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ABSTRACT: Spike timing-dependent plasticity (STDP) has been proposed as one of the key mechanisms underlying learning and memory. Repetitive median nerve stimulation (MNS) followed by transcranial magnetic stimulation (TMS) of the contralateral primary motor cortex (M1), defined as paired associative stimulation (PAS), has been used as an in vivo model of STDP in humans. PAS-induced excitability changes in M1 have been repeatedly shown to be time-dependent in an STDP-like fashion since synchronous arrival of inputs within M1 induces long term potentiation (LTP)-like effects while an asynchronous arrival induces long term depression (LTD)-like effects. Here we show that interhemispheric inhibition of the sensorimotor network during PAS with the peripheral stimulation over the hand ipsilateral to the motor cortex receiving TMS (ipsi-PAS) results in an LTD-like effect, as opposed to the standard STDP-like effect seen for contralateral PAS. Furthermore, we could show that this reversed associative plasticity critically depends on the timing interval between afferent and cortical stimulation. These results indicate that the outcome of associative stimulation in the human brain depends on functional network interactions (inhibition or facilitation) at a systems level and can either follow standard or reversed STDP-like plasticity.
Journal of Neurophysiology 02/2013; · 3.32 Impact Factor
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ABSTRACT: Spike timing-dependent plasticity (STDP) has been proposed as one of the key mechanisms underlying learning and memory. Repetitive median nerve stimulation (MNS) followed by transcranial magnetic stimulation (TMS) of the contralateral primary motor cortex (M1), defined as paired associative stimulation (PAS), has been used as an in vivo model of STDP in humans. PAS-induced excitability changes in M1 have been repeatedly shown to be time-dependent in an STDP-like fashion since synchronous arrival of inputs within M1 induces long term potentiation (LTP)-like effects while an asynchronous arrival induces long term depression (LTD)-like effects. Here we show that interhemispheric inhibition of the sensorimotor network during PAS with the peripheral stimulation over the hand ipsilateral to the motor cortex receiving TMS (ipsi-PAS) results in an LTD-like effect, as opposed to the standard STDP-like effect seen for contralateral PAS. Furthermore, we could show that this reversed associative plasticity critically depends on the timing interval between afferent and cortical stimulation. These results indicate that the outcome of associative stimulation in the human brain depends on functional network interactions (inhibition or facilitation) at a systems level and can either follow standard or reversed STDP-like plasticity.
Journal of Neurophysiology 02/2013; · 3.32 Impact Factor
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ABSTRACT: In this chapter we address the phenomena of neural plasticity, operationally defined as the ability of the central nervous system to adapt in response to changes in the environment or lesions. At the cellular level, we discuss basic changes in membrane excitability, synaptic plasticity as well as structural changes in dendritic and axonal anatomy that support behavioral expressions of plasticity and functional recovery. We consider the different levels at which these changes can occur and possible links with modification of cognitive strategies, recruitment of new/different neural networks, or changes in strength of such connections or specific brain areas in charge of carrying out a particular task (i.e., movement, language, vision, hearing). The study of neuroplasticity has wide-reaching implications for understanding reorganization of action and cognition in the healthy and lesioned brain.
Handbook of Clinical Neurology 01/2013; 110:3-12.
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ABSTRACT: Performance of unimanual movements is associated with bihemispheric activity in the motor cortex in old adults. However, the causal functional role of the ipsilateral MC (iMC) for motor control is still not completely known. Here, the behavioral consequences of interference of the iMC during training of a complex motor skill were tested. Healthy old (58-85 years) and young volunteers (22-35 years) were tested in a double-blind, cross-over, sham-controlled design. Participants attended 2 different study arms with either cathodal transcranial direct current stimulation (ctDCS) or sham concurrent with training. Motor performance was evaluated before, during, 90 min, and 24 h after training. During training, a reduced slope of performance with ctDCS relative to sham was observed in old compared with young (F = 5.8, P = 0.02), with a decrease of correctly rehearsed sequences, an effect that was evident even after 2 consecutive retraining periods without intervention. Furthermore, the older the subject, the more prominent was the disruptive effect of ctDCS (R(2) = 0.50, P = 0.01). These data provide direct evidence for a causal functional link between the iMC and motor skill acquisition in old subjects pointing toward the concept that the recruitment of iMC in old is an adaptive process in response to age-related declines in motor functions.
