- Email: [email protected]
P 172. Focal tDCS in Chronic Stroke patients: A pilot study of physiological effects using TMS and concurrent EEG
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Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
before and after iTBS. Changes in MEP amplitudes after iTBS were examined as measures of long term potentiation (LTP) like plasticity. Results: Within the first 20 min following iTBS baseline corrected MEPs were significantly larger for healthy subjects (1.32 ± 0.21 mV) compared to patients with AD (0.92 ± 0.08 mV; p = 0.023) and DM2 (0.69 ± 0.15 mV; p = 0.007) (Fig. 1). There was no significant difference between AD and DM2 (p = 0.63). Interestingly, while iTBS had almost no effect on AD patients it tended to have a paradoxically inhibitory effect in patients with DM2. Conclusion: The iTBS-induced modulation of corticospinal excitability is impaired in both AD and DM2. This finding supports the notion of aberrant LTP-like mechanisms of plasticity in DM2 and AD, and suggests a pathophysiologic link between the two diseases. This link may account for the epidemiologically increased risk for patients with DM2 to develop AD. Further studies and longitudinal assessments are needed to explore such a link further, but in this context, TMS-methods appear promising and may become a valuable early biomarker for AD and individuals at risk. Acknowledgements: The study was sponsored and supported by the Harvard Catalyst, Nexstim, Neuronix Ltd., the National Institutes of Health, and the Berenson-Allen Foundation.
rent was constantly delivered during resting state and task-related fMRI. Task-related fMRI analysis was carried out with SPM8; resting state data were analyzed with Lipsia using low-frequency spectral Eigenvector Centrality Mapping (ECM). Task-specific analyses revealed differential effects of the two active tDCS conditions. Compared with anodal tDCS, dual tDCS yielded stronger activations in bilateral primary motor cortices when either the left or right index fingers were used. In the resting state analysis, ECM values in left prefrontal and cingulate cortices were higher in the dual condition as compared to sham. Anodal yielded higher ECM values in the left prefrontal as well as left ventral premotor cortex when compared with sham; lower values were found in right M1 and the left precuneus. Comparing the two active tDCS conditions, increased connectivity of the cingulate cortex and decreased connectivity in the right cerebellum was found under dual compared to anodal tDCS (all p < .001, Monte Carlo-corrected). In conclusion, tDCS induced specific changes of M1 activation in task-specific activations, dependent on the electrode set-up. As a complement, the resting state analysis demonstrated altered connectivity within a multimodal network including motor cortices as well as prefrontal regions, indicating that the previously documented stronger behavioral effects of dual as compared to anodal tDCS may not be merely mediated by a “simple” add-on effect of cathodal stimulation, but rather due to complex bihemispheric network modulations. doi:10.1016/j.clinph.2013.04.248
P 172. Focal tDCS in Chronic Stroke patients: A pilot study of physiological effects using TMS and concurrent EEG—D. Boratyn a, G. Ruffini b, M. Cortes a, A. Rykman a, A. Medeiros a, A. PascualLeone c,d, D. Edwards a (a Burke Medical Research Institute, Noninvasive Brain Stimulation and Human Motor Control Laboratory, White Plains, NY, United States, b Starlab Barcelona S.L, Barcelona, Spain, c Institut Guttmann, Hospital de Neurorehabilitació, Universitat Autònoma de Barcelona, Barcelona, Spain, d Beth Israel Deaconess Medical Center and Harvard Medical School, Berenson-Allen Center for Noninvasive Brain Stimulation, Boston, MA, United States)
doi:10.1016/j.clinph.2013.04.247
P 171. Bihemispheric motor cortex stimulation in older adults induces modulations of resting state and task-related activity—R. Lindenberg, L. Nachtigall, M. Meinzer, M.M. Sieg, A. Flöel (Charité University Medicine, Neurology, Berlin, Germany) Bihemispheric transcranial direct current stimulation (“dual” tDCS) of primary motor cortices has been described to enhance motor learning in healthy subjects and to facilitate motor recovery after stroke. In order to investigate the neural correlates of its mode of action, we compared different tDCS montages in a group of healthy older adults in a cross-over design (‘dual’ vs. ‘anodal’ vs. ‘sham’). 20 subjects (mean age 68.7 ± 4.7 years, all right-handed) underwent tDCS and simultaneous MRI at 3T, including resting state fMRI and a choice reaction time task. In the task, subjects were presented with different symbols in a randomized order and required to respond with button presses using either left or right index fingers. In both active stimulation conditions, the anode was placed over left primary motor cortex (M1). The cathode was positioned over right M1 (dual) or the contralateral supraorbital region (anodal). The cur-
