Publications by authors named "Leonardo G Cohen"

219 Publications

Statistical learning occurs during practice while high-order rule learning during rest period.

NPJ Sci Learn 2021 Jul 1;6(1):14. Epub 2021 Jul 1.

MEMO Team, Lyon Neuroscience Research Center (CRNL), INSERM U1028, CNRS UMR5292, Université Claude Bernard Lyon 1, Lyon, France.

Knowing when the brain learns is crucial for both the comprehension of memory formation and consolidation and for developing new training and neurorehabilitation strategies in healthy and patient populations. Recently, a rapid form of offline learning developing during short rest periods has been shown to account for most of procedural learning, leading to the hypothesis that the brain mainly learns during rest between practice periods. Nonetheless, procedural learning has several subcomponents not disentangled in previous studies investigating learning dynamics, such as acquiring the statistical regularities of the task, or else the high-order rules that regulate its organization. Here we analyzed 506 behavioral sessions of implicit visuomotor deterministic and probabilistic sequence learning tasks, allowing the distinction between general skill learning, statistical learning, and high-order rule learning. Our results show that the temporal dynamics of apparently simultaneous learning processes differ. While high-order rule learning is acquired offline, statistical learning is evidenced online. These findings open new avenues on the short-scale temporal dynamics of learning and memory consolidation and reveal a fundamental distinction between statistical and high-order rule learning, the former benefiting from online evidence accumulation and the latter requiring short rest periods for rapid consolidation.
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http://dx.doi.org/10.1038/s41539-021-00093-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249495PMC
July 2021

Consolidation of human skill linked to waking hippocampo-neocortical replay.

Cell Rep 2021 Jun;35(10):109193

Human Cortical Physiology and Neurorehabilitation Section, NINDS, NIH, Bethesda, MD, USA. Electronic address:

The introduction of rest intervals interspersed with practice strengthens wakeful consolidation of skill. The mechanisms by which the brain binds discrete action representations into consolidated, highly temporally resolved skill sequences during waking rest are not known. To address this question, we recorded magnetoencephalography (MEG) during acquisition and rapid consolidation of a sequential motor skill. We report the presence of prominent, fast waking neural replay during the same rest periods in which rapid consolidation occurs. The observed replay is temporally compressed by approximately 20-fold relative to the acquired skill, is selective for the trained sequence, and predicts the magnitude of skill consolidation. Replay representations extend beyond the hippocampus and entorhinal cortex to the contralateral sensorimotor cortex. These results document the presence of robust hippocampo-neocortical replay supporting rapid wakeful consolidation of skill.
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http://dx.doi.org/10.1016/j.celrep.2021.109193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259719PMC
June 2021

The prevalence of the Val66Met polymorphism in musicians: Possible evidence for compensatory neuroplasticity from a pilot study.

PLoS One 2021 9;16(6):e0245107. Epub 2021 Jun 9.

Music and Health Sciences Research Collaboratory, Faculty of Music, University of Toronto, Toronto, Canada.

The study compared the prevalence of the Val66Met Brain-derived Neurotrophic Factor single nucleotide polymorphism (rs6265) in a sample of musicians (N = 50) to an ethnically matched general population sample from the 1000 Human Genome Project (N = 424). Met-carriers of the polymorphism (Val/Met and Met/Met genotypes) are typically present in 25-30% of the general population and have associated deficits in motor learning and plasticity. Many studies have assessed the benefits of long-term music training for neuroplasticity and motor learning. This study takes a unique genetic approach investigating if the prevalence of the Val66Met BDNF polymorphism, which negatively affects motor learning, is significantly different in musicians from the general population. Our genotype and allele frequency analyses revealed that the distribution of the Val66Met polymorphism was not significantly different in musicians versus the general population (p = 0.6447 for genotype analysis and p = 0.8513 allele analysis). In the Musician sample (N = 50), the prevalence of the Val/Met genotype was 40% and the prevalence of the Met/Met genotype was 2%. In the 1000 Human Genome Project subset (N = 424), the prevalence of Val/Met was 33.25% and the Met/Met genotype prevalence was 4%. Therefore, musicians do exist with the Val66Met polymorphism and the characteristics of long-term music training may compensate for genetic predisposition to motor learning deficits. Since the polymorphism has significant implications for stroke rehabilitation, future studies may consider the implications of the polymorphism in music-based interventions such as Neurologic Music Therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245107PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189506PMC
June 2021

Phase-dependent offline enhancement of human motor memory.

Brain Stimul 2021 May 25;14(4):873-883. Epub 2021 May 25.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Background: Skill learning engages offline activity in the primary motor cortex (M1). Sensorimotor cortical activity oscillates between excitatory trough and inhibitory peak phases of the mu (8-12 Hz) rhythm. We recently showed that these mu phases influence the magnitude and direction of neuroplasticity induction within M1. However, the contribution of M1 activity during mu peak and trough phases to human skill learning has not been investigated.

Objective: To evaluate the effects of phase-dependent TMS during mu peak and trough phases on offline learning of a newly-acquired motor skill.

Methods: On Day 1, three groups of healthy adults practiced an explicit motor sequence learning task with their non-dominant left hand. After practice, phase-dependent TMS was applied to the right M1 during either mu peak or mu trough phases. The third group received sham TMS during random mu phases. On Day 2, all subjects were re-tested on the same task to evaluate offline learning.

