Leonardo Cohen - Academia.edu (original) (raw)

Papers by Leonardo Cohen

Rapid response inhibition of an on-going action or an urge for a habitual response (i.e., an impu... more Rapid response inhibition of an on-going action or an urge for a habitual response (i.e., an impulse) is a critical human cognitive ability. Recent studies identified a prefrontal-basal-ganglia (PBG) neural network underlying response inhibition using a stop-signal response (SSR) task in which subjects were given a stop signal shortly after a “go” response signal (Verbruggen and Logan, 2009). A central assumption of rapid response inhibition (as with the SSR paradigm) is that the inhibition and “go” processes are independent and that active inhibition follows the “go” process. However, the temporal relation between the “go” and inhibition processes is not well understood. We tested the hypothesis that rapid inhibition of a response is influenced by the extent of activation in the inhibitory network prior to all responses. We used an event-related functional magnetic resonance imaging (efMRI) method with three experimental tasks: a modified SSR task, a response-interference (RI) task...

Trends in cognitive sciences, Jan 10, 2015

A vital property of the brain is its plasticity, which manifests as changes in behavioral perform... more A vital property of the brain is its plasticity, which manifests as changes in behavioral performance. Invasive studies at the cellular level in animal models reveal time-restricted windows during which existing memories that are reactivated become susceptible to modification through reconsolidation, and evidence suggests similar effects in humans. In this review we summarize recent work utilizing noninvasive brain stimulation in humans to uncover the systems-level mechanisms underlying memory reconsolidation. This novel understanding of memory dynamics may have far-reaching clinical implications, including the potential to modulate reconsolidation in patients with memory disorders.

Neurorehabilitation and Neural Repair, 2015

In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to inte... more In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to interhemispheric and intracortical inhibition in affected hand muscles. In less fully recovered patients unable to move their hand, the neural substrates of recovered arm movements, crucial for performance of daily living tasks, are not well understood. Here, we evaluated interhemispheric and intracortical inhibition in paretic arm muscles of patients with no recovery of hand movement (n = 16, upper extremity Fugl-Meyer Assessment = 27.0 ± 8.6). We recorded silent periods (contralateral and ipsilateral) induced by transcranial magnetic stimulation during voluntary isometric contraction of the paretic biceps and triceps brachii muscles (correlates of intracortical and interhemispheric inhibition, respectively) and investigated links between the silent periods and motor recovery, an issue that has not been previously explored. We report that interhemispheric inhibition, stronger in the paretic triceps than biceps brachii muscles, significantly correlated with the magnitude of residual impairment (lower Fugl-Meyer scores). In contrast, intracortical inhibition in the paretic biceps brachii, but not in the triceps, correlated positively with motor recovery (Fugl-Meyer scores) and negatively with spasticity (lower Modified Ashworth scores). Our results suggest that interhemispheric inhibition and intracortical inhibition of paretic upper arm muscles relate to motor recovery in different ways. While interhemispheric inhibition may contribute to poorer recovery, muscle-specific intracortical inhibition may relate to successful motor recovery and lesser spasticity.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2014

Interindividual differences in the effects of reward on performance are prevalent and poorly unde... more Interindividual differences in the effects of reward on performance are prevalent and poorly understood, with some individuals being more dependent than others on the rewarding outcomes of their actions. The origin of this variability in reward dependence is unknown. Here, we tested the relationship between reward dependence and brain structure in healthy humans. Subjects trained on a visuomotor skill-acquisition task and received performance feedback in the presence or absence of reward. Reward dependence was defined as the statistical trial-by-trial relation between reward and subsequent performance. We report a significant relationship between reward dependence and the lateral prefrontal cortex, where regional gray-matter volume predicted reward dependence but not feedback alone. Multivoxel pattern analysis confirmed the anatomical specificity of this relationship. These results identified a likely anatomical marker for the prospective influence of reward on performance, which ma...

