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ABSTRACT: BACKGROUND AND PURPOSE: Restorative therapies have the potential to improve function and reduce disability after stroke with a wide therapeutic window. The current study evaluated GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule myelin-associated glycoprotein and also protects oligodendrocytes. METHODS: Patients with mild-moderate stroke were randomized to intravenous GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts of 8-9 subjects) versus placebo (n=17). Infusion 1 was 24 to 72 hours after stroke; infusion 2 was 9±1 days later. The primary objective evaluated safety and tolerability, and the secondary objectives evaluated immunogenicity, pharmacokinetics, biomarkers, neurophysiology, and motor function. RESULTS: Baseline (n=42) characteristics were similar across treatment groups. No safety concerns were found based on adverse events, examination, vital signs, ECG, nerve conduction tests, brain imaging, motor function testing, and laboratory studies. Two of the 25 subjects dosed with GSK249320 developed transient antidrug antibodies after infusion 1. The pharmacokinetics profile was as expected for an IgG1 type monoclonal antibody. Serum levels of the biomarker S100β did not differ between groups. Global outcome measures were similar across groups. Modality-specific end points could be consistently measured in the first few days after stroke, and one of these, gait velocity, demonstrated a trend toward improvement with GSK249320 compared with placebo. CONCLUSIONS: GSK249320 was generally well tolerated. No major safety issues were identified in this first study of a monoclonal antibody to modulate the neurobiology of brain repair after stroke. Future studies might explore the efficacy of GSK249320 as a restorative therapy for stroke.Clinical Trial Registration:URL:http://www.clinicaltrials.gov. Unique Identifier: ID#NCT00833989.
Stroke 03/2013; · 5.73 Impact Factor
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ABSTRACT: Many restorative therapies that promote brain repair are under development. Stroke is very heterogeneous, highlighting the need to identify target populations and to understand intersubject differences in treatment response. Several neuroimaging measures have shown promise as biomarkers and predictors, including measures of structure and function, in gray matter and white matter. The choice of biomarker and predictor can differ with the content of therapy and with the population under study, for example, contralesional hemisphere measures may be of particular importance in patients with more severe injury. Studies of training effects in healthy subjects provide insights useful to brain repair. Limitations of published studies include a focus on chronic stroke, however the brain is most galvanized to respond to restorative therapies in the early days after stroke. Multimodal approaches might be the most robust approach for stratifying patients and so for optimizing prescription of restorative therapies after stroke.
Current Neurology and Neuroscience Reports 02/2013; 13(2):329. · 3.45 Impact Factor
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ABSTRACT: Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.
PLoS ONE 01/2013; 8(4):e61197. · 4.09 Impact Factor
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ABSTRACT: The brain derived neurotrophic factor (BDNF) val(66)met polymorphism affects function of the motor system in young subjects, but little is known about motor system effects in the elderly. The current study assessed motor system physiology and behavior, plus a measure of short-term motor cortex plasticity using transcranial magnetic stimulation, in 38 elderly subjects, then examined whether findings varied in relation to BDNF genotype. Baseline data were also collected from 14 young subjects. At baseline, elderly subjects had poorer motor performances, larger motor cortex maps, and smaller motor evoked potentials compared to young subjects. Degree of age-related differences in neurophysiology correlated inversely with motor performance, for example, larger map area correlated with weaker pinch grip force (r=-0.42, P=0.01). In elderly subjects, baseline behavior and neurophysiology did not differ in relation to BDNF genotype. In addition, although map area increased significantly (P=0.03) across 30 minutes of exercise, this change did not vary according to BDNF genotype. Aging is associated with changes in neurophysiology that might represent a compensatory response. The data do not support an association between BDNF genotype and behavior, neurophysiology, or short-term cortical plasticity in the motor system of healthy elderly subjects.
Brain research 12/2012; · 2.46 Impact Factor
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ABSTRACT: Robot-assisted movement training can help individuals with stroke reduce arm and hand impairment, but robot therapy is typically only about as effective as conventional therapy. Refining the way that robots assist during training may make them more effective than conventional therapy. Here, the authors measured the therapeutic effect of a robot that required individuals with a stroke to achieve virtual tasks in three dimensions against gravity.