Motor dysfunction is known to be a prominent residual impairment in stroke survivors. There is evidence supporting short-term behavioral changes correlated with electrophysiological changes using electric brain stimulation. Studies suggest that altering cortical excitability may prime the cortex for subsequent training and improve functional activity. Using Neuroelectrics’ Starstim novel multichannel wireless device, which allows for simultaneous electroencephalography (EEG), 3D accelerometry and transcranial direct current stimulation (tDCS) using relatively small, gelled, Ag/AgCl electrodes (1 cm diameter), we aimed to determine the effects of anodal stimulation tDCS on EEG and transcranial magnetic stimulation (TMS) response, as well as kinematic movement performance in chronic stroke survivors with residual motor deficit in the arm. Fifteen chronic stroke patients with hemiparesis following a first single unilateral lesion received 20 min of bilateral 1 mA anodal tDCS over the motor cortex of the lesioned hemisphere. Four neurophysiological and motor evaluations were conducted during the experiment: one prior to stimulation and three at different time points following stimulation. Evaluations consisted of a 5 min EEG recording at rest and assessment of cortical excitability properties of the lesioned hemisphere using TMS. During the TMS evaluations, motor evoked potentials (MEP) were recorded via surface electromyography (EMG) electrodes both at rest and during maximal voluntary contraction. In addition, EEG was recorded during tDCS stimulation.
Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
We report results of MEPs, EEG, and motor behavior. We show, for the first time, that tDCS and EEG recording can be concurrently applied in stroke patients. Bilateral M1 stimulation using small Ag/ AgCl electrodes is well tolerated and can augment corticospinal excitability in the affected hemisphere. In the literature, there is only one prior studying using concurrent EEG recording during cathodal tDCS in healthy subjects and two patients with epileptic encephalopathy (Faria et al., 2012). As far as we know, no studies have applied tDCS simultaneous with EEG recording in chronic stroke patients. We report the first study investigating feasibility and proof-of-concept of tDCS in 15 chronic stroke patients using EEG recording simultaneously with tDCS. With continuous EEG recording and neurophysiological data, we hope to gain insight into the mechanisms of biological responses to tDCS and the behavioral changes resulting from stimulation. doi:10.1016/j.clinph.2013.04.249
P 173. Motor skill acquisition in neurofibromatosis type 1 patients—M. Zimerman a, M. Wessel a, J. Timmermann a, C. Gerloff a, V.-F. Mautner b, F.C. Hummel a (a University Medical Center Hamburg-Eppendorf, Neurology, Hamburg, Germany, b University Medical Center Hamburg-Eppendorf, Neurofibromatoseambulanz, Department of Neurology, Hamburg, Germany) Introduction: Neurofibromatosis type 1 (NF-1) is the most common single gene disorder affecting the human nervous system, with an estimated prevalence of two to three cases per 10,000 population. The disorder is inherited in an autosomal dominant manner with equal sex incidence. Cognitive deficits and academic learning difficulties are the most common neurological complication, and can be responsible for significant lifetime morbidity. Recent animal studies proposed increased GABA-mediated inhibition with concomitant deficits in long-term potentiation as a potential mechanism for the learning impairment in these patients. The aim of the present study was to investigate the acquisition of a new motor skill in a group of young NF-1 patients without any neurological impairment. Furthermore, we used double-pulse TMS (dpTMS) in order to determine NF1-related effects on inhibitory (GABAergic) and facilitatory (Glutamatergic) motorcortical circuits during the process of motor skill acquisition. Methods: In this Pilot study, a group of NF-1 patients without any cognitive or learning deficit and healthy controls participated in an explicit motor learning experiment (for details see Zimerman et al. 2012), composed of a sequential pressing of nine-elements sequence on a four-button electronic keyboard with the left hand. All participants attended five consecutive days of training and two follow-up measurements 10 and 20 days after training, where the task was re-evaluated. dpTMS measurements were performed at baseline, immediately