Frontiers in behavioral neuroscience, 2014

Transcranial direct current stimulation (tDCS) improves motor learning and can affect emotional p... more Transcranial direct current stimulation (tDCS) improves motor learning and can affect emotional processing and attention. However, it is unclear whether learned electroencephalography (EEG)-based brain-machine interface (BMI) control during tDCS is feasible, how application of transcranial electric currents during BMI control would interfere with feature-extraction of physiological brain signals and how it affects brain control performance. Here we tested this combination and evaluated stimulation-dependent artifacts across different EEG frequencies and stability of motor imagery-based BMI control. Ten healthy volunteers were invited to two BMI-sessions, each comprising two 60-trial blocks. During the trials, learned desynchronization of mu-rhythms (8-15 Hz) associated with motor imagery (MI) recorded over C4 was translated into online cursor movements on a computer screen. During block 2, either sham (session A) or anodal tDCS (session B) was applied at 1 mA with the stimulation el...

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002

The human motor cortex contains a dynamic and distributed network of motor representations. Forma... more The human motor cortex contains a dynamic and distributed network of motor representations. Formation, maintenance, and modification of these representations is an activity-driven process. Repeated stimulation of one representation results in increased motor output from this representation, a process referred to as "within-representation plasticity." We showed previously that within-representation plasticity of the upper arm representation occurs when repetitive transcranial magnetic stimulation (rTMS) is delivered to that representation during transient ischemic nerve block (INB) of the contralateral hand. INB reduces inhibition in the motor cortex and thus lowers the threshold for stimulation-induced plasticity. Here we studied the effects of rTMS delivered to nearby body part representations on the motor output from the upper arm representation. Six healthy subjects underwent INB-alone (control), or INB plus 30 min of focal 0.1 Hz rTMS of either the face, hand, arm, leg...

Journal of Cognitive Neuroscience, 2015

■ Sequence learning relies on formation of unconscious transitional and conscious ordinal memorie... more ■ Sequence learning relies on formation of unconscious transitional and conscious ordinal memories. The influence of practice type on formation of these memories that compose skill and systems level neural substrates is not known. Here, we studied learning of transitional and ordinal memories in participants trained on motor sequences while scanned using fMRI. Practice structure was varied or grouped (mixing or grouping sequences during training, respectively). Memory was assessed 30 min and 1 week later. Varied practice improved transitional memory and enhanced coupling of the dorsal premotor cortex with thalamus, cerebellum, and lingual and cingulate regions and greater transitional memory correlated with this coupling. Thus, varied practice improves unconscious transitional memories in proportion to coupling within a corticosubcortical network linked to premotor cortex. This result indicates that practice structure influences unconscious transitional memory formation and identifies underlying systems level mechanisms. ■

Frontiers in Human Neuroscience, 2014

Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallet... more Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallett, Editors 2013 Published by Elsevier B.V.

Annals of Clinical and Translational Neurology, 2014

Objective: Stroke is a leading cause of long-term motor disability. Stroke patients with severe h... more Objective: Stroke is a leading cause of long-term motor disability. Stroke patients with severe hand weakness do not profit from rehabilitative treatments. Recently, brain-controlled robotics and sequential functional electrical stimulation allowed some improvement. However, for such therapies to succeed, it is required to decode patients' intentions for different arm movements. Here, we evaluated whether residual muscle activity could be used to predict movements from paralyzed joints in severely impaired chronic stroke patients. Methods: Muscle activity was recorded with surface-electromyography (EMG) in 41 patients, with severe hand weakness (Fugl-Meyer Assessment [FMA] hand subscores of 2.93 AE 2.7), in order to decode their intention to perform six different motions of the affected arm, required for voluntary muscle activity and to control neuroprostheses. Decoding of paretic and nonparetic muscle activity was performed using a feed-forward neural network classifier. The contribution of each muscle to the intended movement was determined. Results: Decoding of up to six arm movements was accurate (>65%) in more than 97% of nonparetic and 46% of paretic muscles. Interpretation: These results demonstrate that some level of neuronal innervation to the paretic muscle remains preserved and can be used to implement neurorehabilitative treatments in 46% of patients with severe paralysis and extensive cortical and/or subcortical lesions. Such decoding may allow these patients for the first time after stroke to control different motions of arm prostheses through muscle-triggered rehabilitative treatments.

