Stroke patients undergoing rehabilitation who receive repeated brain stimulation do better in terms of recovering movement than those who don't, a new study shows.
The randomized trial compared anodal transcranial direct-current stimulation (tDCS) to sham stimulation and showed significant improvements in the group receiving tDCS, improvement that persisted after treatment stopped.
"Any technique that can be used to enhance the effects of a given dose of rehabilitation is important because rehabilitation is really expensive to deliver," study author Heidi Johansen-Berg, professor of cognitive neuroscience, University of Oxford, United Kingdom, told Medscape Medical News.
"This study shows that we can basically boost the effects of the dose, which has important implications for trying to ensure that patents reach their true recovery potential," she said.
Their results were published online March 16 in Science Translational Medicine.
The trial included 24 patients who had experienced a single unilateral ischemic or hemorrhagic stroke that affected motor function in the contralesional hand at least 6 months previously.
All patients were scheduled for daily motor training in the Graded Repetitive Arm Supplementary Program (GRASP), delivered in 1-hour sessions over 9 consecutive working days. Patients began the program at various levels, depending on assessment of their motor abilities.
Researchers randomly assigned 11 of these patients to receive anodal tDCS and 13 to get sham stimulation for the first 20 minutes of the rehab sessions.
In all patients, investigators placed electrodes over the motor cortex in the stroke-affected hemisphere and applied 1 milliamp of positive current over this brain area.
The current was increased from zero to 1 milliamp over the first 10 seconds. Most patients can't feel this current, although some might feel a slight tingling or tickling sensation, said Dr Johansen-Berg.
In the treatment group, the current stayed at this level over 20 minutes, but in the sham group, it was switched back to zero. "Once the current is stable, or at that plateau of 1 milliamp, people can't generally feel anything," said Dr Johansen-Berg.
The two groups were similar in terms of age, sex, time since stroke, lesion location and volume, and motor ability.
Researchers looked at three clinical measures at multiple time points (1 day, 1 week, 1 month, and 3 months after intervention) to assess upper-limb function. These were Upper Extremity Fugl-Meyer Assessment (UEFM), Action Research Arm Test (ARAT), and Wolf Motor Function Test (WMFT). These measures all assess the ability to move the hand or arm, but in slightly different ways.
Scores for each of these measures increased in both groups. But after combining all clinical measures and all four postintervention time points, the anodal tDCS group had greater scores than the sham group (P = .008).
Repeating the analysis for each measure separately, the researchers found higher scores in the treatment group for both ARAT (P = .031) and WMFT (P = .037), but not for UEFM (P = 0.329).
At the 3-month time point, pooling across all clinical measures showed greater scores in the anodal tDCS group compared with the sham group (P = .004). At this point, scores were higher in the treatment group for both ARAT (P = .045) and WMFT (P = .001), but not for UEFM (P = .550). All P values were corrected for multiple comparisons across measures and time points as appropriate.
Table. Mean Absolute Difference in Clinical Scores Between Treatment and Sham Groups at 3 Months
|Endpoint||Mean Absolute Difference (95% Confidence Interval)||P Value|
|UEFM||2.898 (–2.136 to 7.932)||.550|
|ARAT||5.763 (1.560 - 9.966)||.045|
|WMFT||6.871 (3.411 -10.331)||.001|
That the improvement of the treatment group over the sham group persisted to 3 months after the training ended is important, stressed Dr Johansen-Berg. It means, she said, that brain stimulation might boost the benefits of rehabilitation to help stroke patients achieve their recovery potential.
MRI data were available for 11 participants per group. The data showed greater increases in functional MRI activation of ipsilesional motor and premotor cortical regions during movement of the affected hand.
Structural MRI showed an increase in grey matter volume in cortical areas in the treatment group but not the sham group.
The MRI findings "showed that following the training, the stimulation group had greater increases in brain activity in the targeted region, so it mirrors the behavior of the clinical results," noted Dr Johansen-Berg. "It shows that we have been able to increase the amount of activity that can be evoked in that stimulated brain region."
The researchers don't believe that the brain stimulation directly improves impairment but rather that it facilitates relearning through brain plasticity.
"We know that when stroke patients receive rehabilitation training, they're effectively having to relearn a function that was damaged as a result of the stroke," said Dr Johansen-Berg. "Brain stimulation alters the bit of brain that we're stimulating in such a way that plasticity is more likely to occur."
Dr Johansen-Berg doesn't think that the brain stimulation alone — without the rehabilitation — would be as effective. "In my mind, the rationale for using brain stimulation rests on there being some sort of behavioral intervention that induces learning," she said.
The study was too small to determine whether certain subgroups of patients benefit more from brain stimulation. "That would be a really important next step because we expect that not all patients will benefit from this," said Dr Johansen-Berg.
It would also be useful to determine the optimal amount of stimulation, she said. "Ideally, you would want to do a dose-finding study like you'd do in a drug study, and calibrate every possible parameter, whether it's the amount of current, the number of days, the gaps between the days, all those things."
Unfortunately, though, doing such research is "a massive undertaking," she said. Nevertheless, the intervention should be a "feasible" future addition to post-stroke rehabilitation "once we have kind of joined up the dots and understand who's going to benefit most," said Dr Johansen-Berg.
"It's very cheap; it's very portable; it's very easily tolerated, and it would be quite realistic to imagine that this could be added on routinely to any type of rehabilitation intervention."
Enhancing the Gain
Reached for a comment, Professor Yves Vandermeeren, MD, PhD, Neurology Department, Université catholique de Louvain, Brussels, Belgium, said the study confirms the results of a growing body of research.
Dr Vandermeeren, who has also done research on post-stroke brain stimulation in conjunction with rehabilitation, called the new study "very clean" and "well designed."
He noted the relatively large number of patients included in the study and the fact that it was randomized and double-blind. He also pointed out the importance of significant changes in scores on the ARAF and WMFT because these tests measure activity levels, not just impairment.
"So from a clinical point of view, that's very interesting."
What was also "extremely interesting," according to Dr Vandermeeren, is that the treatment group retained the improvement for "a very long time."
"What is really exciting here is that we are coming to a point where we will likely, maybe in a few years, be able to launch a large, randomized controlled trial across multiple centers."
However, Dr Vandermeeren agreed that before that can happen, researchers need to figure out which kind of stimulation to apply to each patient. "We have to decide that for patients with this level of function and this type of injury, the best rehabilitation training would be this one, and we need to determine the best intensity and duration of stimulation, and whether we should apply the stimulation during, before or after rehabilitation."
It's possible that "large and intensive sessions" might need to be supplemented with bouts of maintenance stimulation, said Dr Vandermeeren.
He also agreed that stimulation alone is not sufficient. "If we apply the right stimulation at the right time for the right patient, we are likely to enhance the gain of neuro-rehab, maybe to speed the recovery so the patient recovers faster and so the hospitalization will be shorter and it will be cost less, and hopefully, we will be able to bring them to a higher level of recovery."
The study was supported by the Dunhill Medical Trust, Oxford National Institute for Health Research) Biomedical Research Centre, Wellcome Trust, Medical Research Council, and The People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/ under Research Executive Agency grant agreement no. PITN-GA-2011-290011. The authors have disclosed no relevant financial relationships.
Sci Translat Med. Published online March 16, 2016. Abstract
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Cite this: Brain Stimulation After Stroke Aids Recovery - Medscape - Mar 23, 2016.