Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

Abstract:

:Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.

journal_name

Nat Med

journal_title

Nature medicine

authors

Gill ML,Grahn PJ,Calvert JS,Linde MB,Lavrov IA,Strommen JA,Beck LA,Sayenko DG,Van Straaten MG,Drubach DI,Veith DD,Thoreson AR,Lopez C,Gerasimenko YP,Edgerton VR,Lee KH,Zhao KD

doi

10.1038/s41591-018-0175-7

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

1677-1682

issue

11

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-018-0175-7

journal_volume

24

pub_type

杂志文章
  • Deacetylase inhibition promotes the generation and function of regulatory T cells.

    abstract::Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive fun...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1652

    authors: Tao R,de Zoeten EF,Ozkaynak E,Chen C,Wang L,Porrett PM,Li B,Turka LA,Olson EN,Greene MI,Wells AD,Hancock WW

    更新日期:2007-11-01 00:00:00

  • Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury.

    abstract::Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the i...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/11387

    authors: Springer JE,Azbill RD,Knapp PE

    更新日期:1999-08-01 00:00:00

  • Senolytics improve physical function and increase lifespan in old age.

    abstract::Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0092-9

    authors: Xu M,Pirtskhalava T,Farr JN,Weigand BM,Palmer AK,Weivoda MM,Inman CL,Ogrodnik MB,Hachfeld CM,Fraser DG,Onken JL,Johnson KO,Verzosa GC,Langhi LGP,Weigl M,Giorgadze N,LeBrasseur NK,Miller JD,Jurk D,Singh RJ,Allison

    更新日期:2018-08-01 00:00:00

  • Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma.

    abstract::Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responde...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.4401

    authors: Tan DSW,Chong FT,Leong HS,Toh SY,Lau DP,Kwang XL,Zhang X,Sundaram GM,Tan GS,Chang MM,Chua BT,Lim WT,Tan EH,Ang MK,Lim TKH,Sampath P,Chowbay B,Skanderup AJ,DasGupta R,Iyer NG

    更新日期:2017-10-01 00:00:00

  • Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection.

    abstract::Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/72309

    authors: Baba TW,Liska V,Hofmann-Lehmann R,Vlasak J,Xu W,Ayehunie S,Cavacini LA,Posner MR,Katinger H,Stiegler G,Bernacky BJ,Rizvi TA,Schmidt R,Hill LR,Keeling ME,Lu Y,Wright JE,Chou TC,Ruprecht RM

    更新日期:2000-02-01 00:00:00

  • Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis.

    abstract::Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in n...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.1945

    authors: Binder NB,Niederreiter B,Hoffmann O,Stange R,Pap T,Stulnig TM,Mack M,Erben RG,Smolen JS,Redlich K

    更新日期:2009-04-01 00:00:00

  • Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy.

    abstract::Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identi...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-019-0374-x

    authors: Wang J,Sun J,Liu LN,Flies DB,Nie X,Toki M,Zhang J,Song C,Zarr M,Zhou X,Han X,Archer KA,O'Neill T,Herbst RS,Boto AN,Sanmamed MF,Langermann S,Rimm DL,Chen L

    更新日期:2019-04-01 00:00:00

  • Notch3 signaling promotes the development of pulmonary arterial hypertension.

    abstract::Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevati...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.2021

    authors: Li X,Zhang X,Leathers R,Makino A,Huang C,Parsa P,Macias J,Yuan JX,Jamieson SW,Thistlethwaite PA

    更新日期:2009-11-01 00:00:00

  • Angiopoietin-related growth factor antagonizes obesity and insulin resistance.

    abstract::Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked ob...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1214

    authors: Oike Y,Akao M,Yasunaga K,Yamauchi T,Morisada T,Ito Y,Urano T,Kimura Y,Kubota Y,Maekawa H,Miyamoto T,Miyata K,Matsumoto S,Sakai J,Nakagata N,Takeya M,Koseki H,Ogawa Y,Kadowaki T,Suda T

    更新日期:2005-04-01 00:00:00

  • An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.

    abstract::Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-mi...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1559

    authors: Rakhit R,Robertson J,Vande Velde C,Horne P,Ruth DM,Griffin J,Cleveland DW,Cashman NR,Chakrabartty A