Frontiers in Human Neuroscience, 2015

Frontiers in Aging Neuroscience, 2014

Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder tr... more Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder triggers reconsolidation, a time-limited period during which existing memories can be modified (i.e., weakened or strengthened). Episodic memory refers to our ability to recall specific past events about what happened, including where and when. Difficulties in this form of long-term memory commonly occur in healthy aging. Because episodic memory is critical for daily life functioning, the development of effective interventions to reduce memory loss in elderly individuals is of great importance. Previous studies in young adults showed that the dorsolateral prefrontal cortex (DLPFC) plays a causal role in strengthening of verbal episodic memories through reconsolidation. The aim of the present study was to explore the extent to which facilitatory transcranial direct current stimulation (anodal tDCS) over the left DLPFC would strengthen existing episodic memories through reconsolidation in elderly individuals. On Day 1, older adults learned a list of 20 words. On Day 2 (24 h later), they received a reminder or not, and after 10 min tDCS was applied over the left DLPFC. Memory recall was tested on Day 3 (48 h later) and . Surprisingly, anodal tDCS over the left DLPFC (i.e., with or without the reminder) strengthened existing verbal episodic memories and reduced forgetting compared to sham stimulation. These results provide a framework for testing the hypothesis that facilitatory tDCS of left DLPFC might strengthen existing episodic memories and reduce memory loss in older adults with amnestic mild cognitive impairment.

Frontiers in Neuroscience, 2005

Proceedings of the National Academy of Sciences, 2009

Motor skills can take weeks to months to acquire and can diminish over time in the absence of con... more Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and betweenday (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention.

Neurorehabilitation and Neural Repair, 2011

Background-The neurophysiological mechanisms underlying improved upper-extremity motor skills hav... more Background-The neurophysiological mechanisms underlying improved upper-extremity motor skills have been partially investigated in patients with good motor recovery but are poorly understood in more impaired individuals, the majority of stroke survivors.

Neurorehabilitation and Neural Repair, 2010

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corti... more Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non-invasively. Since these early studies, the development of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up-to-date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

Neurorehabilitation and Neural Repair, 2013

Background. Abnormal task-related activation in primary motor cortices (M1) has been consistently... more Background. Abnormal task-related activation in primary motor cortices (M1) has been consistently found in functional imaging studies of subcortical stroke. Whether the abnormal activations are associated with neuronal alterations in the same or homologous area is not known. Objective. Our goal was to establish the relationships between M1 measures of motor-task-related activation and a neuronal marker, N-acetylaspartate (NAA), in patients with severe to mild hemiparesis. Methods. A total of 18 survivors of an ischemic subcortical stroke (confirmed on T2-weighted images) at more than six months post-onset and 16 age- and sex-matched right-handed healthy controls underwent functional MRI during a handgrip task (impaired hand in patients, dominant hand in controls) and proton magnetic resonance spectroscopy ((1)H-MRS) imaging. Spatial extent and magnitude of blood oxygen level-dependent response (or activation) and NAA levels were measured in each M1. Relationships between activation and NAA were determined. Results. Compared with controls, patients had a greater extent of contralesional (ipsilateral to impaired hand, P < .001) activation and a higher magnitude of activation and lower NAA in both ipsilesional (P = .008 and P < .001, respectively) and contralesional (P < .0001, P < .05) M1. There were significant negative correlations between extent of activation and NAA in each M1 (P = .02) and a trend between contralesional activation and ipsilesional NAA (P = .08) in patients but not in controls. Conclusions. Our results suggest that after stroke greater neuronal recruitment could be a compensatory response to lower neuronal metabolism. Thus, dual-modality imaging may be a powerful tool for providing complementary probes of post-stroke brain reorganization.