Cerebral Cortex 12/2012; · 6.54 Impact Factor
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ABSTRACT: OBJECTIVE: Decline in cognitive functions, including impaired acquisition of novel skills, is a feature of older age that impacts activities of daily living, independence, and integration in modern societies. METHODS: We tested whether the acquisition of a complex motor skill can be enhanced in old subjects by the application of transcranial direct current stimulation (tDCS) to the motor cortex. RESULTS: The main finding was that old participants experienced substantial improvements when training was applied concurrent with tDCS, with effects lasting for at least 24 hours. INTERPRETATION: These results suggest noninvasive brain stimulation as a promising and safe tool to potentially assist functional independence of aged individuals in daily life. ANN NEUROL 2012.
Annals of Neurology 09/2012; · 11.09 Impact Factor
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ABSTRACT: The adult mammalian brain has a remarkable capacity to learn in both the perceptual and motor domains through the formation and consolidation of memories. Such practice-enabled procedural learning results in perceptual and motor skill improvements. Here, we examine evidence supporting the notion that perceptual and motor learning in humans exhibit analogous properties, including similarities in temporal dynamics and the interactions between primary cortical and higher-order brain areas. These similarities may point to the existence of a common general mechanism for learning in humans.
Nature Reviews Neuroscience 08/2012; 13(9):658-64. · 26.48 Impact Factor
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ABSTRACT: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.
We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).
Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.
Since long interval intracortical inhibition and cortical silent period are thought to reflect GABA(B) receptor-mediated inhibitory circuits, our results point to a particularly GABA(B)-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABA(B) receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABA(B)-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders.
Neurology 06/2012; 79(1):47-54. · 8.31 Impact Factor
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ABSTRACT: Mechanisms of skill learning are paramount components for stroke recovery. Recent noninvasive brain stimulation studies demonstrated that decreasing activity in the contralesional motor cortex might be beneficial, providing transient functional improvements after stroke. The more crucial question, however, is whether this intervention can also enhance the acquisition of complex motor tasks, yielding longer-lasting functional improvements. In the present study, we tested the capacity of cathodal transcranial direct current stimulation (tDCS) applied over the contralesional motor cortex during training to enhance the acquisition and retention of complex sequential finger movements of the paretic hand.
Twelve well-recovered chronic patients with subcortical stroke attended 2 training sessions during which either cathodal tDCS or a sham intervention were applied to the contralesional motor cortex in a double-blind, crossover design. Two different motor sequences, matched for their degree of complexity, were tested in a counterbalanced order during as well as 90 minutes and 24 hours after the intervention. Potential underlying mechanisms were evaluated with transcranial magnetic stimulation.
tDCS facilitated the acquisition of a new motor skill compared with sham stimulation (P=0.04) yielding better task retention results. A significant correlation was observed between the tDCS-induced improvement during training and the tDCS-induced changes of intracortical inhibition (R(2)=0.63).
These results indicate that tDCS is a promising tool to improve not only motor behavior, but also procedural learning. They further underline the potential of noninvasive brain stimulation as an adjuvant treatment for long-term recovery, at least in patients with mild functional impairment after stroke.
Stroke 05/2012; 43(8):2185-91. · 5.73 Impact Factor
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ABSTRACT: The human brain possesses a remarkable ability to adapt in response to changing anatomical (e.g., aging) or environmental modifications. This form of neuroplasticity is important at all stages of life but is critical in neurological disorders such as amblyopia and stroke. This review focuses upon our new understanding of possible mechanisms underlying functional deficits evidenced after adult-onset stroke. We review the functional interactions between different brain regions that may contribute to motor disability after stroke and, based on this information, possible interventional approaches to motor stroke disability. New information now points to the involvement of non-primary motor areas and their interaction with the primary motor cortex as areas of interest. The emergence of this new information is likely to impact new efforts to develop more effective neurorehabilitative interventions using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) that may be relevant to other neurological disorders such as amblyopia.
Developmental Psychobiology 04/2012; 54(3):254-62. · 2.98 Impact Factor
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ABSTRACT: Transcranial magnetic stimulation and neuroimaging data have revealed bilateral posterior parietal cortex (PPC) involvement during verbal n-back working memory (WM). In this task as n (i.e., WM load) increases, subjects show poorer behavioral performance as well as greater activation of this brain area. Moreover, there is evidence that a brief period of practice or even increased familiarity with the task can improve WM performance and lead to activation changes in the PPC. The aim of this study was to investigate, using transcranial direct current stimulation (tDCS), the effects on WM load performance induced by different PPC modulation after increased familiarity with the task. After a short practice, we tested verbal WM using an n-back task (1-back vs. 2-back) before and after the application of bilateral tDCS over PPCs (left anodal-right cathodal, left cathodal-right anodal or sham). ANOVA showed a significant interaction between tDCS and task. In the 1-back task, left anodal-right cathodal modulation abolished improvement in reaction times observed in the other two modulation conditions. Conversely, in the 2-back task the same effect was observed after left cathodal-right anodal modulation relative to the other two modulation conditions. This double dissociation demonstrates either a differential engagement of each PPC or changes in the interhemispheric balance of activity across this brain region. Neuroimaging studies show parametric activation of the PPC as difficulty increases, but activation does not switch sides. Thus, our observed effects cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we suggest that these findings reflect the use of different processing strategies to perform these two tasks. In conclusion, after increased familiarity with the task, different tDCS modulations lead to changes in a task-related region depending on differences in processing strategies in 1-back vs. 2-back.