Results: Subjects who received phase-dependent TMS during mu trough phases showed increased offline skill learning compared to those who received phase-dependent TMS during mu peak phases or sham TMS during random mu phases. Additionally, phase-dependent TMS during mu trough phases elicited stronger whole-brain broadband oscillatory power responses than phase-dependent TMS during mu peak phases.

Conclusions: We conclude that sensorimotor mu trough phases reflect brief windows of opportunity during which TMS can strengthen newly-acquired skill memories.
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http://dx.doi.org/10.1016/j.brs.2021.05.009DOI Listing
May 2021

Crowdsourcing in Cognitive and Systems Neuroscience.

Neuroscientist 2021 May 25:10738584211017018. Epub 2021 May 25.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

Behavioral research in cognitive and human systems neuroscience has been largely carried out in-person in laboratory settings. Underpowering and lack of reproducibility due to small sample sizes have weakened conclusions of these investigations. In other disciplines, such as neuroeconomics and social sciences, crowdsourcing has been extensively utilized as a data collection tool, and a means to increase sample sizes. Recent methodological advances allow scientists, for the first time, to test online more complex cognitive, perceptual, and motor tasks. Here we review the nascent literature on the use of online crowdsourcing in cognitive and human systems neuroscience. These investigations take advantage of the ability to reliably track the activity of a participant's computer keyboard, mouse, and eye gaze in the context of large-scale studies online that involve diverse research participant pools. Crowdsourcing allows for testing the generalizability of behavioral hypotheses in real-life environments that are less accessible to lab-designed investigations. Crowdsourcing is further useful when in-laboratory studies are limited, for example during the current COVID-19 pandemic. We also discuss current limitations of crowdsourcing research, and suggest pathways to address them. We conclude that online crowdsourcing is likely to widen the scope and strengthen conclusions of cognitive and human systems neuroscience investigations.
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http://dx.doi.org/10.1177/10738584211017018DOI Listing
May 2021

The Intersection of Offline Learning and Rehabilitation.

Front Hum Neurosci 2021 21;15:667574. Epub 2021 Apr 21.

Department of Physical Therapy and Rehabilitation Science, School of Medicine, University of Maryland, Baltimore, MD, United States.

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http://dx.doi.org/10.3389/fnhum.2021.667574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098688PMC
April 2021

Induction of LTD-like corticospinal plasticity by low-frequency rTMS depends on pre-stimulus phase of sensorimotor μ-rhythm.

Brain Stimul 2020 Nov - Dec;13(6):1580-1587. Epub 2020 Sep 17.

Department of Neurology & Stroke, University of Tübingen, Germany; Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany.

Background: Neural oscillations reflect rapidly changing brain excitability states. We have demonstrated previously with EEG-triggered transcranial magnetic stimulation (TMS) of human motor cortex that the positive vs. negative peak of the sensorimotor μ-oscillation reflect corticospinal low-vs. high-excitability states. In vitro experiments showed that induction of long-term depression (LTD) by low-frequency stimulation depends on the postsynaptic excitability state.

Objective/hypothesis: We tested the hypothesis that induction of LTD-like corticospinal plasticity in humans by 1 Hz repetitive TMS (rTMS) is enhanced when rTMS is synchronized with the low-excitability state, but decreased or even shifted towards long-term (LTP)-like plasticity when synchronized with the high-excitability state.

Methods: We applied real-time EEG-triggered 1-Hz-rTMS (900 pulses) to the hand area of motor cortex in healthy subjects. In a randomized double-blind three-condition crossover design, pulses were synchronized to either the positive or negative peak of the sensorimotor μ-oscillation, or were applied at random phase (control). The amplitude of motor evoked potentials was recorded as an index of corticospinal excitability before and after 1-Hz-rTMS.

Results: 1-Hz-rTMS at random phase resulted in a trend towards LTD-like corticospinal plasticity. RTMS in the positive peak condition (i.e., the low-excitability state) induced significant LTD-like plasticity. RTMS in the negative peak condition (i.e., the high-excitability state) showed a trend towards LTP-like plasticity, which was significantly different from the other two conditions.

Conclusion: The level of corticospinal depolarization reflected by phase of the μ-oscillation determines the degree of corticospinal plasticity induced by low-frequency rTMS, a finding that may guide future personalized therapeutic stimulation.
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http://dx.doi.org/10.1016/j.brs.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710977PMC
March 2021

Phase-dependent transcranial magnetic stimulation of the lesioned hemisphere is accurate after stroke.

Brain Stimul 2020 Sep - Oct;13(5):1354-1357. Epub 2020 Jul 17.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1016/j.brs.2020.07.005DOI Listing
July 2020

Mechanisms of offline motor learning at a microscale of seconds in large-scale crowdsourced data.

NPJ Sci Learn 2020 4;5. Epub 2020 Jun 4.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20814 USA.