    更新日期:2007-06-01 00:00:00

  • A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects.

    abstract::The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.4478

    authors: Kagoya Y,Tanaka S,Guo T,Anczurowski M,Wang CH,Saso K,Butler MO,Minden MD,Hirano N

    更新日期:2018-03-01 00:00:00

  • Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer.

    abstract::Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine i...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1556

    authors: Spira A,Beane JE,Shah V,Steiling K,Liu G,Schembri F,Gilman S,Dumas YM,Calner P,Sebastiani P,Sridhar S,Beamis J,Lamb C,Anderson T,Gerry N,Keane J,Lenburg ME,Brody JS

    更新日期:2007-03-01 00:00:00

  • RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.

    abstract::Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm890

    authors: Deane R,Du Yan S,Submamaryan RK,LaRue B,Jovanovic S,Hogg E,Welch D,Manness L,Lin C,Yu J,Zhu H,Ghiso J,Frangione B,Stern A,Schmidt AM,Armstrong DL,Arnold B,Liliensiek B,Nawroth P,Hofman F,Kindy M,Stern D,Zlokov

    更新日期:2003-07-01 00:00:00

  • Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions.

    abstract::The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing o...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0323-0

    authors: Teixeira VH,Pipinikas CP,Pennycuick A,Lee-Six H,Chandrasekharan D,Beane J,Morris TJ,Karpathakis A,Feber A,Breeze CE,Ntolios P,Hynds RE,Falzon M,Capitanio A,Carroll B,Durrenberger PF,Hardavella G,Brown JM,Lynch AG,Fa

    更新日期:2019-03-01 00:00:00

  • Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.

    abstract::Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular m...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0299-9

    authors: Shen CJ,Zheng D,Li KX,Yang JM,Pan HQ,Yu XD,Fu JY,Zhu Y,Sun QX,Tang MY,Zhang Y,Sun P,Xie Y,Duan S,Hu H,Li XM

    更新日期:2019-02-01 00:00:00

  • Natural regulatory T cells control the development of atherosclerosis in mice.

    abstract::Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibit...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1343

    authors: Ait-Oufella H,Salomon BL,Potteaux S,Robertson AK,Gourdy P,Zoll J,Merval R,Esposito B,Cohen JL,Fisson S,Flavell RA,Hansson GK,Klatzmann D,Tedgui A,Mallat Z

    更新日期:2006-02-01 00:00:00

  • Thymosin beta 15: a novel regulator of tumor cell motility upregulated in metastatic prostate cancer.

    abstract::The Dunning rat prostatic carcinoma is a model system where cell motility closely correlates with the metastatic phenotype. We have identified a novel gene, upregulated in the highly motile and metastatic Dunning cancer cell lines, that represents a new member of the thymosin-beta family, thymosin beta 15. Transfectio...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1296-1322

    authors: Bao L,Loda M,Janmey PA,Stewart R,Anand-Apte B,Zetter BR

    更新日期:1996-12-01 00:00:00

  • Local immune monitoring.

    abstract:: ...

    journal_title:Nature medicine

    pub_type: 评论,杂志文章

    doi:10.1038/s41591-018-0332-z

    authors: Stower H

    更新日期:2019-01-01 00:00:00

  • Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo.

    abstract::Proliferation of smooth muscle cells of the arterial wall in response to local injury is an important aetiologic factor of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Ras proteins are key transducers of mitogenic signals from membrane to nucleus in many cell types. We inv...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm0695-541

    authors: Indolfi C,Avvedimento EV,Rapacciuolo A,Di Lorenzo E,Esposito G,Stabile E,Feliciello A,Mele E,Giuliano P,Condorelli G

    更新日期:1995-06-01 00:00:00

  • Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease.

    abstract::Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asp...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3700

    authors: Zhang Z,Song M,Liu X,Kang SS,Kwon IS,Duong DM,Seyfried NT,Hu WT,Liu Z,Wang JZ,Cheng L,Sun YE,Yu SP,Levey AI,Ye K

    更新日期:2014-11-01 00:00:00

  • Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.

    abstract::Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two ...