Neuropsychologia 02/2012; 50(3):396-402. · 3.64 Impact Factor
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ABSTRACT: Chronic stroke patients with heterogeneous lesions, but no direct damage to the primary sensorimotor cortex, are capable of longitudinally acquiring the ability to modulate sensorimotor rhythms using grasping imagery of the affected hand. Volitional modulation of neural activity can be used to drive grasping functions of the paralyzed hand through a brain-computer interface. The neural substrates underlying this skill are not known. Here, we investigated the impact of individual patient's lesion pathology on functional and structural network integrity related to this volitional skill. Magnetoencephalography data acquired throughout training was used to derive functional networks. Structural network models and local estimates of extralesional white matter microstructure were constructed using T(1)-weighted and diffusion-weighted magnetic resonance imaging data. We employed a graph theoretical approach to characterize emergent properties of distributed interactions between nodal brain regions of these networks. We report that interindividual variability in patients' lesions led to differential impairment of functional and structural network characteristics related to successful post-training sensorimotor rhythm modulation skill. Patients displaying greater magnetoencephalography global cost-efficiency, a measure of information integration within the distributed functional network, achieved greater levels of skill. Analysis of lesion damage to structural network connectivity revealed that the impact on nodal betweenness centrality of the ipsilesional primary motor cortex, a measure that characterizes the importance of a brain region for integrating visuomotor information between frontal and parietal cortical regions and related thalamic nuclei, correlated with skill. Edge betweenness centrality, an analogous measure, which assesses the role of specific white matter fibre pathways in network integration, showed a similar relationship between skill and a portion of the ipsilesional superior longitudinal fascicle connecting premotor and posterior parietal visuomotor regions known to be crucially involved in normal grasping behaviour. Finally, estimated white matter microstructure integrity in regions of the contralesional superior longitudinal fascicle adjacent to primary sensorimotor and posterior parietal cortex, as well as grey matter volume co-localized to these specific regions, positively correlated with sensorimotor rhythm modulation leading to successful brain-computer interface control. Thus, volitional modulation of ipsilesional neural activity leading to control of paralyzed hand grasping function through a brain-computer interface after longitudinal training relies on structural and functional connectivity in both ipsilesional and contralesional parietofrontal pathways involved in visuomotor information processing. Extant integrity of this structural network may serve as a future predictor of response to longitudinal therapeutic interventions geared towards training sensorimotor rhythms in the lesioned brain, secondarily improving grasping function through brain-computer interface applications.
Brain 02/2012; 135(Pt 2):596-614. · 9.46 Impact Factor
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Adriana B Conforto,
Sarah M Anjos,
Gustavo Saposnik,
Eduardo A Mello,
Erina M Nagaya,
Waldyr Santos,
Karina N Ferreiro,
Eduardo S Melo,
Felipe I Reis,
Milberto Scaff, Leonardo G Cohen
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ABSTRACT: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere can enhance function of the paretic hand in patients with mild motor impairment. Effects of low-frequency rTMS to the contralesional motor cortex at an early stage of mild to severe hemiparesis after stroke are unknown. In this pilot, randomized, double-blind clinical trial we compared the effects of low-frequency rTMS or sham rTMS as add-on therapies to outpatient customary rehabilitation, in 30 patients within 5-45 days after ischemic stroke, and mild to severe hand paresis. The primary feasibility outcome was compliance with the interventions. The primary safety outcome was the proportion of intervention-related adverse events. Performance of the paretic hand in the Jebsen-Taylor test and pinch strength were secondary outcomes. Outcomes were assessed at baseline, after ten sessions of treatment administered over 2 weeks and at 1 month after end of treatment. Baseline clinical features were comparable across groups. For the primary feasibility outcome, compliance with treatment was 100% in the active group and 94% in the sham group. There were no serious intervention-related adverse events. There were significant improvements in performance in the Jebsen-Taylor test (mean, 12.3% 1 month after treatment) and pinch force (mean, 0.5 Newtons) in the active group, but not in the sham group. Low-frequency rTMS to the contralesional motor cortex early after stroke is feasible, safe and potentially effective to improve function of the paretic hand, in patients with mild to severe hemiparesis. These promising results will be valuable to design larger randomized clinical trials.
