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ABSTRACT: Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.
Brain 07/2011; 134(Pt 7):1987-2004. · 9.46 Impact Factor
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Steven L Wolf,
Paul A Thompson,
Carolee J Winstein,
J Phillip Miller,
Sarah R Blanton,
Deborah S Nichols-Larsen,
David M Morris,
Gitendra Uswatte,
Edward Taub,
Kathye E Light, Lumy Sawaki
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ABSTRACT: Although constraint-induced movement therapy (CIMT) has been shown to improve upper extremity function in stroke survivors at both early and late stages after stroke, the comparison between participants within the same cohort but receiving the intervention at different time points has not been undertaken. Therefore, the purpose of this study was to compare functional improvements between stroke participants randomized to receive this intervention within 3 to 9 months (early group) to participants randomized on recruitment to receive the identical intervention 15 to 21 months after stroke (delayed group).
Two weeks of CIMT was delivered to participants immediately after randomization (early group) or 1 year later (delayed group). Evaluators blinded to group designation administered primary (Wolf Motor Function Test, Motor Activity Log) and secondary (Stroke Impact Scale) outcome measures among the 106 early participants and 86 delayed participants before delivery of CIMT, 2 weeks thereafter, and 4, 8, and 12 months later.
Although both groups showed significant improvements from pretreatment to 12 months after treatment, the earlier CIMT group showed greater improvement than the delayed CIMT group in Wolf Motor Function Test Performance Time and the Motor Activity Log (P<0.0001), as well as in Stroke Impact Scale Hand and Activities domains (P<0.0009 and 0.0214, respectively). Early and delayed group comparison of scores on these measures 24 months after enrollment showed no statistically significant differences between groups.
CIMT can be delivered to eligible patients 3 to 9 months or 15 to 21 months after stroke. Both patient groups achieved approximately the same level of significant arm motor function 24 months after enrollment. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00057018.
Stroke 10/2010; 41(10):2309-15. · 5.73 Impact Factor
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ABSTRACT: Subjective sensory experiences are constructed by the integration of afferent sensory information with information about the uniquely personal internal cognitive state. The insular cortex is anatomically positioned to serve as one potential interface between afferent processing mechanisms and more cognitively oriented modulatory systems. However, the role of the insular cortex in such modulatory processes remains poorly understood. Two individuals with extensive lesions to the insula were examined to better understand the contribution of this brain region to the generation of subjective sensory experiences. Despite substantial differences in the extent of the damage to the insular cortex, three findings were common to both individuals. First, both subjects had substantially higher pain intensity ratings of acute experimental noxious stimuli than age-matched control subjects. Second, when pain-related activation of the primary somatosensory cortex was examined during left- and right-sided stimulation, both individuals exhibited dramatically elevated activity of the primary somatosensory cortex ipsilateral to the lesioned insula in relation to healthy control subjects. Finally, both individuals retained the ability to evaluate pain despite substantial insular damage and no evidence of detectable insular activity. Together, these results indicate that the insula may be importantly involved in tuning cortical regions to appropriately use previous cognitive information during afferent processing. Finally, these data suggest that a subjectively available experience of pain can be instantiated by brain mechanisms that do not require the insular cortex.
Journal of Neuroscience 04/2009; 29(9):2684-94. · 7.11 Impact Factor
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ABSTRACT: To evaluate the role of 2 noradrenergic drugs in modulating use-dependent plasticity in humans.
Double-blind, randomized, and placebo-controlled crossover design.
A laboratory in a hospital.
A convenience sample of 10 healthy subjects.
An established paradigm that measures motor memory as a short-term model of use-dependent plasticity. Subjects attended 3 sessions, separated by at least 1 week to allow drug washout. Subjects received atomoxetine (Strattera), venlafaxine (Effexor), or placebo.
Increase in the proportion of movements into the training target zone (TTZ), an indicator of enhanced plasticity.
Atomoxetine, but not venlafaxine, significantly increased movements into the TTZ.