Performance improvements during early human motor skill learning are suggested to be driven by short periods of rest during practice, at the scale of seconds. To reveal the unknown mechanisms behind these "micro-offline" gains, we leveraged the sampling power offered by online crowdsourcing (cumulative over all experiments = 951). First, we replicated the original in-lab findings, demonstrating generalizability to subjects learning the task in their daily living environment ( = 389). Second, we show that offline improvements during rest are equivalent when significantly shortening practice period duration, thus confirming that they are not a result of recovery from performance fatigue ( = 118). Third, retroactive interference immediately after each practice period reduced the learning rate relative to interference after passage of time ( = 373), indicating stabilization of the motor memory at a microscale of several seconds. Finally, we show that random termination of practice periods did not impact offline gains, ruling out a contribution of predictive motor slowing ( = 71). Altogether, these results demonstrate that micro-offline gains indicate rapid, within-seconds consolidation accounting for early skill learning.
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http://dx.doi.org/10.1038/s41539-020-0066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272649PMC
June 2020

Treatment of Upper Limb Paresis With Repetitive Peripheral Nerve Sensory Stimulation and Motor Training: Study Protocol for a Randomized Controlled Trial.

Front Neurol 2020 25;11:196. Epub 2020 Mar 25.

Human Cortical Physiology and Stroke Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.

Repetitive peripheral nerve sensory stimulation (RPSS) has emerged as a potential adjuvant strategy to motor training in stroke rehabilitation. The aim of this study is to test the hypothesis that 3 h sessions of active RPSS associated with functional electrical stimulation (FES) and task-specific training (TST) distributed three times a week, over 6 weeks, is more beneficial to improve upper limb motor function than sham RPSS in addition to FES and TST, in subjects with moderate to severe hand motor impairments in the chronic phase (>6 months) after stroke. In this single-center, randomized, placebo controlled, parallel-group, double-blind study we compare the effects of 18 sessions of active and sham RPSS as add-on interventions to FES and task-specific training of the paretic upper limb, in 40 subjects in the chronic phase after ischemic or hemorrhagic stroke, with Fugl-Meyer upper limb scores ranging from 7 to 50 and able to voluntarily activate any active range of wrist extension. The primary outcome measure is the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. The secondary outcomes are the WMFT at 3, 10, and 18 weeks after beginning of treatment, as well as the following outcomes measured at 3, 6, 10, and 18 weeks: Motor Activity Log; active range of motion of wrist extension and flexion; grasp and pinch strength in the paretic and non-paretic sides (the order of testing is randomized within and across subjects); Modified Ashworth Scale; Fugl-Meyer Assessment-Upper Limb in the paretic arm; Barthel Index; Stroke Impact Scale. This project represents a major step in developing a rehabilitation strategy with potential to have impact on the treatment of stroke patients with poor motor recovery in developing countries worldwide. The study preliminarily evaluates a straightforward, non-invasive, inexpensive intervention. If feasibility and preliminary efficacy are demonstrated, further investigations of the proposed intervention (underlying mechanisms/ effects in larger numbers of patients) should be performed. NCT02658578.
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http://dx.doi.org/10.3389/fneur.2020.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109324PMC
March 2020

Beta rhythm events predict corticospinal motor output.

Sci Rep 2019 12 4;9(1):18305. Epub 2019 Dec 4.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.

The beta rhythm (15-30 Hz) is a prominent signal of sensorimotor cortical activity. This rhythm is not sustained but occurs non-rhythmically as brief events of a few (1-2) oscillatory cycles. Recent work on the relationship between these events and sensorimotor performance suggests that they are the biologically relevant elements of the beta rhythm. However, the influence of these events on corticospinal excitability, a mechanism through which the primary motor cortex controls motor output, is unknown. Here, we addressed this question by evaluating relationships between beta event characteristics and corticospinal excitability in healthy adults. Results show that the number, amplitude, and timing of beta events preceding transcranial magnetic stimulation (TMS) each significantly predicted motor-evoked potential (MEP) amplitudes. However, beta event characteristics did not explain additional MEP amplitude variance beyond that explained by mean beta power alone, suggesting that conventional beta power measures and beta event characteristics similarly captured natural variation in human corticospinal excitability. Despite this lack of additional explained variance, these results provide first evidence that endogenous beta oscillatory events shape human corticospinal excitability.
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http://dx.doi.org/10.1038/s41598-019-54706-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892943PMC
December 2019

Low-Frequency Brain Oscillations Track Motor Recovery in Human Stroke.

Ann Neurol 2019 12 30;86(6):853-865. Epub 2019 Oct 30.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: The majority of patients with stroke survive the acute episode and live with enduring disability. Effective therapies to support recovery of motor function after stroke are yet to be developed. Key to this development is the identification of neurophysiologic signals that mark recovery and are suitable and susceptible to interventional therapies. Movement preparatory low-frequency oscillations (LFOs) play a key role in cortical control of movement. Recent animal data point to a mechanistic role of motor cortical LFOs in stroke motor deficits and demonstrate neuromodulation intervention with therapeutic benefit. Their relevance in human stroke pathophysiology is unknown.

Methods: We studied the relationship between movement-preparatory LFOs during the performance of a visuomotor grip task and motor function in a longitudinal (<5 days, 1 and 3 months) cohort study of 33 patients with motor stroke and in 19 healthy volunteers.

Results: Acute stroke-lesioned brains fail to generate the LFO signal. Whereas in healthy humans, a transient occurrence of LFOs preceded movement onset at predominantly contralateral frontoparietal motor regions, recordings in patients revealed that movement-preparatory LFOs were substantially diminished to a level of 38% after acute stroke. LFOs progressively increased at 1 and 3 months. This re-emergence closely tracked the recovery of motor function across several movement qualities including grip strength, fine motor skills, and synergies and was frequency band specific.