    journal_title:Nature medicine

    pub_type: 杂志文章,多中心研究

    doi:10.1038/s41591-020-1085-z

    authors: van Dijk N,Gil-Jimenez A,Silina K,Hendricksen K,Smit LA,de Feijter JM,van Montfoort ML,van Rooijen C,Peters D,Broeks A,van der Poel HG,Bruining A,Lubeck Y,Sikorska K,Boellaard TN,Kvistborg P,Vis DJ,Hooijberg E,Schumac

    更新日期:2020-12-01 00:00:00

  • Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.

    abstract::The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/9473

    authors: Polack FP,Auwaerter PG,Lee SH,Nousari HC,Valsamakis A,Leiferman KM,Diwan A,Adams RJ,Griffin DE

    更新日期:1999-06-01 00:00:00

  • A new activity for SAMHD1 in HIV restriction.

    abstract::Restriction factors are host cell proteins that inhibit retroviral infection. A new study using mutants of human HIV-1 restriction factor SAMHD1 suggests that it inhibits infection through degradation of viral RNA rather than through its dNTPase activity as previously suggested. ...

    journal_title:Nature medicine

    pub_type: 评论,杂志文章

    doi:10.1038/nm.3657

    authors: Yang Z,Greene WC

    更新日期:2014-08-01 00:00:00

  • IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.

    abstract::Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1615

    authors: Orinska Z,Maurer M,Mirghomizadeh F,Bulanova E,Metz M,Nashkevich N,Schiemann F,Schulmistrat J,Budagian V,Giron-Michel J,Brandt E,Paus R,Bulfone-Paus S

    更新日期:2007-08-01 00:00:00

  • Development of universal antidotes to control aptamer activity.

    abstract::With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.1990

    authors: Oney S,Lam RT,Bompiani KM,Blake CM,Quick G,Heidel JD,Liu JY,Mack BC,Davis ME,Leong KW,Sullenger BA

    更新日期:2009-10-01 00:00:00

  • Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network.

    abstract::Computerized electrocardiogram (ECG) interpretation plays a critical role in the clinical ECG workflow1. Widely available digital ECG data and the algorithmic paradigm of deep learning2 present an opportunity to substantially improve the accuracy and scalability of automated ECG analysis. However, a comprehensive eval...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0268-3

    authors: Hannun AY,Rajpurkar P,Haghpanahi M,Tison GH,Bourn C,Turakhia MP,Ng AY

    更新日期:2019-01-01 00:00:00

  • Vaccines: past, present and future.

    abstract::The vaccines developed over the first two hundred years since Jenner's lifetime have accomplished striking reductions of infection and disease wherever applied. Pasteur's early approaches to vaccine development, attenuation and inactivation, are even now the two poles of vaccine technology. Today, purification of micr...

    journal_title:Nature medicine

    pub_type: 历史文章,杂志文章

    doi:10.1038/nm1209

    authors: Plotkin SA

    更新日期:2005-04-01 00:00:00

  • Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus.

    abstract::Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14-15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, wit...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3891

    authors: Hanssen MJ,Hoeks J,Brans B,van der Lans AA,Schaart G,van den Driessche JJ,Jörgensen JA,Boekschoten MV,Hesselink MK,Havekes B,Kersten S,Mottaghy FM,van Marken Lichtenbelt WD,Schrauwen P

    更新日期:2015-08-01 00:00:00

  • Publisher Correction: Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency.

    abstract::In the version of this article originally published, there was an error in the legend for Extended Data Fig. 7. The legend for panel f was originally: "f, FACS analysis of IL7R-, CD62L- and CD45RA- expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per...

    journal_title:Nature medicine

    pub_type: 已发布勘误

    doi:10.1038/s41591-019-0360-3

    authors: Feucht J,Sun J,Eyquem J,Ho YJ,Zhao Z,Leibold J,Dobrin A,Cabriolu A,Hamieh M,Sadelain M

    更新日期:2019-03-01 00:00:00

  • Chip-NMR biosensor for detection and molecular analysis of cells.

    abstract::Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify mole...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.1711

    authors: Lee H,Sun E,Ham D,Weissleder R

    更新日期:2008-08-01 00:00:00