Neuron, 2010

Despite its increasing use in experimental and clinical settings, the cellular and molecular mech... more Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNFsecretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Nature Communications, 2013

Brain oscillations reflect pattern formation of cell assemblies&a... more Brain oscillations reflect pattern formation of cell assemblies' activity, which is often disturbed in neurological and psychiatric diseases like depression, schizophrenia and stroke. In the neurobiological analysis and treatment of these conditions, transcranial electric currents applied to the brain proved beneficial. However, the direct effects of these currents on brain oscillations have remained an enigma because of the inability to record them simultaneously. Here we report a novel strategy that resolves this problem. We describe accurate reconstructed localization of dipolar sources and changes of brain oscillatory activity associated with motor actions in primary cortical brain regions undergoing transcranial electric stimulation. This new method allows for the first time direct measurement of the effects of non-invasive electrical brain stimulation on brain oscillatory activity and behavior.

Journal of Neurophysiology, 2005

Abnormalities of inhibitory neuronal mechanisms in the motor cortex of patients with schizophreni... more Abnormalities of inhibitory neuronal mechanisms in the motor cortex of patients with schizophrenia. Pharmacopsychiatry 37: 74 -80, 2004. Boroojerdi B, Hungs M, Mull M, Topper R, and Noth J. Interhemispheric inhibition in patients with multiple sclerosis. Electroencephalogr Clin Neurophysiol 109: 230 -237, 1998. Boroojerdi B, Topper R, Foltys H, and Meincke U. Transcallosal inhibition and motor conduction studies in patients with schizophrenia using transcranial magnetic stimulation. . One-hertz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans. Neurosci Lett 336: 131-133, 2003. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, and Cohen LG. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48: 1398 -1403, 1997. Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky RB, and Kapur S. Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. Arch Gen Psychiatry 59: 347-354, 2002a. Daskalakis ZJ, Christensen BK, Fitzgerald PB, Roshan L, and Chen R. The mechanisms of interhemispheric inhibition in the human motor cortex. J Physiol 15: 317-326, 2002b. Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, Tonali P, and Rothwell JC. Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation. Exp Brain Res 124: 520 -524, 1999. Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, and Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol 453: 525-546, 1992. Gazzaniga MS. Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition? Brain 123: 1293-1326, 2000. Geffen GM, Jones DL, and Geffen LB. Interhemispheric control of manual motor activity. Behav Brain Res 20: 131-140, 1994. Gerloff C, Cohen LG, Floeter MK, Chen R, Corwell B, and Hallett M. Inhibitory influence of the ipsilateral cortex on responses to stimulation of the human cortex and pyramidal tract. J Physiol 510: 249 -259, 1998. Hanajima R, Ugawa Y, Okabe S, Yuasa K, Shiio Y, Iwata NK, and Kanazawa I. Interhemispheric interaction between the hand motor areas in patients with cortical myclonus. magnetic stimulation as a complementary treatment for aphasia. Semin Speech Lang 25: 181-191, 2004. Murase N, Duque J, Mazzocchio R, and Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke.

Rapid response inhibition of an on-going action or an urge for a habitual response (i.e., an impu... more Rapid response inhibition of an on-going action or an urge for a habitual response (i.e., an impulse) is a critical human cognitive ability. Recent studies identified a prefrontal-basal-ganglia (PBG) neural network underlying response inhibition using a stop-signal response (SSR) task in which subjects were given a stop signal shortly after a “go” response signal (Verbruggen and Logan, 2009). A central assumption of rapid response inhibition (as with the SSR paradigm) is that the inhibition and “go” processes are independent and that active inhibition follows the “go” process. However, the temporal relation between the “go” and inhibition processes is not well understood. We tested the hypothesis that rapid inhibition of a response is influenced by the extent of activation in the inhibitory network prior to all responses. We used an event-related functional magnetic resonance imaging (efMRI) method with three experimental tasks: a modified SSR task, a response-interference (RI) task...

