments (upper extremity Fugl-Meyer score: 15 [severe] to 63 [mild]) underwent single 1-hour sessions of CCFES and cNMES. We measured whether CCFES and cNMES produced different effects on interhemispheric inhibition (IHI) to the ipsilesional hemisphere, ipsilesional corticospinal output, and ipsilateral corticospinal output originating from the contralesional hemisphere. Results. CCFES reduced IHI and maintained ipsilesional output when compared with cNMES. We found no effect on ipsilateral output for either condition. Finally, the less-impaired participants demonstrated a greater increase in ipsilesional output following CCFES. Conclusions. Our results suggest that bilateral therapies are capable of alleviating inhibition on the ipsilesional hemisphere and enhancing output to the paretic limb.

Transcranial direct current stimulation (tDCS) paired with massed practice training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: A pilot study.

OBJECTIVE: Our goal was to determine if pairing transcranial direct current stimulation (tDCS) with rehabilitation for two weeks could augment adaptive plasticity offered by these residual pathways to elicit longer-lasting improvements in motor function in incomplete spinal cord injury (iSCI). DESIGN: Longitudinal, randomized, controlled, double-blinded cohort study. SETTING: Cleveland Clinic Foundation, Cleveland, Ohio, USA. PARTICIPANTS: Eight male subjects with chronic incomplete motor tetraplegia. INTERVENTIONS: Massed practice (MP) training with or without tDCS for 2 hrs, 5 times a week. OUTCOME MEASURES: We assessed neurophysiologic and functional outcomes before, after and three months following intervention. Neurophysiologic measures were collected with transcranial magnetic stimulation (TMS). TMS measures included excitability, representational volume, area and distribution of a weaker and stronger muscle motor map. Functional assessments included a manual muscle test (MMT), upper extremity motor score (UEMS), action research arm test (ARAT) and nine hole peg test (NHPT). RESULTS: We observed that subjects receiving training paired with tDCS had more increased strength of weak proximal (15% vs 10%), wrist (22% vs 10%) and hand (39% vs. 16%) muscles immediately and three months after intervention compared to the sham group. Our observed changes in muscle strength were related to decreases in strong muscle map volume (r=0.851), reduced weak muscle excitability (r=0.808), a more focused weak muscle motor map (r=0.675) and movement of weak muscle motor map (r=0.935). CONCLUSION: Overall, our results encourage the establishment of larger clinical trials to confirm the potential benefit of pairing tDCS with training to improve the effectiveness of rehabilitation interventions for individuals with SCI. TRIAL REGISTRATION: NCT01539109.

Exposure to Low-Dose X-Ray Radiation Alters Bone Progenitor Cells and Bone Microarchitecture.

Exposure to high-dose ionizing radiation during medical treatment exerts well-documented deleterious effects on bone health, reducing bone density and contributing to bone growth retardation in young patients and spontaneous fracture in postmenopausal women. However, the majority of human radiation exposures occur in a much lower dose range than that used in the radiation oncology clinic. Furthermore, very few studies have examined the effects of low-dose ionizing radiation on bone integrity and results have been inconsistent. In this study, mice were irradiated with a total-body dose of 0.17, 0.5 or 1 Gy to quantify the early (day 3 postirradiation) and delayed (day 21 postirradiation) effects of radiation on bone microarchitecture and bone marrow stromal cells (BMSCs). Female BALBc mice (4 months old) were divided into four groups: irradiated (0.17, 0.5 and 1 Gy) and sham-irradiated controls (0 Gy). Micro-computed tomography analysis of distal femur trabecular bone from animals at day 21 after exposure to 1 Gy of X-ray radiation revealed a 21% smaller bone volume (BV/TV), 22% decrease in trabecular numbers (Tb.N) and 9% greater trabecular separation (Tb.Sp) compared to sham-irradiated controls (P < 0.05). We evaluated the differentiation capacity of bone marrow stromal cells harvested at days 3 and 21 postirradiation into osteoblast and adipocyte cells. Osteoblast and adipocyte differentiation was decreased when cells were harvested at day 3 postirradiation but enhanced in cells isolated at day 21 postirradiation, suggesting a compensatory recovery process. Osteoclast differentiation was increased in 1 Gy irradiated BMSCs harvested at day 3 postirradiation, but not in those harvested at day 21 postirradiation, compared to controls. This study provides evidence of an early, radiation-induced decrease in osteoblast activity and numbers, as well as a later recovery effect after exposure to 1 Gy of X-rays, whereas osteoclastogenesis was enhanced. A better understanding of the effects of radiation on osteoprogenitor cell populations could lead to more effective therapeutic interventions that protect bone integrity for individuals exposed to low-dose ionizing radiation.

Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation.