after the training days and before the follow-up times. Additionally, factors that might potentially influence motor learning, such as level of attention, perception of fatigue or discomfort were evaluated. Results: Preliminary results suggested an impairment in motor skill acquisition in NF-1 patients (F = 2.8; p = .05), driven mainly by a decrease on ‘offline improvement’ in NF-1 compared to healthy subjects (T = 2.9; p = .03). In healthy subjects a reduction of intracortical inhibition in the motor cortex was apparent after the learning task compared to baseline, this was not the case for the NF-1 patients, who did not show any change due to learning. Furthermore, reduced intracortical facilitation was obvious in the patients. Conclusions: The present pilot study provides a first hint that the acquisition of a skill might be impaired in even clinically intact NF-1 patients. One potential mechanism that could at least in part contribute to explain these behavioural deficits observed in NF1-
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patients is alteration of intracortical circuits related to GABAergic and/or glutamatergic neurotransmission. Further experiments are necessary to support the present findings and to gather greater understanding of the pathophysiological mechanisms of NF1, an important basis to design appropriate interventions to support skill acquisition in these patients. doi:10.1016/j.clinph.2013.04.250
P 174. Effects of paired associative stimulation on developmental motor plasticity in children—O. Damji a, J. Roe b, S. Shinde c, O. Kotsovsky d, A. Kirton e (a University of Calgary, Neurosciences, Calgary, Canada, b Mount Royal University, Health Sciences, Calgary, Canada, c University of Calgary, Cellular, Molecular, and Microbial Biology, Calgary, Canada, d Alberta Children’s Hospital, Calgary Pediatric Stroke Program, Calgary, Canada, e Alberta Children’s Hospital, Department of Pediatrics and Clinical Neurosciences, Calgary, Canada) Introduction: Transcranial magnetic stimulation (TMS) offers increasingly sophisticated means of assessing neurophysiology and neuroplasticity mechanisms but applications in children have been limited. Paired associative stimulation (PAS) is an advanced TMS method that pairs peripheral sensory stimulation with TMS primary motor cortex (M1) stimulation. PAS induces rapid, reversible and topographically specific increases in adult motor cortex excitability consistent with NMDAR-dependent long-term potentiation. PAS has not been studied in the more plastic brains of children. Objectives: Our aim wasto define the developmental profile of PAS in children. We hypothesized that rates of PAS MEP enhancement would be higher in children compared to adults. Methods: Healthy, right-handed children aged 6–18 years were recruited from the Alberta Perinatal Stroke Project (APSP) healthy control cohort and general population. Median nerve stimulation (300% sensory threshold) was delivered 25 ms prior to suprathreshold (1 mV) left M1 stimulation (90 pairings, 7 min).Difference in mean peak-to-peak amplitude of right APB motor evoked potentials (MEP) was the primary outcome. Forty single pulse TMS measures were obtained at baseline, immediately after, and 15, 30, 45, and 75 min post-PAS. PAS effects were categorized as definitive (significantly elevated post-MEP at multiple timepoints), possible (single timepoint only) or no effect. Secondary outcomes included change in slope of stimulus response curve (SRC) post-PAS and standard safety and tolerability evaluations. Results: Of 15 children (9 male, mean age 12 years), 8 (53%) showed definitive positive PAS effects, 2 were possible, and 5 showed no MEP change following PAS (none showed a decrease). Despite this, mean SRC slope increased across the entire group (pre 5.43 ± 1.09, post 6.50 ± 1.14, p = 0.05). Of the 8 children with definite PAS, maximal mean MEP increase was immediately postPAS in 5 and at 15 min in 3. PAS effect was not clearly associated with age (p = 0.24). PAS procedures were well tolerated with no serious adverse events. Recorded tolerability scores were favorable, scoring better than “a long car ride” on average. Wrist pain was common (20%) but became quickly tolerated. Other side effects (headache, neck pain, tingling, nausea, presyncope) were infrequent (<7%) and mild. Conclusions: PAS paradigms appear safe and well tolerated in children. Frequency of positive PAS effects may be higher in children (>50%) than in adults. SRC curves may be more sensitive than mean MEP amplitude changes to PAS effects. PAS may provide new insights into mechanisms of developmental motor plasticity and inform therapeutic interventions in cerebral palsy and motor disorders of childhood.
Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
before and after iTBS. Changes in MEP amplitudes after iTBS were examined as measures of long term potentiation (LTP) like plasticity. Results: Within the first 20 min following iTBS baseline corrected MEPs were significantly larger for healthy subjects (1.32 ± 0.21 mV) compared to patients with AD (0.92 ± 0.08 mV; p = 0.023) and DM2 (0.69 ± 0.15 mV; p = 0.007) (Fig. 1). There was no significant difference between AD and DM2 (p = 0.63). Interestingly, while iTBS had almost no effect on AD patients it tended to have a paradoxically inhibitory effect in patients with DM2. Conclusion: The iTBS-induced modulation of corticospinal excitability is impaired in both AD and DM2. This finding supports the notion of aberrant LTP-like mechanisms of plasticity in DM2 and AD, and suggests a pathophysiologic link between the two diseases. This link may account for the epidemiologically increased risk for patients with DM2 to develop AD. Further studies and longitudinal assessments are needed to explore such a link further, but in this context, TMS-methods appear promising and may become a valuable early biomarker for AD and individuals at risk. Acknowledgements: The study was sponsored and supported by the Harvard Catalyst, Nexstim, Neuronix Ltd., the National Institutes of Health, and the Berenson-Allen Foundation.
rent was constantly delivered during resting state and task-related fMRI. Task-related fMRI analysis was carried out with SPM8; resting state data were analyzed with Lipsia using low-frequency spectral Eigenvector Centrality Mapping (ECM). Task-specific analyses revealed differential effects of the two active tDCS conditions. Compared with anodal tDCS, dual tDCS yielded stronger activations in bilateral primary motor cortices when either the left or right index fingers were used. In the resting state analysis, ECM values in left prefrontal and cingulate cortices were higher in the dual condition as compared to sham. Anodal yielded higher ECM values in the left prefrontal as well as left ventral premotor cortex when compared with sham; lower values were found in right M1 and the left precuneus. Comparing the two active tDCS conditions, increased connectivity of the cingulate cortex and decreased connectivity in the right cerebellum was found under dual compared to anodal tDCS (all p < .001, Monte Carlo-corrected). In conclusion, tDCS induced specific changes of M1 activation in task-specific activations, dependent on the electrode set-up. As a complement, the resting state analysis demonstrated altered connectivity within a multimodal network including motor cortices as well as prefrontal regions, indicating that the previously documented stronger behavioral effects of dual as compared to anodal tDCS may not be merely mediated by a “simple” add-on effect of cathodal stimulation, but rather due to complex bihemispheric network modulations. doi:10.1016/j.clinph.2013.04.248
P 172. Focal tDCS in Chronic Stroke patients: A pilot study of physiological effects using TMS and concurrent EEG—D. Boratyn a, G. Ruffini b, M. Cortes a, A. Rykman a, A. Medeiros a, A. PascualLeone c,d, D. Edwards a (a Burke Medical Research Institute, Noninvasive Brain Stimulation and Human Motor Control Laboratory, White Plains, NY, United States, b Starlab Barcelona S.L, Barcelona, Spain, c Institut Guttmann, Hospital de Neurorehabilitació, Universitat Autònoma de Barcelona, Barcelona, Spain, d Beth Israel Deaconess Medical Center and Harvard Medical School, Berenson-Allen Center for Noninvasive Brain Stimulation, Boston, MA, United States)
doi:10.1016/j.clinph.2013.04.247
P 171. Bihemispheric motor cortex stimulation in older adults induces modulations of resting state and task-related activity—R. Lindenberg, L. Nachtigall, M. Meinzer, M.M. Sieg, A. Flöel (Charité University Medicine, Neurology, Berlin, Germany) Bihemispheric transcranial direct current stimulation (“dual” tDCS) of primary motor cortices has been described to enhance motor learning in healthy subjects and to facilitate motor recovery after stroke. In order to investigate the neural correlates of its mode of action, we compared different tDCS montages in a group of healthy older adults in a cross-over design (‘dual’ vs. ‘anodal’ vs. ‘sham’). 20 subjects (mean age 68.7 ± 4.7 years, all right-handed) underwent tDCS and simultaneous MRI at 3T, including resting state fMRI and a choice reaction time task. In the task, subjects were presented with different symbols in a randomized order and required to respond with button presses using either left or right index fingers. In both active stimulation conditions, the anode was placed over left primary motor cortex (M1). The cathode was positioned over right M1 (dual) or the contralateral supraorbital region (anodal). The cur-