Trends in cognitive sciences, Jan 10, 2015

A vital property of the brain is its plasticity, which manifests as changes in behavioral perform... more A vital property of the brain is its plasticity, which manifests as changes in behavioral performance. Invasive studies at the cellular level in animal models reveal time-restricted windows during which existing memories that are reactivated become susceptible to modification through reconsolidation, and evidence suggests similar effects in humans. In this review we summarize recent work utilizing noninvasive brain stimulation in humans to uncover the systems-level mechanisms underlying memory reconsolidation. This novel understanding of memory dynamics may have far-reaching clinical implications, including the potential to modulate reconsolidation in patients with memory disorders.

Neurorehabilitation and Neural Repair, 2015

In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to inte... more In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to interhemispheric and intracortical inhibition in affected hand muscles. In less fully recovered patients unable to move their hand, the neural substrates of recovered arm movements, crucial for performance of daily living tasks, are not well understood. Here, we evaluated interhemispheric and intracortical inhibition in paretic arm muscles of patients with no recovery of hand movement (n = 16, upper extremity Fugl-Meyer Assessment = 27.0 ± 8.6). We recorded silent periods (contralateral and ipsilateral) induced by transcranial magnetic stimulation during voluntary isometric contraction of the paretic biceps and triceps brachii muscles (correlates of intracortical and interhemispheric inhibition, respectively) and investigated links between the silent periods and motor recovery, an issue that has not been previously explored. We report that interhemispheric inhibition, stronger in the paretic triceps than biceps brachii muscles, significantly correlated with the magnitude of residual impairment (lower Fugl-Meyer scores). In contrast, intracortical inhibition in the paretic biceps brachii, but not in the triceps, correlated positively with motor recovery (Fugl-Meyer scores) and negatively with spasticity (lower Modified Ashworth scores). Our results suggest that interhemispheric inhibition and intracortical inhibition of paretic upper arm muscles relate to motor recovery in different ways. While interhemispheric inhibition may contribute to poorer recovery, muscle-specific intracortical inhibition may relate to successful motor recovery and lesser spasticity.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2014

Interindividual differences in the effects of reward on performance are prevalent and poorly unde... more Interindividual differences in the effects of reward on performance are prevalent and poorly understood, with some individuals being more dependent than others on the rewarding outcomes of their actions. The origin of this variability in reward dependence is unknown. Here, we tested the relationship between reward dependence and brain structure in healthy humans. Subjects trained on a visuomotor skill-acquisition task and received performance feedback in the presence or absence of reward. Reward dependence was defined as the statistical trial-by-trial relation between reward and subsequent performance. We report a significant relationship between reward dependence and the lateral prefrontal cortex, where regional gray-matter volume predicted reward dependence but not feedback alone. Multivoxel pattern analysis confirmed the anatomical specificity of this relationship. These results identified a likely anatomical marker for the prospective influence of reward on performance, which ma...

Frontiers in behavioral neuroscience, 2014

Transcranial direct current stimulation (tDCS) improves motor learning and can affect emotional p... more Transcranial direct current stimulation (tDCS) improves motor learning and can affect emotional processing and attention. However, it is unclear whether learned electroencephalography (EEG)-based brain-machine interface (BMI) control during tDCS is feasible, how application of transcranial electric currents during BMI control would interfere with feature-extraction of physiological brain signals and how it affects brain control performance. Here we tested this combination and evaluated stimulation-dependent artifacts across different EEG frequencies and stability of motor imagery-based BMI control. Ten healthy volunteers were invited to two BMI-sessions, each comprising two 60-trial blocks. During the trials, learned desynchronization of mu-rhythms (8-15 Hz) associated with motor imagery (MI) recorded over C4 was translated into online cursor movements on a computer screen. During block 2, either sham (session A) or anodal tDCS (session B) was applied at 1 mA with the stimulation el...