These results support a role for norepinephrine in enhancing cortical plasticity and suggest potential benefits in using these drugs for improving motor recovery after stroke.
Archives of Physical Medicine and Rehabilitation 03/2006; 87(2):216-21. · 2.28 Impact Factor
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ABSTRACT: There is a need to develop strategies to enhance the beneficial effects of motor training, including use-dependent plasticity (UDP), in neurorehabilitation. Peripheral nerve stimulation (PNS) modulates motor cortical excitability in healthy humans and could influence training effects in stroke patients.
We compared the ability of PNS applied to the (1) arm, (2) leg, and (3) idle time to influence training effects in the paretic hand in 7 chronic stroke patients. The end point measure was the magnitude of UDP.
UDP was more prominent with arm stimulation (increased by 22.8%) than with idle time (by 2.9%) or leg stimulation (by 6.4%).
PNS applied to the paretic limb paired with motor training enhances training effects on cortical plasticity in stroke patients.
Stroke 02/2006; 37(1):246-7. · 5.73 Impact Factor
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ABSTRACT: Mirror neurons discharge with both action observation and action execution. It has been proposed that the mirror neuron system is instrumental in motor learning. The human primary motor cortex (M1) displays mirror activity in response to movement observation, is capable of forming motor memories, and is involved in motor learning. However, it is not known whether movement observation can lead directly to the formation of motor memories in the M1, which is considered a likely physiological step in motor learning. Here, we used transcranial magnetic stimulation (TMS) to show that observation of another individual performing simple repetitive thumb movements gives rise to a kinematically specific memory trace of the observed motions in M1. An extended period of observation of thumb movements that were oriented oppositely to the previously determined habitual directional bias increased the probability of TMS-evoked thumb movements to fall within the observed direction. Furthermore, the acceleration of TMS-evoked thumb movements along the principal movement axis and the balance of excitability of muscle representations active in the observed movements were altered in favor of the observed movement direction. These findings support a role for the mirror neuron system in memory formation and possibly human motor learning.
Journal of Neuroscience 11/2005; 25(41):9339-46. · 7.11 Impact Factor
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ABSTRACT: The ability of the central nervous system to form motor memories, a process contributing to motor learning and skill acquisition, decreases with age. Dopaminergic activity, one of the mechanisms implicated in memory formation, experiences a similar decline with aging. It is possible that restoring dopaminergic function in elderly adults could lead to improved formation of motor memories with training. We studied the influence of a single oral dose of levodopa (100mg) administered preceding training on the ability to encode an elementary motor memory in the primary motor cortex of elderly and young healthy volunteers in a randomized, double-blind, placebo-controlled design. Attention to the task and motor training kinematics were comparable across age groups and sessions. In young subjects, encoding a motor memory under placebo was more prominent than in older subjects, and the encoding process was accelerated by intake of levodopa. In the elderly group, diminished motor memory encoding under placebo was enhanced by intake of levodopa to levels present in younger subjects. Therefore, upregulation of dopaminergic activity accelerated memory formation in young subjects and restored the ability to form a motor memory in elderly subjects; possible mechanisms underlying the beneficial effects of dopaminergic agents on motor learning in neurorehabilitation.