Interpretation: Our results provide the first human evidence for a link between movement-preparatory LFOs and functional recovery after stroke, promoting their relevance for movement control. These results suggest that it may be interesting to explore targeted, LFOs-restorative brain stimulation therapy in human stroke patients. ANN NEUROL 2019;86:853-865.
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http://dx.doi.org/10.1002/ana.25615DOI Listing
December 2019

Plasticity and recovery of function.

Handb Clin Neurol 2019 ;163:473-483

Human Cortical Physiology and Neurorehabilitation Section, NINDS, Bethesda, MD, United States. Electronic address:

The frontal lobe plays a crucial role in human motor behavior. It is one of the last areas of the brain to mature, especially the prefrontal regions. After a brief historical perspective on the perceived dichotomy between the view of the brain as a static organ and that of a plastic, constantly changing structure, we discuss the stability/plasticity dilemma including examples of documented cortical reorganization taking place at multiple spatial and temporal scales. We pose that while plasticity is needed for motor learning, stability of the system is necessary for storage and maintenance of memorized skills. We discuss how this plasticity/stability dilemma is resolved along the life span and after a brain injury. We then examine the main challenges that clinicians have to overcome to promote recovery of function in patients with brain lesions, including attempts to use neurostimulation techniques as adjuvant to training-based customary neurorehabilitation.
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http://dx.doi.org/10.1016/B978-0-12-804281-6.00025-2DOI Listing
February 2020

Transcranial direct current stimulation facilitates response inhibition through dynamic modulation of the fronto-basal ganglia network.

Brain Stimul 2020 Jan - Feb;13(1):96-104. Epub 2019 Aug 7.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.

Background: Response inhibition refers to the ability to stop an on-going action quickly when it is no longer appropriate. Previous studies showed that transcranial direct current stimulation (tDCS) applied with the anode over the right inferior frontal cortex (rIFC), a critical node of the fronto-basal ganglia inhibitory network, improved response inhibition. However, the tDCS effects on brain activity and network connectivity underlying this behavioral improvement are not known.

Objective: This study aimed to address the effects of tDCS applied with the anode over the rIFC on brain activity and network functional connectivity underlying the behavioral change in response inhibition.

Methods: Thirty participants performed a stop-signal task in a typical laboratory setting as a baseline during the first study visit (i.e., Session 1). In the second visit (at least 24 h after Session 1), all participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans before and after 1.5 mA tDCS (Anodal or Sham). Immediately following the post-tDCS rsfMRI, participants performed the same stop-signal task as in Session 1 during an event-related fMRI (efMRI) scan in a 3T scanner. Changes in task performance, i.e., the stop-signal response time (SSRT), a measure of response inhibition efficiency, was determined relative to the participants' own baseline performance in Session 1.

Results: Consistent with previous findings, Anodal tDCS facilitated the SSRT. efMRI results showed that Anodal tDCS strengthened the functional connectivity between right pre-supplementary motor area (rPreSMA) and subthalamic nuclei during Stop responses. rsfMRI revealed changes in intrinsic connectivity between rIFC and caudate, and between rIFC, rPreSMA, right inferior parietal cortex (rIPC), and right dorsolateral prefrontal cortex (rDLPFC) after Anodal tDCS. In addition, corresponding to the regions of rsfMRI connectivity change, the efMRI BOLD signal in the rDLPFC and rIPC during Go responses accounted for 74% of the variance in SSRT after anodal tDCS, indicating an effect of tDCS on the Go-Stop process.

Conclusion: These results indicate that tDCS with the anode over the rIFC facilitates response inhibition by modulating neural activity and functional connectivity in the fronto-basal ganglia as well as rDLPFC and rIPC as an integral part of the response inhibition network.
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http://dx.doi.org/10.1016/j.brs.2019.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889034PMC
June 2020

Reversing working memory decline in the elderly.

Nat Neurosci 2019 05;22(5):686-688

Human Cortical Physiology and Neurorehabilitation Section, NINDS, NIH, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1038/s41593-019-0386-3DOI Listing
May 2019

A Rapid Form of Offline Consolidation in Skill Learning.

Curr Biol 2019 04 28;29(8):1346-1351.e4. Epub 2019 Mar 28.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20814, USA. Electronic address:

The brain strengthens memories through consolidation, defined as resistance to interference (stabilization) or performance improvements between the end of a practice session and the beginning of the next (offline gains) [1]. Typically, consolidation has been measured hours or days after the completion of training [2], but the same concept may apply to periods of rest that occur interspersed in a series of practice bouts within the same session. Here, we took an unprecedented close look at the within-seconds time course of early human procedural learning over alternating short periods of practice and rest that constitute a typical online training session. We found that performance did not markedly change over short periods of practice. On the other hand, performance improvements in between practice periods, when subjects were at rest, were significant and accounted for early procedural learning. These offline improvements were more prominent in early training trials when the learning curve was steep and no performance decrements during preceding practice periods were present. At the neural level, simultaneous magnetoencephalographic recordings showed an anatomically defined signature of this phenomenon. Beta-band brain oscillatory activity in a predominantly contralateral frontoparietal network predicted rest-period performance improvements. Consistent with its role in sensorimotor engagement [3], modulation of beta activity may reflect replay of task processes during rest periods. We report a rapid form of offline consolidation that substantially contributes to early skill learning and may extend the concept of consolidation to a time scale in the order of seconds, rather than the hours or days traditionally accepted.
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http://dx.doi.org/10.1016/j.cub.2019.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482074PMC
April 2019

Differential Brain Mechanisms of Selection and Maintenance of Information during Working Memory.