The robot continuously estimated how much assistance patients needed to perform the tasks and provided slightly less assistance than needed to reduce patient slacking. Individuals with a chronic stroke (n = 26; baseline upper limb Fugl-Meyer score, 23 ± 8) were randomized into two groups and underwent 24 one-hour training sessions over 2 mos. One group received the assist-as-needed robot training and the other received conventional tabletop therapy with the supervision of a physical therapist.
Training helped both groups significantly reduce their motor impairment, as measured by the primary outcome measure, the Fugl-Meyer score, but the improvement was small (3.0 ± 4.9 points for robot therapy vs. 0.9 ± 1.7 for conventional therapy). There was a trend for greater reduction for the robot-trained group (P = 0.07). The robot group largely sustained this gain at the 3-mo follow-up. The robot-trained group also experienced significant improvements in Box and Blocks score and hand grip strength, whereas the control group did not, but these improvements were not sustained at follow-up. In addition, the robot-trained group showed a trend toward greater improvement in sensory function, as measured by the Nottingham Sensory Test (P = 0.06).
These results suggest that in patients with chronic stroke and moderate-severe deficits, assisting in three-dimensional virtual tasks with an assist-as-needed controller may make robotic training more effective than conventional tabletop training.
American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 11/2012; 91(11 Suppl 3):S232-41. · 1.56 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: The fields of clinical genetics and pharmacogenetics are rapidly expanding. Genetic factors have numerous associations with injury and with treatment effects in the setting of neural plasticity and recovery. RECENT FINDINGS: Evidence is reviewed that established genetic variants, as well as some more recently described variants, are related to outcome after neural injury and in some cases are useful for predicting clinical course. In many cases, the interaction of genetics with clinical factors such as experience and therapy may be important. As an extension of this, genetic factors have been associated with differential response to a number of forms of therapy, including pharmacological, brain stimulation, psychotherapy, and meditation. Genetic variation might also have a significant effect on plasticity and recovery through key covariates such as depression or stress. A key point is that genetic associations might be most accurately identified when studied in relation to distinct forms of a disorder rather than in relation to broad clinical syndromes. SUMMARY: Understanding genetic variation gives clinicians a biological signal that could be used to predict who is most likely to recover from neural injury, to choose the optimal treatment for a patient, or to supplement rehabilitation therapy.
Current opinion in neurology 10/2012; · 5.43 Impact Factor
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Steven C Cramer
Stroke 12/2011; 42(12):3659-60. · 5.73 Impact Factor
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Steven C Cramer
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ABSTRACT: Stroke remains a leading cause of disability. Most patients show some degree of spontaneous recovery, but this is generally incomplete. Studies on the neurobiology of this recovery are providing clues to therapeutic interventions that aim to improve patient outcomes. A number of potential such restorative therapies are reviewed. Numerous treatment strategies are under study. Most have a time window measured in days or weeks and so have the potential to help a large fraction of patients. This review considers these therapies, as well as points to consider in translating their application to human trials.
Head & Neck 09/2011; 33 Suppl 1:S5-7. · 2.40 Impact Factor
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ABSTRACT: The val(66)met polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts activity-dependent secretion of BDNF and modifies short-term cortical plasticity. The current study examined whether sustained training overcomes polymorphism effects on short-term plasticity and also examined polymorphism effects on long-term plasticity. Twenty-four subjects completed a 12-day protocol of daily training on a marble navigation task that required intense use of the first dorsal interosseus (FDI) muscle. In parallel, transcranial magnetic stimulation (TMS) mapping was used to assess serial measures of short-term cortical motor map plasticity, plus long-term cortical motor map plasticity, of the cortical FDI map. On Day 1, subjects with the polymorphism did not show significant short-term cortical motor map plasticity over 30 min of FDI activity, but subjects without the polymorphism did. After 5 days of intense training, a genotype-based difference in short-term cortical motor map plasticity was no longer found, as both groups showed short-term plasticity across the 30 min of FDI activity. Also, across 12 days of training, map area decreased significantly, in a manner that did not vary in relation to genotype. Training of sufficient intensity and duration overcomes effects that the val(66)met polymorphism has on short-term cortical motor map plasticity. The polymorphism-related differences seen with short-term plasticity are not found with long-term cortical motor map plasticity.
