Background Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. Methods In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. Results At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], −0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, −0.14 points; 95% CI, −2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, −8.10 seconds; 95% CI, −13.61 to −2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. Conclusions In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

Clinical recovery after stroke can be significant and has been attributed to plastic reorganization and recruitment of novel areas previously not engaged in a given task. As equivocal results have been reported in studies using single imaging or electrophysiological methods, here we applied an integrative multimodal approach to a group of well-recovered chronic stroke patients (n = 11; aged 50-81 years) with left capsular lesions. Focal activation during recovered hand movements was assessed with EEG spectral analysis and H2(15)O-PET with EMG monitoring, cortico-cortical connectivity with EEG coherence analysis (cortico-cortical coherence) and corticospinal connectivity with transcranial magnetic stimulation (TMS). As seen from comparisons with age-matched controls, our patients showed enhanced recruitment of the lateral premotor cortex of the lesioned hemisphere [Brodmann area (BA) 6], lateral premotor and to a lesser extent primary sensorimotor and parietal cortex of the contralesional hemisphere (CON-H; BA 4 and superior parietal lobule) and left cerebellum (patients versus controls, Z > 3.09). EEG coherence analysis showed that after stroke cortico-cortical connections were reduced in the stroke hemisphere but relatively increased in the CON-H (ANOVA, contrast analysis, P < 0.05), suggesting a shift of functional connectivity towards the CON-H. Nevertheless, fast conducting corticospinal transmission originated exclusively from the lesioned hemisphere. No direct ipsilateral motor evoked potentials (MEPs) could be elicited with TMS over the contralesional primary motor cortex (iM1) in stroke patients. We conclude that (i) effective recovery is based on enhanced utilization of ipsi- and contralesional resources, (ii) basic corticospinal commands arise from the lesioned hemisphere without recruitment of ('latent') uncrossed corticospinal tract fibres and (iii) increased contralesional activity probably facilitates control of recovered motor function by operating at a higher-order processing level, similar to but not identical with the extended network concerned with complex movements in healthy subjects.

Stroke is the leading cause of disability, causing impairments in movement and sensation. Animal models suggest that there is about a month of heightened plasticity in the brain early after stroke when most recovery from impairment occurs. This heightened plasticity occurs against background changes in excitatory/inhibitory balance, is apparent structurally as neurite remodeling, and changes in the extent and responsiveness of cortical maps. The best time for experience to improve outcome is unclear, but in animal models only very early (< 5 days from onset) and intense activities lead to increased histological damage. Conversely, late rehabilitation (>30 days) is much less effective both in terms of outcome and morphological changes. In clinical practice, rehabilitation after disabling strokes involves a relatively brief period of inpatient rehabilitation that does not come close to matching intensity levels investigated in animal models, and it involves training compensatory strategies with minimal impact on impairment. Research on the effect of Constraint-induced and robotic therapy has been conducted almost entirely in chronic stroke but earlier does seem better. Current rehabilitation treatments have a disappointingly modest effect on impairment early or late after stroke. Translation from animal models will require: (1) substantial increases in the intensity and dosage of treatments offered in the first month after stroke with an emphasis on impairment, (2) Treatment combination approaches, for example, non-invasive brain stimulation with robotics, based on current understanding of motor learning and brain plasticity, and (3) Research that emphasizes mechanistic phase II studies over premature phase III clinical trials.

Constraint-induced movement therapy (CI), a standardized intensive rehabilitation intervention, was given to patients a year or more following stroke. The goal was to determine if CI was more effective than a less-intensive control intervention in changing motor function and/or brain physiology and to gain insight into the mechanisms underlying this recovery process. Subjects were recruited and randomized more than 1 year after a single subcortical infarction. Clinical assessments performed before and after the intervention and at 6 months postintervention included the Wolf Motor Function Test (WMFT), the Motor Activity Log (MAL), and the Assessment of Motor and Process Skills (AMPS). Transcranial magnetic stimulation was used to map the motor cortex. Positron emission tomography was used to measure changes in motor task-related activation due to the intervention. MAL increased by 1.08 after CI therapy and decreased by 0.01 after control therapy. The difference between groups was significant (P < 0.001). Changes in WMFT and AMPS were not significantly different between groups. Cerebral activation during a motor task decreased significantly, and motor map size increased in the affected hemisphere motor cortex in CI patients but not in control patients. Both changes may reflect improved ability of upper motor neurons to produce movement.

Background-Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke.

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 detectible 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.

This is a novel therapeutic strategy that may help improve hand function in patients with long-term weakness after stroke.

Crossmodal plasticity occurs when loss of input in one sensory modality leads to reorganization in brain representations of other sensory modalities. In congenital blindness the visual cortex becomes responsive to somatosensory input such as occurs during Braille reading. The route by which somatosensory information reaches the visual cortex is not known. Here, we used repetitive transcranial magnetic stimulation (rTMS) to probe the connection between primary somatosensory cortex (S1) and early visual cortex (V1 and neighboring areas), combining rTMS with positron emission tomography (PET). We applied stimulation over S1 in sighted, early blind and late blind individuals. Baseline regional cerebral blood flow in occipital cortex was highest in early blind and lowest in late blind individuals. Only the early blind group showed significant activation of early visual areas when rTMS was delivered over S1. This activation was significantly higher in early than in late blind, but not relative to sighted controls. These results are consistent with the hypothesis that tactile information may reach early visual areas in early blind humans through cortico-cortical pathways, possibly supporting enhanced tactile information processing.