J Neurosci 2019 05 4;39(19):3728-3740. Epub 2019 Mar 4.

Human Cortical Physiology and Neurorehabilitation Section, NINDS, NIH, Bethesda, Maryland 20892.

Working memory is our ability to select and temporarily hold information as needed for complex cognitive operations. The temporal dynamics of sustained and transient neural activity supporting the selection and holding of memory content is not known. To address this problem, we recorded magnetoencephalography in healthy participants performing a retro-cue working memory task in which the selection rule and the memory content varied independently. Multivariate decoding and source analyses showed that selecting the memory content relies on prefrontal and parieto-occipital persistent oscillatory neural activity. By contrast, the memory content was reactivated in a distributed occipitotemporal posterior network, preceding the working memory decision and in a different format than during the visual encoding. These results identify a neural signature of content selection and characterize differentiated spatiotemporal constraints for subprocesses of working memory. Our brain selects and maintains information during short time windows in a way that is essential to reasoning and learning. Recent advances in multivariate analysis of brain activity allowed the characterization of brain regions that stores the memory. We applied multivariate analysis to time-resolved brain signals to characterize the spatiotemporal signature underlying these subprocesses. The selection of information relies on sustained oscillatory activity in a network that includes the ventrolateral prefrontal cortex while memory content is transiently replayed in an occipitotemporal network that differs from encoding. Our results characterized differentiated spatiotemporal activity underlying encoding, selection, and maintenance of information during working memory.
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http://dx.doi.org/10.1523/JNEUROSCI.2764-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510345PMC
May 2019

Transcutaneous spinal direct current stimulation improves locomotor learning in healthy humans.

Brain Stimul 2019 May - Jun;12(3):628-634. Epub 2019 Jan 29.

Human Cortical Physiology and Neurorehabilitation Section, NINDS, USA.

Background: Ambulation is an essential aspect of daily living and is often impaired after brain and spinal cord injuries. Despite the implementation of standard neurorehabilitative care, locomotor recovery is often incomplete.

Objective: In this randomized, sham-controlled, double-blind, parallel design study, we aimed to determine if anodal transcutaneous spinal direct current stimulation (anodal tsDCS) could improve training effects on locomotion compared to sham (sham tsDCS) in healthy subjects.

Methods: 43 participants underwent a single backwards locomotion training (BLT) session on a reverse treadmill with concurrent anodal (n = 22) or sham (n = 21) tsDCS. The primary outcome measure was speed gain measured 24 h post-training. We hypothesized that anodal tsDCS + BLT would improve training effects on backward locomotor speed compared to sham tsDCS + BLT. A subset of participants (n = 31) returned for two additional training days of either anodal (n = 16) or sham (n = 15) tsDCS and underwent (n = 29) H-reflex testing immediately before, immediately after, and 30 min post-training over three consecutive days.

Results: A single session of anodal tsDCS + BLT elicited greater speed gain at 24 h relative to sham tsDCS + BLT (p = 0.008, two-sample t-test, adjusted for one interim analysis after the initial 12 subjects). Anodal tsDCS + BLT resulted in higher retention of the acquired skill at day 30 relative to sham tsDCS + BLT (p = 0.002) in the absence of significant group differences in online or offline learning over the three training days (p = 0.467 and p = 0.131). BLT resulted in transient down-regulation of H-reflex amplitude (Hmax/Mmax) in both test groups (p < 0.0001). However, the concurrent application of anodal-tsDCS with BLT elicited a longer lasting effect than sham-tsDCS + BLT (p = 0.050).

Conclusion: tsDCS improved locomotor skill acquisition and retention in healthy subjects and prolonged the physiological exercise-mediated downregulation of excitability of the alpha motoneuron pool. These results suggest that this strategy is worth exploring in neurorehabilitation of locomotor function.
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http://dx.doi.org/10.1016/j.brs.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326485PMC
July 2019

Brain-Machine Interface in Chronic Stroke: Randomized Trial Long-Term Follow-up.

Neurorehabil Neural Repair 2019 03 5;33(3):188-198. Epub 2019 Feb 5.

1 University of Tubingen, Tübingen, Germany.

Background: Brain-machine interfaces (BMIs) have been recently proposed as a new tool to induce functional recovery in stroke patients.

Objective: Here we evaluated long-term effects of BMI training and physiotherapy in motor function of severely paralyzed chronic stroke patients 6 months after intervention.

Methods: A total of 30 chronic stroke patients with severe hand paresis from our previous study were invited, and 28 underwent follow-up assessments. BMI training included voluntary desynchronization of ipsilesional EEG-sensorimotor rhythms triggering paretic upper-limb movements via robotic orthoses (experimental group, n = 16) or random orthoses movements (sham group, n = 12). Both groups received identical physiotherapy following BMI sessions and a home-based training program after intervention. Upper-limb motor assessment scores, electromyography (EMG), and functional magnetic resonance imaging (fMRI) were assessed before (Pre), immediately after (Post1), and 6 months after intervention (Post2).