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002

The human motor cortex contains a dynamic and distributed network of motor representations. Forma... more The human motor cortex contains a dynamic and distributed network of motor representations. Formation, maintenance, and modification of these representations is an activity-driven process. Repeated stimulation of one representation results in increased motor output from this representation, a process referred to as "within-representation plasticity." We showed previously that within-representation plasticity of the upper arm representation occurs when repetitive transcranial magnetic stimulation (rTMS) is delivered to that representation during transient ischemic nerve block (INB) of the contralateral hand. INB reduces inhibition in the motor cortex and thus lowers the threshold for stimulation-induced plasticity. Here we studied the effects of rTMS delivered to nearby body part representations on the motor output from the upper arm representation. Six healthy subjects underwent INB-alone (control), or INB plus 30 min of focal 0.1 Hz rTMS of either the face, hand, arm, leg...

Journal of Cognitive Neuroscience, 2015

■ Sequence learning relies on formation of unconscious transitional and conscious ordinal memorie... more ■ Sequence learning relies on formation of unconscious transitional and conscious ordinal memories. The influence of practice type on formation of these memories that compose skill and systems level neural substrates is not known. Here, we studied learning of transitional and ordinal memories in participants trained on motor sequences while scanned using fMRI. Practice structure was varied or grouped (mixing or grouping sequences during training, respectively). Memory was assessed 30 min and 1 week later. Varied practice improved transitional memory and enhanced coupling of the dorsal premotor cortex with thalamus, cerebellum, and lingual and cingulate regions and greater transitional memory correlated with this coupling. Thus, varied practice improves unconscious transitional memories in proportion to coupling within a corticosubcortical network linked to premotor cortex. This result indicates that practice structure influences unconscious transitional memory formation and identifies underlying systems level mechanisms. ■

Frontiers in Human Neuroscience, 2014

Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallet... more Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallett, Editors 2013 Published by Elsevier B.V.

Annals of Clinical and Translational Neurology, 2014

Objective: Stroke is a leading cause of long-term motor disability. Stroke patients with severe h... more Objective: Stroke is a leading cause of long-term motor disability. Stroke patients with severe hand weakness do not profit from rehabilitative treatments. Recently, brain-controlled robotics and sequential functional electrical stimulation allowed some improvement. However, for such therapies to succeed, it is required to decode patients' intentions for different arm movements. Here, we evaluated whether residual muscle activity could be used to predict movements from paralyzed joints in severely impaired chronic stroke patients. Methods: Muscle activity was recorded with surface-electromyography (EMG) in 41 patients, with severe hand weakness (Fugl-Meyer Assessment [FMA] hand subscores of 2.93 AE 2.7), in order to decode their intention to perform six different motions of the affected arm, required for voluntary muscle activity and to control neuroprostheses. Decoding of paretic and nonparetic muscle activity was performed using a feed-forward neural network classifier. The contribution of each muscle to the intended movement was determined. Results: Decoding of up to six arm movements was accurate (>65%) in more than 97% of nonparetic and 46% of paretic muscles. Interpretation: These results demonstrate that some level of neuronal innervation to the paretic muscle remains preserved and can be used to implement neurorehabilitative treatments in 46% of patients with severe paralysis and extensive cortical and/or subcortical lesions. Such decoding may allow these patients for the first time after stroke to control different motions of arm prostheses through muscle-triggered rehabilitative treatments.