Journal of Neurology 12/2011; 259(7):1399-405. · 3.47 Impact Factor
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ABSTRACT: Purposeful manipulation of cortical plasticity and excitability within somatosensory regions may have therapeutic potential. Non-invasive brain stimulation (NBS) techniques such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) have shown promise towards this end with certain NBS protocols augmenting somatosensory processing and others down-regulating it. Here, we review NBS protocols which, when applied to primary somatosensory cortex, facilitate cortical excitability and tactile acuity (i.e., high-frequency repetitive TMS (rTMS), intermittent theta burst stimulation (TBS), paired associative stimulation (PAS) N20-5 to 0, anodal tDCS), and protocols that inhibit the same (i.e., low-frequency rTMS, continuous TBS, PAS N20-20, cathodal tDCS). Other studies have targeted multisensory regions of the brain to modulate somatosensory processing. These studies in full present a wide array of strategies in which NBS can be utilized to influence somatosensory processing in a behaviorally and clinically relevant capacity.
Restorative neurology and neuroscience 11/2011; 29(6):427-37. · 2.51 Impact Factor
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ABSTRACT: Recent years have seen significant progress in our understanding of the neural substrates of motor skill learning. Advances in neuroimaging provide new insight into functional reorganization associated with the acquisition, consolidation, and retention of motor skills. Plastic changes involving structural reorganization in gray and white matter architecture that occur over shorter time periods than previously thought have been documented as well. Data from experimental animals provided crucial information on plausible cellular and molecular substrates contributing to brain reorganization underlying skill acquisition in humans. Here, we review findings demonstrating functional and structural plasticity across different spatial and temporal scales that mediate motor skill learning while identifying converging areas of interest and possible avenues for future research.
Neuron 11/2011; 72(3):443-54. · 14.74 Impact Factor
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ABSTRACT: Event-related desynchronization (ERD) of sensori-motor rhythms (SMR) can be used for online brain-machine interface (BMI) control, but yields challenges related to the stability of ERD and feedback strategy to optimize BMI learning.Here, we compared two approaches to this challenge in 20 right-handed healthy subjects (HS, five sessions each, S1-S5) and four stroke patients (SP, 15 sessions each, S1-S15). ERD was recorded from a 275-sensor MEG system. During daily training,motor imagery-induced ERD led to visual and proprioceptive feedback delivered through an orthotic device attached to the subjects' hand and fingers. Group A trained with a heterogeneous reference value (RV) for ERD detection with binary feedback and Group B with a homogenous RV and graded feedback (10 HS and 2 SP in each group). HS in Group B showed better BMI performance than Group A (p < 0.001) and improved BMI control from S1 to S5 (p = 0.012) while Group A did not. In spite of the small n, SP in Group B showed a trend for a higher BMI performance (p = 0.06) and learning was significantly better (p < 0.05). Using a homogeneous RV and graded feedback led to improved modulation of ipsilesional activity resulting in superior BMI learning relative to use of a heterogeneous RV and binary feedback.
IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society 10/2011; 19(5):542-9. · 2.42 Impact Factor
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ABSTRACT: Transcranial magnetic (TMS) and direct current (tDCS) stimulation are non-invasive brain stimulation techniques that allow researchers to purposefully modulate cortical excitability in focal areas of the brain. Recent work has provided preclinical evidence indicating that TMS and tDCS can facilitate motor performance, motor memory formation, and motor skill learning in healthy subjects and possibly in patients with brain lesions. Although the optimal stimulation parameters to accomplish these goals remain to be determined, and controlled multicentre clinical studies are lacking, these findings suggest that cortical stimulation techniques could become in the future adjuvant strategies in the rehabilitation of motor deficits. The aim of this article is to critically review these findings and to discuss future directions regarding the possibility of combining these techniques with other interventions in neurorehabilitation.