Experimental Brain Research 09/2011; 213(4):415-22. · 2.39 Impact Factor
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ABSTRACT: Preclinical studies found that epidural motor cortex stimulation improved motor deficits after stroke, but a phase III trial in humans did not corroborate these results. The current retrospective analysis examined subjects randomized to stimulation in order to identify features distinguishing responders from nonresponders.
Anatomic (MRI measures of gray matter thickness and of white matter tract injury) and physiologic methods (motor evoked responses) were examined as predictors of treatment response.
Among 60 subjects randomized to cortical stimulation, both anatomic and physiologic measures at baseline predicted behavioral response to therapy. Anatomically, those achieving the primary efficacy endpoint had a smaller fraction of the corticospinal tract injured by stroke compared to those who did not (44% vs 72%, p < 0.04), and rarely had severe tract injury. Physiologically, the primary efficacy endpoint was reached more often (67%) by those with preserved motor evoked responses (MER) upon cortical stimulation compared to those lacking MER (27%, p < 0.05). Those with an elicitable MER also had a lower rate of precentral gyrus injury (0% vs 33%, p < 0.05) by stroke, as compared to those lacking MER, and had higher gray matter volume compared to those lacking MER in regions including ipsilesional precentral gyrus.
In this clinical stroke trial, the more that the physiologic integrity of the motor system was preserved, the more likely that a patient was to derive gains from subsequent therapy, consistent with preclinical models. Functional and structural preservation of key brain substrates are important to deriving gain from a restorative therapy.
Neurology 08/2011; 77(11):1076-83. · 8.31 Impact Factor
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Steven C Cramer
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ABSTRACT: The fluoxetine for motor recovery after acute ischemic stroke study was a double blind, placebo-controlled trial examining the effects of fluoxetine in patients five- to 10 days after an ischemic stroke. The study found motor improvement to 90 days poststroke, measured as the change in the Fugl-Meyer score, was significantly greater in the fluoxetine group as compared with the placebo group, and that this finding was significant after adjusting for depression. Patients randomized to fluoxetine also had less disability (modified Rankin Scale 0-2). The study adds to the weight of data suggesting that viable strategies exist to improve patient outcomes by initiating a restorative agent, days after stroke injury is fixed. Stroke remains among the leading causes of human disability. Currently, a minority of patients can access approved reperfusion therapies, and among those so treated a substantial fraction derives limited benefit. Therapies that target restorative events have a time window measured in days-weeks and so hold the potential to help many patients with stroke.
International Journal of Stroke 08/2011; 6(4):315-6. · 2.38 Impact Factor
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Steven C Cramer,
Mriganka Sur,
Bruce H Dobkin,
Charles O'Brien,
Terence D Sanger,
John Q Trojanowski,
Judith M Rumsey,
Ramona Hicks,
Judy Cameron,
Daofen Chen, [......],
Patrick S McQuillen,
Ralph Nitkin,
Alvaro Pascual-Leone,
Patricia Reuter-Lorenz,
Nicholas Schiff,
Anu Sharma,
Lana Shekim,
Michael Stryker,
Edith V Sullivan,
Sophia Vinogradov
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ABSTRACT: Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.