Annals of Neurology 08/2005; 58(1):121-30. · 11.09 Impact Factor
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Agnes Flöel MD,
Caterina Breitenstein PhD,
Friedhelm Hummel MD,
Pablo Celnik MD,
Christian Gingert BS,
Lumy Sawaki MD,
Stefan Knecht MD,
Leonardo G. Cohen MD,
Agnes Flöel,
Caterina Breitenstein,
Friedhelm Hummel,
Pablo Celnik,
Christian Gingert, Lumy Sawaki,
Stefan Knecht,
Leonardo G. Cohen
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ABSTRACT: The ability of the central nervous system to form motor memories, a process contributing to motor learning and skill acquisition, decreases with age. Dopaminergic activity, one of the mechanisms implicated in memory formation, experiences a similar decline with aging. It is possible that restoring dopaminergic function in elderly adults could lead to improved formation of motor memories with training. We studied the influence of a single oral dose of levodopa (100mg) administered preceding training on the ability to encode an elementary motor memory in the primary motor cortex of elderly and young healthy volunteers in a randomized, double-blind, placebo-controlled design. Attention to the task and motor training kinematics were comparable across age groups and sessions. In young subjects, encoding a motor memory under placebo was more prominent than in older subjects, and the encoding process was accelerated by intake of levodopa. In the elderly group, diminished motor memory encoding under placebo was enhanced by intake of levodopa to levels present in younger subjects. Therefore, upregulation of dopaminergic activity accelerated memory formation in young subjects and restored the ability to form a motor memory in elderly subjects; possible mechanisms underlying the beneficial effects of dopaminergic agents on motor learning in neurorehabilitation. Ann Neurol 2005;58:121–130
Annals of Neurology 06/2005; 58(1):121 - 130. · 11.09 Impact Factor
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ABSTRACT: Motor training consisting of repetitive thumb movements results in encoding of motor memories in the primary motor cortex. It is not known if proprioceptive input originating in the training movements is sufficient to produce this effect. In this study, we compared the ability of training consisting of voluntary (active) and passively-elicited (passive) movements to induce this form of plasticity. Active training led to successful encoding accompanied by characteristic changes in corticomotor excitability, while passive training did not. These results support a pivotal role for voluntary motor drive in coding motor memories in the primary motor cortex.
Journal of Neurophysiology 03/2005; 93(2):1099-103. · 3.32 Impact Factor
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ABSTRACT: Cortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.
Brain 12/2004; 127(Pt 11):2506-17. · 9.46 Impact Factor
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ABSTRACT: Motor training consisting of repetition of directionally specific voluntary thumb movements elicits a short-term memory trace that encodes the kinematic details of the practiced motions in the primary motor cortex. Here, we studied activation patterns associated with this form of training using functional magnetic resonance imaging under careful monitoring of motor training kinematics and electromyography. We identified task-specific reductions in activation in contralateral motor cortex, a region that controls executive motor output, as well as somatosensory cortex and inferior parietal lobule, regions in charge of monitoring motor training kinematics. Our findings are consistent with the hypothesis that a short training period consisting of repetition of finger motions leads to cortical reorganization characterized by a smaller and more efficient network that is specific for the trained movement direction.
NeuroImage 04/2004; 21(3):1182-7. · 5.89 Impact Factor
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ABSTRACT: In healthy individuals, motor training elicits cortical plasticity that encodes the kinematic details of the practiced movements and is thought to underlie recovery of function after stroke. The influence of age on this form of plasticity is incompletely understood. We studied 55 healthy subjects and identified a substantial decrease in training-dependent plasticity as a function of age in the absence of differences in training kinematics. These results suggest that the ability of the healthy aging motor cortex to reorganize in response to training decreases with age.
Annals of Neurology 05/2003; 53(4):521-4. · 11.09 Impact Factor
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ABSTRACT: this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact
11/2002;
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ABSTRACT: An internal model of the dynamics of a tool or an object is part of the motor memory acquired when learning to use the tool or to manipulate the object. Changes in synaptic efficacy may underlie acquisition and storage of memories. Here we studied the effect of pharmacological agents that interfere with synaptic plasticity on acquisition of new motor memories and on recall of a previously learned internal model. Forty-nine subjects, divided into six groups, made reaching movements while holding a robotic arm that applied forces to the hand. On day 1, all subjects learned to move in force field A. On day 2, each group of subjects was tested on their ability to recall field A and their ability to learn a new internal model in field B. Four groups participated in the experiments of day 2 under the effects of lorazepam (LZ; a GABA type A receptor-positive allosteric modulator), dextromethorphan [DM; an N-methyl-D-aspartate (NMDA) receptor blocker], lamotrigine (LG, a drug that blocks voltage-gated Na(+) and Ca(2+) channel), or scopolamine (SP; muscarinic receptor antagonist). Two control groups were tested in a drug-free condition: one group that was not exposed to additional experimental protocols (NP) and another group was tested under ~24 h of sleep deprivation between completion of learning on day 1 and start of testing on day 2 (SD). Recall of field A was normal in all groups. Learning of field B was reduced by LZ and DM but not by SP, LG, SD or in the NP condition. These results suggest that a 24-h sleep-deprivation period may have little or no effect on consolidation of this motor memory and that NMDA receptor activation and GABAergic inhibition are mechanisms operating in the acquisition but not recall of new motor memories in humans.