Results: The experimental group presented with upper-limb Fugl-Meyer assessment (cFMA) scores significantly higher in Post2 (13.44 ± 1.96) as compared with the Pre session (11.16 ± 1.73; P = .015) and no significant changes between Post1 and Post2 sessions. The Sham group showed no significant changes on cFMA scores. Ashworth scores and EMG activity in both groups increased from Post1 to Post2. Moreover, fMRI-BOLD laterality index showed no significant difference from Pre or Post1 to Post2 sessions.

Conclusions: BMI-based rehabilitation promotes long-lasting improvements in motor function of chronic stroke patients with severe paresis and represents a promising strategy in severe stroke neurorehabilitation.
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http://dx.doi.org/10.1177/1545968319827573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420378PMC
March 2019

Susceptibility of consolidated procedural memory to interference is independent of its active task-based retrieval.

PLoS One 2019 17;14(1):e0210876. Epub 2019 Jan 17.

McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, Quebec, Canada.

Reconsolidation theory posits that upon retrieval, consolidated memories are destabilized and need to be restabilized in order to persist. It has been suggested that experience with a competitive task immediately after memory retrieval may interrupt these restabilization processes leading to memory loss. Indeed, using a motor sequence learning paradigm, we have recently shown that, in humans, interference training immediately after active task-based retrieval of the consolidated motor sequence knowledge may negatively affect its performance levels. Assessing changes in tapping pattern before and after interference training, we also demonstrated that this performance deficit more likely indicates a genuine memory loss rather than an initial failure of memory retrieval. Here, applying a similar approach, we tested the necessity of the hypothetical retrieval-induced destabilization of motor memory to allow its impairment. The impact of memory retrieval on performance of a new motor sequence knowledge acquired during the interference training was also evaluated. Similar to the immediate post-retrieval interference, interference training alone without the preceding active task-based memory retrieval was also associated with impairment of the pre-established motor sequence memory. Performance levels of the sequence trained during the interference training, on the other hand, were impaired only if this training was given immediately after memory retrieval. Noteworthy, an 8-hour interval between memory retrieval and interference allowed to express intact performance levels for both sequences. The current results suggest that susceptibility of the consolidated motor memory to behavioral interference is independent of its active task-based retrieval. Differential effects of memory retrieval on performance levels of the new motor sequence encoded during the interference training further suggests that memory retrieval may influence the way new information is stored by facilitating its integration within the retrieved memory trace. Thus, impairment of the pre-established motor memory may reflect interference from a competing memory trace rather than involve interruption of reconsolidation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336251PMC
October 2019

Correction: Brain-Computer Interface-Based Communication in the Completely Locked-In State.

PLoS Biol 2018 12 12;16(12):e3000089. Epub 2018 Dec 12.

[This corrects the article DOI: 10.1371/journal.pbio.1002593.].
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http://dx.doi.org/10.1371/journal.pbio.3000089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291112PMC
December 2018

Sensorimotor Oscillatory Phase-Power Interaction Gates Resting Human Corticospinal Output.

Cereb Cortex 2019 08;29(9):3766-3777

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Oscillatory activity within sensorimotor networks is characterized by time-varying changes in phase and power. The influence of interactions between sensorimotor oscillatory phase and power on human motor function, like corticospinal output, is unknown. We addressed this gap in knowledge by delivering transcranial magnetic stimulation (TMS) to the human motor cortex during electroencephalography recordings in 20 healthy participants. Motor evoked potentials, a measure of corticospinal excitability, were categorized offline based on the mu (8-12 Hz) and beta (13-30 Hz) oscillatory phase and power at the time of TMS. Phase-dependency of corticospinal excitability was evaluated across a continuous range of power levels using trial-by-trial linear mixed-effects models. For mu, there was no effect of PHASE or POWER (P > 0.51), but a significant PHASE × POWER interaction (P = 0.002). The direction of phase-dependency reversed with changing mu power levels: corticospinal output was higher during mu troughs versus peaks when mu power was high while the opposite was true when mu power was low. A similar PHASE × POWER interaction was not present for beta oscillations (P > 0.11). We conclude that the interaction between sensorimotor oscillatory phase and power gates human corticospinal output to an extent unexplained by sensorimotor oscillatory phase or power alone.
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http://dx.doi.org/10.1093/cercor/bhy255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686752PMC
August 2019

Repetitive Peripheral Sensory Stimulation and Upper Limb Performance in Stroke: A Systematic Review and Meta-analysis.

Neurorehabil Neural Repair 2018 10 10;32(10):863-871. Epub 2018 Sep 10.

6 National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Background: Enhancement of sensory input in the form of repetitive peripheral sensory stimulation (RPSS) can enhance excitability of the motor cortex and upper limb performance.

Objective: To perform a systematic review and meta-analysis of effects of RPSS compared with control stimulation on improvement of motor outcomes in the upper limb of subjects with stroke.

Methods: We searched studies published between 1948 and December 2017 and selected 5 studies that provided individual data and applied a specific paradigm of stimulation (trains of 1-ms pulses at 10 Hz, delivered at 1 Hz). Continuous data were analyzed with means and standard deviations of differences in performance before and after active or control interventions. Adverse events were also assessed.