Brain 06/2011; 134(Pt 6):1591-609. · 9.46 Impact Factor
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ABSTRACT: This study tested the hypothesis that executive dysfunction, common in temporal lobe epilepsy (TLE), is associated with an abnormal frontostriatal network. Structural and diffusion tensor MR scans, the Wisconsin Card Sorting Test (WCST) targeting cognitive flexibility, and the Trail Making Test B examining parallel sequencing were obtained from 9 patients with left TLE and 17 healthy controls. The five major findings were: (1) Caudate volume is reduced on the left side in TLE. (2) The atrophy involves the dorsal and ventral head of the caudate. (3) These atrophic caudate regions have a corresponding high probability of connections to dorsal prefrontal, anterior cingulate, and orbitofrontal cortex. (4) Smaller caudate volumes are linked to greater numbers of WCST perseverative errors. (5) Reduced connections between caudate and dorsal prefrontal cortex correlated with poorer scores on the Trail Making Test B. The results suggest that atrophy in the dorsal head of the caudate might disrupt frontostriatal networks that are critical for executive functioning in TLE.
Epilepsy & Behavior 05/2011; 21(1):80-7. · 2.34 Impact Factor
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ABSTRACT: Many therapies are emerging that aim to improve motor function in people with stroke. Identifying key biological substrates needed for treatment gains would help to predict treatment effects and to maximize treatment impact. The current study addressed the hypothesis that behavioral gains from therapy targeting distal upper extremity are predicted by the structural integrity of key motor system white matter tracts.
Twenty-three subjects with chronic left-sided stroke underwent robotic therapy targeting the distal right upper extremity. MRI was obtained at baseline and used to outline the infarct. For each subject, the degree to which stroke injured each of 4 descending white matter tracts (from the primary motor cortex, supplementary motor area, dorsal premotor cortex, and ventral premotor cortex, respectively) was determined. Correlations between tract-specific injury and behavioral gains from therapy were then examined.
Numerous examples were found whereby tract-specific injury predicted treatment gains. The strongest correlations pertained to stroke injury to tracts descending from the primary motor cortex and dorsal premotor cortex. Infarct volume and baseline behavior were weak predictors of treatment gains.
Extent of injury to specific motor tracts predicts behavioral gains from treatment in subjects with chronic stroke. This supports a role for these tracts in mediating treatment effects and reinforces the importance of lesion location in stroke. Tract-specific injury was stronger than infarct volume or baseline clinical status at predicting gains, identifies subjects with sufficient biological substrate to improve from therapy, and so might be useful as an entry criterion in repair-based trials.
Stroke 02/2011; 42(2):421-6. · 5.73 Impact Factor
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Michael Brainin,
Bo Norrving,
Katharina S Sunnerhagen,
Larry B Goldstein, Steven C Cramer,
Geoffrey A Donnan,
Pamela W Duncan,
Gerard Francisco,
David Good,
Glenn Graham,
Brett M Kissela,
John Olver,
Anthony Ward,
Jörg Wissel,
Richard Zorowitz
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ABSTRACT: This paper represents the opinion of a group of researchers and clinicians with an established interest in poststroke care and is based on the recognised need for long-term care following stroke, especially in view of the global increase of disability due to stroke. Among the more frequent long-term complications following stroke are spasticity-related disabilities. Although spasticity alone occurs in up to 60% of stroke survivors, disabling spasticity affects only 4-10%. Spasticity further interferes with important functions of daily life when it occurs in association with pain, motor impairment, and overall declines of cognitive and neurological function. It is proposed that the aftermath of stroke be considered a chronic disease requiring a multifactorial and multilevel approach. There are, however, knowledge gaps related to the prediction and recognition of poststroke disability. Interventions to prevent or minimise such disabilities require further development and evaluation. Poststroke spasticity research should focus on reducing disability and be considered as part of a continuum of chronic care requirements and should be recognised as a part of a comprehensive poststroke disease management programme.