Journal of Neurophysiology 11/2002; 88(4):2114-23. · 3.32 Impact Factor
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ABSTRACT: In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2-h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M-responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABA(A) receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double-blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory-evoked potentials or (iii) M-responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.
The Journal of Physiology 05/2002; 540(Pt 2):623-33. · 4.72 Impact Factor
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ABSTRACT: Use-dependent plasticity, thought to contribute to functional recovery after brain injury, is elicited by motor training. The purpose of this study was to determine if administration of d-amphetamine facilitates the effects of motor training on use-dependent plasticity. Healthy human volunteers underwent a training period of voluntary thumb movements under the effects of placebo or d-amphetamine in different sessions in a randomized double-blind, counterbalanced design. Previous work in a drug-naive condition showed that such training causes changes in the direction of thumb movements evoked by transcranial magnetic stimulation and in transcranial magnetic stimulation-evoked electromyographic responses. The endpoint measure of the study was the magnitude of training-induced changes in transcranial magnetic stimulation-evoked kinematic and electromyographic responses in the d-amphetamine and in the placebo conditions. Motor training resulted in increased magnitude, faster development and longer lasting duration of use-dependent plasticity under d-amphetamine compared to the placebo session. These results document a facilitatory effect of d-amphetamine on use-dependent plasticity, a possible mechanism mediating the beneficial effect of this drug on functional recovery after cortical lesions.
Annals of Neurology 02/2002; 51(1):59-68. · 11.09 Impact Factor
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Lumy Sawaki
IEEE Engineering in Medicine and Biology Magazine 24(1):36-9. · 2.06 Impact Factor
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Lumy Sawaki,
Andrew J Butler,
Xiaoyan Leng,
Peter A Wassenaar,
Yousef M Mohammad,
Sarah Blanton,
K Sathian,
Deborah S Nichols-Larsen,
Steven L Wolf,
David C Good,
George F Wittenberg
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ABSTRACT: Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke.
The present study represents the first multi-center effort to measure cortical reorganization induced by CIMT in subjects who are in the subacute stage of recovery.
A total of 30 stroke subjects in the subacute phase (>3 and <9 months poststroke) were recruited and randomized into experimental (receiving CIMT immediately after baseline evaluation) and control (receiving CIMT after 4 months) groups. Each subject was evaluated using transcranial magnetic stimulation (TMS) at baseline, 2 weeks after baseline, and at 4-month follow-up (ie, after CIMT in the experimental groups and before CIMT in the control groups). The primary clinical outcome measure was the Wolf Motor Function Test.
Both experimental and control groups demonstrated improved hand motor function 2 weeks after baseline. The experimental group showed significantly greater improvement in grip force after the intervention and at follow-up (P = .049). After adjusting for the baseline measures, the experimental group had an increase in the TMS motor map area compared with the control group over a 4-month period; this increase was of borderline significance (P = .053).
Among subjects who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 4 months. The corresponding enlargement of TMS motor maps, similar to that found in earlier studies of chronic stroke subjects, appears to play an important role in CIMT-dependent plasticity.
Neurorehabilitation and neural repair 22(5):505-13. · 4.49 Impact Factor