Motor dysfunction is known to be a prominent residual impairment in stroke survivors. There is evidence supporting short-term behavioral changes correlated with electrophysiological changes using electric brain stimulation. Studies suggest that altering cortical excitability may prime the cortex for subsequent training and improve functional activity. Using Neuroelectrics’ Starstim novel multichannel wireless device, which allows for simultaneous electroencephalography (EEG), 3D accelerometry and transcranial direct current stimulation (tDCS) using relatively small, gelled, Ag/AgCl electrodes (1 cm diameter), we aimed to determine the effects of anodal stimulation tDCS on EEG and transcranial magnetic stimulation (TMS) response, as well as kinematic movement performance in chronic stroke survivors with residual motor deficit in the arm. Fifteen chronic stroke patients with hemiparesis following a first single unilateral lesion received 20 min of bilateral 1 mA anodal tDCS over the motor cortex of the lesioned hemisphere. Four neurophysiological and motor evaluations were conducted during the experiment: one prior to stimulation and three at different time points following stimulation. Evaluations consisted of a 5 min EEG recording at rest and assessment of cortical excitability properties of the lesioned hemisphere using TMS. During the TMS evaluations, motor evoked potentials (MEP) were recorded via surface electromyography (EMG) electrodes both at rest and during maximal voluntary contraction. In addition, EEG was recorded during tDCS stimulation.
Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
We report results of MEPs, EEG, and motor behavior. We show, for the first time, that tDCS and EEG recording can be concurrently applied in stroke patients. Bilateral M1 stimulation using small Ag/ AgCl electrodes is well tolerated and can augment corticospinal excitability in the affected hemisphere. In the literature, there is only one prior studying using concurrent EEG recording during cathodal tDCS in healthy subjects and two patients with epileptic encephalopathy (Faria et al., 2012). As far as we know, no studies have applied tDCS simultaneous with EEG recording in chronic stroke patients. We report the first study investigating feasibility and proof-of-concept of tDCS in 15 chronic stroke patients using EEG recording simultaneously with tDCS. With continuous EEG recording and neurophysiological data, we hope to gain insight into the mechanisms of biological responses to tDCS and the behavioral changes resulting from stimulation. doi:10.1016/j.clinph.2013.04.249
P 173. Motor skill acquisition in neurofibromatosis type 1 patients—M. Zimerman a, M. Wessel a, J. Timmermann a, C. Gerloff a, V.-F. Mautner b, F.C. Hummel a (a University Medical Center Hamburg-Eppendorf, Neurology, Hamburg, Germany, b University Medical Center Hamburg-Eppendorf, Neurofibromatoseambulanz, Department of Neurology, Hamburg, Germany) Introduction: Neurofibromatosis type 1 (NF-1) is the most common single gene disorder affecting the human nervous system, with an estimated prevalence of two to three cases per 10,000 population. The disorder is inherited in an autosomal dominant manner with equal sex incidence. Cognitive deficits and academic learning difficulties are the most common neurological complication, and can be responsible for significant lifetime morbidity. Recent animal studies proposed increased GABA-mediated inhibition with concomitant deficits in long-term potentiation as a potential mechanism for the learning impairment in these patients. The aim of the present study was to investigate the acquisition of a new motor skill in a group of young NF-1 patients without any neurological impairment. Furthermore, we used double-pulse TMS (dpTMS) in order to determine NF1-related effects on inhibitory (GABAergic) and facilitatory (Glutamatergic) motorcortical circuits during the process of motor skill acquisition. Methods: In this Pilot study, a group of NF-1 patients without any cognitive or learning deficit and healthy controls participated in an explicit motor learning experiment (for details see Zimerman et al. 2012), composed of a sequential pressing of nine-elements sequence on a four-button electronic keyboard with the left hand. All participants attended five consecutive days of training and two follow-up measurements 10 and 20 days after training, where the task was re-evaluated. dpTMS measurements were performed at baseline, immediately after the training days and