International Journal of Stroke 02/2011; 6(1):42-6. · 2.38 Impact Factor
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ABSTRACT: When healthy subjects undergo brain imaging, incidental findings are not rare. The optimal response to such findings has been the focus of considerable discussion. The current report describes the operations and results of a system that provides a review of incidental findings by an appropriate medical professional. A web-based system was created whereby investigators performing brain MRI scans on healthy subjects could refer images with suspected concerns to a board certified radiologist who had a Certificate of Added Qualification in Neuroradiology. The specific details of this system are described. Among 27 scans suspected by an investigator of having a significant finding, all but one were referred by a researcher with a PhD. The most common concerns described by these investigators were for the possible presence of a cyst or of enlarged ventricles. The most common findings reported by the radiologist were Virchow-Robin spaces and cysts. Findings were generally of low clinical significance, with 1 major exception. Identifying the optimal response to incidental findings in neuroimaging research remains a challenge. The current report describes a system for providing expert assistance and so addresses these issues in the setting of suspected incidental findings. To our knowledge the current system is the first to provide a specific means for evaluation of incidental findings in neuroimaging research.
NeuroImage 01/2011; 55(3):1020-3. · 5.89 Impact Factor
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ABSTRACT: Neural plasticity refers to the capability of the brain to alter function or structure in response to a range of events and is a crucial component of both functional recovery after injury and skill learning in healthy individuals. A number of factors influence neural plasticity and recovery of function after brain injury. The current review considers the impact of genetic factors. Polymorphisms in the human genes coding for brain-derived neurotrophic factor and apolipoprotein E have been studied in the context of plasticity and stroke recovery and are discussed here in detail. Several processes involved in plasticity and stroke recovery, such as depression or pharmacotherapy effects, are modulated by other genetic polymorphisms and are also discussed. Finally, new genetic polymorphisms that have not been studied in the context of stroke are proposed as new directions for study. A better understanding of genetic influences on recovery and response to therapy might allow improved treatment after a number of forms of central nervous system injury.
Der Notarzt 12/2010; 2(12 Suppl 2):S227-40. · 0.28 Impact Factor
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Steven C Cramer
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ABSTRACT: A number of therapies are emerging that have the potential to reduce poststroke disability by promoting repair. Careful evaluation of patients with stroke might help distinguish those who are most likely to respond to a restorative therapy from those who lack biological substrate needed to achieve gains. Potential approaches to such stratification are considered, including measures of brain injury or of poststroke brain function.
Stroke 10/2010; 41(10 Suppl):S114-6. · 5.73 Impact Factor
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Vladimir Hachinski,
Geoffrey A Donnan,
Philip B Gorelick,
Werner Hacke, Steven C Cramer,
Markku Kaste,
Marc Fisher,
Michael Brainin,
Alastair M Buchan,
Eng H Lo, [......],
Nils Wahlgren,
Lawrence K Wong,
Antoine Hakim,
Bo Norrving,
Stephen Prudhomme,
Natan M Bornstein,
Stephen M Davis,
Larry B Goldstein,
Didier Leys,
Jaakko Tuomilehto
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ABSTRACT: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures.
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
International Journal of Stroke 08/2010; 5(4):238-56. · 2.38 Impact Factor
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ABSTRACT: Diffusion tensor imaging (DTI) studies have reported substantial white matter abnormalities in patients with temporal lobe epilepsy (TLE). However, limited data exist regarding the extent of white matter tract abnormalities, cognitive effects of these abnormalities, and relationship to clinical factors. The current study examined these issues in subjects with chronic TLE.
DTI data were obtained in 12 TLE subjects and 10 age-matched healthy controls. Voxel-wise statistical analysis of fractional anisotropy (FA) was carried out using tract-based spatial statistics (TBSS). White matter integrity was correlated with cognitive performance and epilepsy-related clinical parameters.
Subjects with TLE, as compared to healthy controls, demonstrated four clusters of reduced FA, in anterior temporal lobe, mesial temporal lobe, and cerebellum ipsilateral, as well as frontoparietal lobe contralateral to the side of seizure onset. Mean FA was positively correlated with delayed memory, in anterior temporal lobe; and immediate memory, in mesial temporal lobe. Lower FA values in the posterior region of corpus callosum were related to earlier age of seizure onset.
TLE is associated with widespread disturbances in white matter tracts and these changes have important cognitive and clinical consequences.
Epilepsia 04/2010; 51(4):536-45. · 3.96 Impact Factor