OBJECTIVE: The standard approach to brain stimulation in stroke is based on the premise that ipsilesional M1 (iM1) is important for motor function of the paretic upper limb, while contralesional cortices compete with iM1. Therefore, the approach typically advocates facilitating iM1 and/or inhibiting contralesional M1 (cM1). But, this approach fails to elicit much improvement in severely affected patients, who on account of extensive damage to ipsilesional pathways, cannot rely on iM1. These patients are believed to instead rely on the undamaged cortices, especially the contralesional dorsal premotor cortex (cPMd), for support of function of the paretic limb. Here, we tested for the first time whether facilitation of cPMd could improve paretic limb function in severely affected patients, and if a cut-off could be identified to separate responders to cPMd from responders to the standard approach to stimulation. METHODS: In a randomized, sham-controlled crossover study, fifteen patients received the standard approach of stimulation involving inhibition of cM1 and a new approach involving facilitation of cPMd using repetitive transcranial magnetic stimulation (rTMS). Patients also received rTMS to control areas. At baseline, impairment [Upper Extremity Fugl-Meyer (UEFMPROXIMAL, max=36)] and damage to pathways [fractional anisotropy (FA)] was measured. We measured changes in time to perform proximal paretic limb reaching, and neurophysiology using TMS. RESULTS: Facilitation of cPMd generated more improvement in severely affected patients, who had experienced greater damage and impairment than a cut-off value of FA (0.5) and UEFMPROXIMAL (26-28). The standard approach instead generated more improvement in mildly affected patients. Responders to cPMd showed alleviation of interhemispheric competition imposed on iM1, while responders to the standard approach showed gains in ipsilesional excitability in association with improvement. CONCLUSIONS: A preliminary cut-off level of severity separated responders for standard approach vs. facilitation of cPMd. SIGNIFICANCE: Cut-offs identified here could help select candidates for tailored stimulation in future studies so patients in all ranges of severity could potentially achieve maximum benefit in function of the paretic upper limb.

Transcranial Direct Current Stimulation Targeting Primary Motor Versus Dorsolateral Prefrontal Cortices: Proof-of-Concept Study Investigating Functional Connectivity of Thalamocortical Networks Specific to Sensory-Affective Information Processing.

The pain matrix is comprised of an extensive network of brain structures involved in sensory and/or affective information processing. The thalamus is a key structure constituting the pain matrix. The thalamus serves as a relay center receiving information from multiple ascending pathways and relating information to and from multiple cortical areas. However, it is unknown how thalamocortical networks specific to sensory-affective information processing are functionally integrated. Here, in a proof-of-concept study in healthy humans, we aimed to understand this connectivity using transcranial direct current stimulation (tDCS) targeting primary motor (M1) or dorsolateral prefrontal cortices (DLPFC). We compared changes in functional connectivity (FC) with DLPFC tDCS to changes in FC with M1 tDCS. FC changes were also compared to further investigate its relation with individual's baseline experience of pain. We hypothesized that resting-state FC would change based on tDCS location and would represent known thalamocortical networks. Ten right-handed individuals received a single application of anodal tDCS (1 mA, 20 min) to right M1 and DLPFC in a single-blind, sham-controlled crossover study. FC changes were studied between ventroposterolateral (VPL), the sensory nucleus of thalamus, and cortical areas involved in sensory information processing and between medial dorsal (MD), the affective nucleus, and cortical areas involved in affective information processing. Individual's perception of pain at baseline was assessed using cutaneous heat pain stimuli. We found that anodal M1 tDCS and anodal DLPFC tDCS both increased FC between VPL and sensorimotor cortices, although FC effects were greater with M1 tDCS. Similarly, anodal M1 tDCS and anodal DLPFC tDCS both increased FC between MD and motor cortices, but only DLPFC tDCS modulated FC between MD and affective cortices, like DLPFC. Our findings suggest that M1 stimulation primarily modulates FC of sensory networks, whereas DLPFC stimulation modulates FC of both sensory and affective networks. Our findings when replicated in a larger group of individuals could provide useful evidence that may inform future studies on pain to differentiate between effects of M1 and DLPFC stimulation. Notably, our finding that individuals with high baseline pain thresholds experience greater FC changes with DLPFC tDCS implies the role of DLPFC in pain modulation, particularly pain tolerance.

The effect of motor overflow on bimanual asymmetric force coordination.