before the follow-up times. Additionally, factors that might potentially influence motor learning, such as level of attention, perception of fatigue or discomfort were evaluated. Results: Preliminary results suggested an impairment in motor skill acquisition in NF-1 patients (F = 2.8; p = .05), driven mainly by a decrease on ‘offline improvement’ in NF-1 compared to healthy subjects (T = 2.9; p = .03). In healthy subjects a reduction of intracortical inhibition in the motor cortex was apparent after the learning task compared to baseline, this was not the case for the NF-1 patients, who did not show any change due to learning. Furthermore, reduced intracortical facilitation was obvious in the patients. Conclusions: The present pilot study provides a first hint that the acquisition of a skill might be impaired in even clinically intact NF-1 patients. One potential mechanism that could at least in part contribute to explain these behavioural deficits observed in NF1-
e147
patients is alteration of intracortical circuits related to GABAergic and/or glutamatergic neurotransmission. Further experiments are necessary to support the present findings and to gather greater understanding of the pathophysiological mechanisms of NF1, an important basis to design appropriate interventions to support skill acquisition in these patients. doi:10.1016/j.clinph.2013.04.250
P 174. Effects of paired associative stimulation on developmental motor plasticity in children—O. Damji a, J. Roe b, S. Shinde c, O. Kotsovsky d, A. Kirton e (a University of Calgary, Neurosciences, Calgary, Canada, b Mount Royal University, Health Sciences, Calgary, Canada, c University of Calgary, Cellular, Molecular, and Microbial Biology, Calgary, Canada, d Alberta Children’s Hospital, Calgary Pediatric Stroke Program, Calgary, Canada, e Alberta Children’s Hospital, Department of Pediatrics and Clinical Neurosciences, Calgary, Canada) Introduction: Transcranial magnetic stimulation (TMS) offers increasingly sophisticated means of assessing neurophysiology and neuroplasticity mechanisms but applications in children have been limited. Paired associative stimulation (PAS) is an advanced TMS method that pairs peripheral sensory stimulation with TMS primary motor cortex (M1) stimulation. PAS induces rapid, reversible and topographically specific increases in adult motor cortex excitability consistent with NMDAR-dependent long-term potentiation. PAS has not been studied in the more plastic brains of children. Objectives: Our aim wasto define the developmental profile of PAS in children. We hypothesized that rates of PAS MEP enhancement would be higher in children compared to adults. Methods: Healthy, right-handed children aged 6–18 years were recruited from the Alberta Perinatal Stroke Project (APSP) healthy control cohort and general population. Median nerve stimulation (300% sensory threshold) was delivered 25 ms prior to suprathreshold (1 mV) left M1 stimulation (90 pairings, 7 min).Difference in mean peak-to-peak amplitude of right APB motor evoked potentials (MEP) was the primary outcome. Forty single pulse TMS measures were obtained at baseline, immediately after, and 15, 30, 45, and 75 min post-PAS. PAS effects were categorized as definitive (significantly elevated post-MEP at multiple timepoints), possible (single timepoint only) or no effect. Secondary outcomes included change in slope of stimulus response curve (SRC) post-PAS and standard safety and tolerability evaluations. Results: Of 15 children (9 male, mean age 12 years), 8 (53%) showed definitive positive PAS effects, 2 were possible, and 5 showed no MEP change following PAS (none showed a decrease). Despite this, mean SRC slope increased across the entire group (pre 5.43 ± 1.09, post 6.50 ± 1.14, p = 0.05). Of the 8 children with definite PAS, maximal mean MEP increase was immediately postPAS in 5 and at 15 min in 3. PAS effect was not clearly associated with age (p = 0.24). PAS procedures were well tolerated with no serious adverse events. Recorded tolerability scores were favorable, scoring better than “a long car ride” on average. Wrist pain was common (20%) but became quickly tolerated. Other side effects (headache, neck pain, tingling, nausea, presyncope) were infrequent (<7%) and mild. Conclusions: PAS paradigms appear safe and well tolerated in children. Frequency of positive PAS effects may be higher in children (>50%) than in adults. SRC curves may be more sensitive than mean MEP amplitude changes to PAS effects. PAS may provide new insights into mechanisms of developmental motor plasticity and inform therapeutic interventions in cerebral palsy and motor disorders of childhood.