Neuropsychological Rehabilitation 09/2011; 21(5):650-75. · 1.72 Impact Factor
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ABSTRACT: We value skills we have learned intentionally, but equally important are skills acquired incidentally without ability to describe how or what is learned, referred to as implicit. Randomized practice schedules are superior to grouped schedules for long-term skill gained intentionally, but its relevance for implicit learning is not known. In a parallel design, we studied healthy subjects who learned a motor sequence implicitly under randomized or grouped practice schedule and obtained diffusion-weighted images to identify white matter microstructural correlates of long-term skill. Randomized practice led to superior long-term skill compared with grouped practice. Whole-brain analyses relating interindividual variability in fractional anisotropy (FA) to long-term skill demonstrated that 1) skill in randomized learners correlated with FA within the corticostriatal tract connecting left sensorimotor cortex to posterior putamen, while 2) skill in grouped learners correlated with FA within the right forceps minor connecting homologous regions of the prefrontal cortex (PFC) and the corticostriatal tract connecting lateral PFC to anterior putamen. These results demonstrate first that randomized practice schedules improve long-term implicit skill more than grouped practice schedules and, second, that the superior skill acquired through randomized practice can be related to white matter microstructure in the sensorimotor corticostriatal network.
Cerebral Cortex 09/2011; 22(7):1671-7. · 6.54 Impact Factor
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ABSTRACT: Neuroplasticity induced by transcranial direct current stimulation (tDCS) contributes to motor learning although the underlying mechanisms are incompletely understood. Here, we investigated the effects of tDCS on resting brain dynamics recorded by whole-head magnetoencephalography (MEG) pre- and up to 35 minutes post-tDCS or sham over the left primary motor cortex (M1) in healthy adults. Owing to superior temporal and spatial resolution of MEG, we sought to apply a robust, blind and data-driven analytic approach such as independent component analysis (ICA) and statistical clustering to these data to investigate potential neuroplastic effects of tDCS during resting state conditions. We found decreased alpha and increased gamma band power that outlasted the real tDCS stimulation period in a fronto-parietal motor network relative to sham. However, this method could not find differences between anodal and cathodal polarities of tDCS. These results suggest that tDCS over M1 modulates resting brain dynamics in a fronto-parietal motor network (that includes the stimulated location), indicative of within-network enhanced localized cortical processing.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:8102-5.
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ABSTRACT: In relapsing-remitting multiple sclerosis (RRMS) the corpus callosum (CC) is often and early affected by macroscopic lesions when investigated by conventional MRI. We sought to determine to which extent microstructural and effective disconnection of the CC are already present in RRMS patients at the earliest stages of the disease prior to evidence of macroscopic CC lesion. We compared 16 very early RRMS patients (median expanded disability status scale (EDSS), 1.5; range, 0-2.0) to an age-matched group of healthy controls and focused analysis to the motor CC, i.e. that part of the CC relaying interhemispheric motor information. A combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure was applied to identify the callosal motor fibers (CMFs) connecting the hand areas of the primary motor cortices of the two hemispheres. Fractional anisotropy (FA) within the motor CC (FA-CC) assessed the CMF microstructural integrity. Bifocal paired transcranial magnetic stimulation (TMS) tested short-interval interhemispheric inhibition (S-IHI), an established measure of CMF effective connectivity. FA-CC and S-IHI were significantly reduced in early RRMS compared to healthy controls. Furthermore, a significant linear correlation between microstructure (FA-CC) and function (S-IHI) in the controls was broken down in the patients. These abnormalities were obtained in the absence of macroscopic CMF lesion in conventional MRI, and whilst motor hand/arm function in the nine-hole-peg test and corticospinal conduction time were normal. Findings suggest that reductions in FA and S-IHI may serve as surrogate markers of motor callosal disconnection at the earliest stages of RRMS prior to development of macroscopic lesion.
Human Brain Mapping 06/2011; 32(6):846-55. · 5.88 Impact Factor
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ABSTRACT: Convergent findings point to a left-sided specialization for the representation of learned actions in right-handed humans, but it is unknown whether analogous hemispheric specialization exists for motor skill learning. In the present study, we explored this question by comparing the effects of anodal transcranial direct current stimulation (tDCS) over either left or right motor cortex (M1) on motor skill learning in either hand, using a tDCS montage to better isolate stimulation to one hemisphere. Results were compared with those previously found with a montage more commonly used in the field. Six groups trained for three sessions on a visually guided sequential pinch force modulation task with their right or left hand and received right M1, left M1, or sham tDCS. A linear mixed-model analysis for motor skill showed a significant main effect for stimulation group (left M1, right M1, sham) but not for hand (right, left) or their interaction. Left M1 tDCS induced significantly greater skill learning than sham when hand data were combined, a result consistent not only with the hypothesized left hemisphere specialization for motor skill learning but also with possible increased left M1 responsiveness to tDCS. The unihemispheric montage effect size was one-half that of the more common montage, and subsequent power analysis indicated that 75 subjects per group would be needed to detect differences seen with only 12 subjects with the customary bihemispheric montage.
Journal of Neurophysiology 05/2011; 106(2):652-61. · 3.32 Impact Factor