Results: There was a statistically significant beneficial effect of RPSS on motor performance (standard mean difference between active and control RPSS, 0.67; 95% CI, 0.09-1.24; I = 65%). Only 1 study included subjects in the subacute phase after stroke. Subgroup analysis of studies that only included subjects in the chronic phase showed a significant effect (1.04; 95% CI, 0.66-1.42) with no heterogeneity. Significant results were obtained for outcomes of body structure and function as well as for outcomes of activity limitation according to the International Classification of Function, Disability and Health, when only studies that included subjects in the chronic phase were analyzed. No serious adverse events were reported.

Conclusions: RPSS is a safe intervention with potential to become an adjuvant tool for upper extremity paresis rehabilitation in subjects with stroke in the chronic phase.
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http://dx.doi.org/10.1177/1545968318798943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404964PMC
October 2018

Distributed cortical structural properties contribute to motor cortical excitability and inhibition.

Brain Struct Funct 2018 Nov 4;223(8):3801-3812. Epub 2018 Aug 4.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

The link between the local structure of the primary motor cortex and motor function has been well documented. However, motor function relies on a network of interconnected brain regions and the link between the structural properties characterizing these distributed brain networks and motor function remains poorly understood. Here, we examined whether distributed patterns of brain structure, extending beyond the primary motor cortex can help classify two forms of motor function: corticospinal excitability and intracortical inhibition. To this effect, we recorded high-resolution structural magnetic resonance imaging scans in 25 healthy volunteers. To measure corticospinal excitability and inhibition in the same volunteers, we recorded motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation and short-interval intracortical inhibition (SICI) in a separate session. Support vector machine (SVM) pattern classification was used to identify distributed multi-voxel gray-matter areas, which distinguished subjects who had lower and higher MEPs and SICIs. We found that MEP and SICI classification could be predicted based on a widely distributed, largely non-overlapping pattern of voxels in frontal, parietal, temporal, occipital, and cerebellar regions. Thus, structural properties distributed over the brain beyond the primary motor cortex relate to motor function.
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http://dx.doi.org/10.1007/s00429-018-1722-1DOI Listing
November 2018

A Preliminary Comparison of Motor Learning Across Different Non-invasive Brain Stimulation Paradigms Shows No Consistent Modulations.

Front Neurosci 2018 23;12:253. Epub 2018 Apr 23.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, United States.

Non-invasive brain stimulation (NIBS) has been widely explored as a way to safely modulate brain activity and alter human performance for nearly three decades. Research using NIBS has grown exponentially within the last decade with promising results across a variety of clinical and healthy populations. However, recent work has shown high inter-individual variability and a lack of reproducibility of previous results. Here, we conducted a small preliminary study to explore the effects of three of the most commonly used excitatory NIBS paradigms over the primary motor cortex (M1) on motor learning (Sequential Visuomotor Isometric Pinch Force Tracking Task) and secondarily relate changes in motor learning to changes in cortical excitability (MEP amplitude and SICI). We compared anodal transcranial direct current stimulation (tDCS), paired associative stimulation (PAS), and intermittent theta burst stimulation (iTBS), along with a sham tDCS control condition. Stimulation was applied prior to motor learning. Participants ( = 28) were randomized into one of the four groups and were trained on a skilled motor task. Motor learning was measured immediately after training (online), 1 day after training (consolidation), and 1 week after training (retention). We did not find consistent differential effects on motor learning or cortical excitability across groups. Within the boundaries of our small sample sizes, we then assessed effect sizes across the NIBS groups that could help power future studies. These results, which require replication with larger samples, are consistent with previous reports of small and variable effect sizes of these interventions on motor learning.
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http://dx.doi.org/10.3389/fnins.2018.00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924807PMC
April 2018

Transcranial Direct Current Stimulation Enhances Motor Skill Learning but Not Generalization in Chronic Stroke.

Neurorehabil Neural Repair 2018 Apr-May;32(4-5):295-308. Epub 2018 Apr 22.

1 University Hospital Freiburg, Freiburg, Germany.

Background: Motor training alone or combined with transcranial direct current stimulation (tDCS) positioned over the motor cortex (M1) improves motor function in chronic stroke. Currently, understanding of how tDCS influences the process of motor skill learning after stroke is lacking.

Objective: To assess the effects of tDCS on the stages of motor skill learning and on generalization to untrained motor function.

Methods: In this randomized, sham-controlled, blinded study of 56 mildly impaired chronic stroke patients, tDCS (anode over the ipsilesional M1 and cathode on the contralesional forehead) was applied during 5 days of training on an unfamiliar, challenging fine motor skill task (sequential visual isometric pinch force task). We assessed online and offline learning during the training period and retention over the following 4 months. We additionally assessed the generalization to untrained tasks.

Results: With training alone (sham tDCS group), patients acquired a novel motor skill. This skill improved online, remained stable during the offline periods and was largely retained at follow-up. When tDCS was added to training (real tDCS group), motor skill significantly increased relative to sham, mostly in the online stage. Long-term retention was not affected by tDCS. Training effects generalized to untrained tasks, but those performance gains were not enhanced further by tDCS.