Motor overflow, typically described in the context of unimanual movements, refers to the natural tendency for a 'resting' limb to move during movement of the opposite limb and is thought to be influenced by inter-hemispheric interactions and intra-cortical networks within the 'resting' hemisphere. It is currently unknown, however, how motor overflow contributes to asymmetric force coordination task accuracy, referred to as bimanual interference, as there is need to generate unequal forces and corticospinal output for each limb. Here, we assessed motor overflow via motor evoked potentials (MEPs) and the regulation of motor overflow via inter-hemispheric inhibition (IHI) and short-intra-cortical inhibition (SICI) using transcranial magnetic stimulation in the presence of unimanual and bimanual isometric force production. All outcomes were measured in the left first dorsal interosseous (test hand) muscle, which maintained 30% maximal voluntary contraction (MVC), while the right hand (conditioning hand) was maintained at rest, 10, 30, or 70% of its MVC. We have found that as higher forces are generated with the conditioning hand, MEP amplitudes at the active test hand decreased and inter-hemispheric inhibition increased, suggesting reduced motor overflow in the presence of bimanual asymmetric forces. Furthermore, we found that subjects with less motor overflow (i.e., reduced MEP amplitudes in the test hemisphere) demonstrated poorer accuracy in maintaining 30% MVC across all conditions. These findings suggest that motor overflow may serve as an adaptive substrate to support bimanual asymmetric force coordination.

Assessment of Vascular Stent Heating with Repetitive Transcranial Magnetic Stimulation.

OBJECTIVE: A high proportion of patients with stroke do not qualify for repetitive transcranial magnetic stimulation (rTMS) clinical studies due to the presence of metallic stents. The ultimate concern is that any metal could become heated due to eddy currents. However, to date, no clinical safety data are available regarding the risk of metallic stents heating with rTMS. METHODS: We tested the safety of common rTMS protocols (1 Hz and 10 Hz) with stents used commonly in stroke, nitinol and elgiloy. In our method, stents were tested in gelled saline at 2 different locations: at the center and at the lobe of the coil. In addition, at each location, stent heating was evaluated in 3 different orientations: parallel to the long axis of coil, parallel to the short axis of the coil, and perpendicular to the plane of the coil. RESULTS: We found that stents did not heat to more than 1°C with either 1 Hz rTMS or 10 Hz rTMS in any configuration or orientation. Heating in general was greater at the lobe when the stent was oriented perpendicularly. CONCLUSIONS: Our study represents a new method for ex vivo quantification of stent heating. We have found that heating of stents was well below the Food and Drug Administration standards of 2°C. Thus, our study paves the way for in vivo testing of rTMS (≤10 Hz) in the presence of implanted magnetic resonance imaging-compatible stents in animal studies. When planning human safety studies though, geometry, orientation, and location relative to the coil would be important to consider as well.

Noninvasive brain stimulation enhances sustained muscle contractions by reducing neuromuscular fatigue: implications for rehabilitation.

Neuromuscular fatigue is due, in part, to central processes that involve failure of the nervous system to drive muscles maximally during exercise. A recent study by Abdelmoula, Baudry, and Duchateau (Neuroscience 322: 94-103, 2016) showed that noninvasive brain stimulation can mitigate neuromuscular fatigue, however, does not rely on enhanced corticospinal excitability of the primary motor cortex. These findings are of high clinical importance because rehabilitative therapies are necessary to mitigate neuromuscular fatigue for patients with central nervous system disorders.

CdiA Effectors from Uropathogenic Escherichia coli Use Heterotrimeric Osmoporins as Receptors to Recognize Target Bacteria.

Many Gram-negative bacterial pathogens express contact-dependent growth inhibition (CDI) systems that promote cell-cell interaction. CDI+ bacteria express surface CdiA effector proteins, which transfer their C-terminal toxin domains into susceptible target cells upon binding to specific receptors. CDI+ cells also produce immunity proteins that neutralize the toxin domains delivered from neighboring siblings. Here, we show that CdiAEC536 from uropathogenic Escherichia coli 536 (EC536) uses OmpC and OmpF as receptors to recognize target bacteria. E. coli mutants lacking either ompF or ompC are resistant to CDIEC536-mediated growth inhibition, and both porins are required for target-cell adhesion to inhibitors that express CdiAEC536. Experiments with single-chain OmpF fusions indicate that the CdiAEC536 receptor is heterotrimeric OmpC-OmpF. Because the OmpC and OmpF porins are under selective pressure from bacteriophages and host immune systems, their surface-exposed loops vary between E. coli isolates. OmpC polymorphism has a significant impact on CDIEC536 mediated competition, with many E. coli isolates expressing alleles that are not recognized by CdiAEC536. Analyses of recombinant OmpC chimeras suggest that extracellular loops L4 and L5 are important recognition epitopes for CdiAEC536. Loops L4 and L5 also account for much of the sequence variability between E. coli OmpC proteins, raising the possibility that CDI contributes to the selective pressure driving OmpC diversification. We find that the most efficient CdiAEC536 receptors are encoded by isolates that carry the same cdi gene cluster as E. coli 536. Thus, it appears that CdiA effectors often bind preferentially to "self" receptors, thereby promoting interactions between sibling cells. As a consequence, these effector proteins cannot recognize nor suppress the growth of many potential competitors. These findings suggest that self-recognition and kin selection are important functions of CDI.