Frontiers in Human Neuroscience, 2015

Frontiers in Aging Neuroscience, 2014

Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder tr... more Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder triggers reconsolidation, a time-limited period during which existing memories can be modified (i.e., weakened or strengthened). Episodic memory refers to our ability to recall specific past events about what happened, including where and when. Difficulties in this form of long-term memory commonly occur in healthy aging. Because episodic memory is critical for daily life functioning, the development of effective interventions to reduce memory loss in elderly individuals is of great importance. Previous studies in young adults showed that the dorsolateral prefrontal cortex (DLPFC) plays a causal role in strengthening of verbal episodic memories through reconsolidation. The aim of the present study was to explore the extent to which facilitatory transcranial direct current stimulation (anodal tDCS) over the left DLPFC would strengthen existing episodic memories through reconsolidation in elderly individuals. On Day 1, older adults learned a list of 20 words. On Day 2 (24 h later), they received a reminder or not, and after 10 min tDCS was applied over the left DLPFC. Memory recall was tested on Day 3 (48 h later) and . Surprisingly, anodal tDCS over the left DLPFC (i.e., with or without the reminder) strengthened existing verbal episodic memories and reduced forgetting compared to sham stimulation. These results provide a framework for testing the hypothesis that facilitatory tDCS of left DLPFC might strengthen existing episodic memories and reduce memory loss in older adults with amnestic mild cognitive impairment.

Frontiers in Neuroscience, 2005

Proceedings of the National Academy of Sciences, 2009

Motor skills can take weeks to months to acquire and can diminish over time in the absence of con... more Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and betweenday (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention.

Neurorehabilitation and Neural Repair, 2011

Background-The neurophysiological mechanisms underlying improved upper-extremity motor skills hav... more Background-The neurophysiological mechanisms underlying improved upper-extremity motor skills have been partially investigated in patients with good motor recovery but are poorly understood in more impaired individuals, the majority of stroke survivors.

Neurorehabilitation and Neural Repair, 2010

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corti... more Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non-invasively. Since these early studies, the development of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up-to-date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

Neurorehabilitation and Neural Repair, 2013

Background. Abnormal task-related activation in primary motor cortices (M1) has been consistently... more Background. Abnormal task-related activation in primary motor cortices (M1) has been consistently found in functional imaging studies of subcortical stroke. Whether the abnormal activations are associated with neuronal alterations in the same or homologous area is not known. Objective. Our goal was to establish the relationships between M1 measures of motor-task-related activation and a neuronal marker, N-acetylaspartate (NAA), in patients with severe to mild hemiparesis. Methods. A total of 18 survivors of an ischemic subcortical stroke (confirmed on T2-weighted images) at more than six months post-onset and 16 age- and sex-matched right-handed healthy controls underwent functional MRI during a handgrip task (impaired hand in patients, dominant hand in controls) and proton magnetic resonance spectroscopy ((1)H-MRS) imaging. Spatial extent and magnitude of blood oxygen level-dependent response (or activation) and NAA levels were measured in each M1. Relationships between activation and NAA were determined. Results. Compared with controls, patients had a greater extent of contralesional (ipsilateral to impaired hand, P < .001) activation and a higher magnitude of activation and lower NAA in both ipsilesional (P = .008 and P < .001, respectively) and contralesional (P < .0001, P < .05) M1. There were significant negative correlations between extent of activation and NAA in each M1 (P = .02) and a trend between contralesional activation and ipsilesional NAA (P = .08) in patients but not in controls. Conclusions. Our results suggest that after stroke greater neuronal recruitment could be a compensatory response to lower neuronal metabolism. Thus, dual-modality imaging may be a powerful tool for providing complementary probes of post-stroke brain reorganization.

Neuron, 2010

Despite its increasing use in experimental and clinical settings, the cellular and molecular mech... more Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNFsecretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Nature Communications, 2013

Brain oscillations reflect pattern formation of cell assemblies&a... more Brain oscillations reflect pattern formation of cell assemblies' activity, which is often disturbed in neurological and psychiatric diseases like depression, schizophrenia and stroke. In the neurobiological analysis and treatment of these conditions, transcranial electric currents applied to the brain proved beneficial. However, the direct effects of these currents on brain oscillations have remained an enigma because of the inability to record them simultaneously. Here we report a novel strategy that resolves this problem. We describe accurate reconstructed localization of dipolar sources and changes of brain oscillatory activity associated with motor actions in primary cortical brain regions undergoing transcranial electric stimulation. This new method allows for the first time direct measurement of the effects of non-invasive electrical brain stimulation on brain oscillatory activity and behavior.

Journal of Neurophysiology, 2005

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