Conclusions: Training of an unfamiliar skill task represents a strategy to improve fine motor function in chronic stroke. tDCS augments motor skill learning, but its additive effect is restricted to the trained skill.
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http://dx.doi.org/10.1177/1545968318769164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350256PMC
February 2019

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop.

Brain Stimul 2018 May - Jun;11(3):465-480. Epub 2017 Dec 29.

Division of Translational Research, National Institute of Mental Health, Bethesda, MD, United States.

Background: Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities.

Objective: This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment.

Methods: The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs.

Results: Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them.

Conclusions: These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders.
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http://dx.doi.org/10.1016/j.brs.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997279PMC
February 2019

Biomarkers of Stroke Recovery: Consensus-Based Core Recommendations from the Stroke Recovery and Rehabilitation Roundtable.

Neurorehabil Neural Repair 2017 Oct-Nov;31(10-11):864-876

14 University of California, Irvine, CA, USA; Depts. Neurology, Anatomy & Neurobiology, and Physical Medicine & Rehabilitation, Irvine, CA, USA.

The most difficult clinical questions in stroke rehabilitation are "What is this patient's potential for recovery?" and "What is the best rehabilitation strategy for this person, given her/his clinical profile?" Without answers to these questions, clinicians struggle to make decisions regarding the content and focus of therapy, and researchers design studies that inadvertently mix participants who have a high likelihood of responding with those who do not. Developing and implementing biomarkers that distinguish patient subgroups will help address these issues and unravel the factors important to the recovery process. The goal of the present paper is to provide a consensus statement regarding the current state of the evidence for stroke recovery biomarkers. Biomarkers of motor, somatosensory, cognitive and language domains across the recovery timeline post-stroke are considered; with focus on brain structure and function, and exclusion of blood markers and genetics. We provide evidence for biomarkers that are considered ready to be included in clinical trials, as well as others that are promising but not ready and so represent a developmental priority. We conclude with an example that illustrates the utility of biomarkers in recovery and rehabilitation research, demonstrating how the inclusion of a biomarker may enhance future clinical trials. In this way, we propose a way forward for when and where we can include biomarkers to advance the efficacy of the practice of, and research into, rehabilitation and recovery after stroke.
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http://dx.doi.org/10.1177/1545968317732680DOI Listing
July 2018

Longitudinal Structural and Functional Differences Between Proportional and Poor Motor Recovery After Stroke.

Neurorehabil Neural Repair 2017 Dec 12;31(12):1029-1041. Epub 2017 Nov 12.

3 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Background: Evolution of motor function during the first months after stroke is stereotypically bifurcated, consisting of either recovery to about 70% of maximum possible improvement ("proportional recovery, PROP") or in little to no improvement ("poor recovery, POOR"). There is currently no evidence that any rehabilitation treatment will prevent POOR and favor PROP.

Objective: To perform a longitudinal and multimodal assessment of functional and structural changes in brain organization associated with PROP.

Methods: Fugl-Meyer Assessments of the upper extremity and high-density electroencephalography (EEG) were obtained from 63 patients, diffusion tensor imaging from 46 patients, at 2 and 4 weeks (T0) and at 3 months (T1) after stroke onset.

Results: We confirmed the presence of 2 distinct recovery patterns (PROP and POOR) in our sample. At T0, PROP patients had greater integrity of the corticospinal tract (CST) and greater EEG functional connectivity (FC) between the affected hemisphere and rest of the brain, in particular between the ventral premotor and the primary motor cortex. POOR patients suffered from degradation of corticocortical and corticofugal fiber tracts in the affected hemisphere between T0 and T1, which was not observed in PROP patients. Better initial CST integrity correlated with greater initial global FC, which was in turn associated with less white matter degradation between T0 and T1.

Conclusions: These findings suggest links between initial CST integrity, systems-level cortical network plasticity, reduction of white matter atrophy, and clinical motor recovery after stroke. This identifies candidate treatment targets.
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http://dx.doi.org/10.1177/1545968317740634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368856PMC
December 2017

Lasting deficit in inhibitory control with mild traumatic brain injury.

Sci Rep 2017 11 2;7(1):14902. Epub 2017 Nov 2.

Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.

Being able to focus on a complex task and inhibit unwanted actions or interfering information (i.e., inhibitory control) are essential human cognitive abilities. However, it remains unknown the extent to which mild traumatic brain injury (mTBI) may impact these critical functions. In this study, seventeen patients and age-matched healthy controls (HC) performed a variant of the Stroop task and attention-demanding 4-choice response tasks (4CRT) with identical stimuli but two contexts: one required only routine responses and the other with occasional response conflicts. The results showed that mTBI patients performed equally well as the HC when the 4CRT required only routine responses. However, when the task conditions included occasional response conflicts, mTBI patients with even a single concussion showed a significant slow-down in all responses and higher error rates relative to the HC. Results from event-related functional magnetic resonance imaging (efMRI) revealed altered neural activity in the mTBI patients in the cerebellum-thalamo-cortical and the fronto-basal-ganglia networks regulating inhibitory control. These results suggest that even without apparent difficulties in performing complex attention-demanding but routine tasks, patients with mTBI may experience long-lasting deficits in regulating inhibitory control when situations call for rapid conflict resolutions.
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http://dx.doi.org/10.1038/s41598-017-14867-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668274PMC
November 2017