Transcranial Brain Stimulation: No Benefit for Stroke Rehab

Erik Greb

September 23, 2021

Anodal transcranial direct-current stimulation (tDCS) does not improve upper extremity recovery in patients with mild to moderate stroke, new data suggest.

In a prospective, randomized trial, improvement in upper extremity function, as measured by the upper-extremity Fugl-Meyer assessment (UEFMA), was 9.07 among patients who received sham stimulation and 8.76 among patients who received active stimulation.

Dr Christian Gerloff

"Both treatment groups showed very good upper extremity recovery up to 12 months after stroke," study investigator Christian Gerloff, MD, professor of neurology and chairman of the Department of Neurology at University Medical Center Hamburg-Eppendorf in Germany, told Medscape Medical News.

"The safety profile of tDCS was favorable," he added. "In particular, there were no seizures related to brain stimulation."

Gerloff presented the findings at the European Stroke Organisation Conference (ESOC) 2021, which was held online.

tDCS vs Sham

Upper extremity dysfunction is a potentially disabling problem that affects 50% to 80% of patients with stroke, said Gerloff. It is a major hurdle to overcome for the resumption of activities of daily living.

A convincing body of experimental evidence suggests that tDCS can modify neuronal excitability in the motor cortex, said Gerloff. "We had some proof-of-principle data in a small group of stroke patients that were very encouraging." Data also indicate that tDCS is safe and can be applied responsibly during the phase of maximum plasticity; that is, during the first weeks after stroke, Gerloff added.

For this analysis, the investigators conducted a prospective, randomized, double-blind, placebo-controlled trial to examine the efficacy and safety of anodal tDCS in patients with cerebral ischemia.

The investigators randomly assigned patients at 5 to 45 days after stroke to tDCS (1 mA for 20 min) or sham stimulation applied to the primary motor cortex of the lesioned hemisphere. Stimulation was administered in 10 sessions over 2 weeks together with standardized rehabilitative training.

The study's primary outcome was upper extremity function, as assessed by UEFMA, at 1 to 7 days after the intervention period. Secondary endpoints included assessments such as the Action Research Arm Test, the nine-hole peg test, grip strength, Stroke Impact Scale, and the Patient Health Questionnaire-9 at multiple timepoints up to 12 months.

"Smarter" Protocols Needed?

Between 2009 and 2019, investigators at 11 centers in three European countries randomly assigned 123 patients to treatment in two groups of approximately equal size. Of this population, 119 patients entered the intention-to-treat (ITT) analysis.

Patients' mean age was 66 years, and 63% were male. The population's mean NIH Stroke Scale score at baseline was 3.84, and mean time since stroke was 20 days. Baseline variables were comparable between the treatment arms.

In the ITT analysis, the adjusted mean improvement of UEFMA from baseline was 9.07 in the placebo group and 8.76 with active stimulation (P = .820). In the per protocol analysis, which included 94 patients, the respective UEFMA differences were 10.25 for placebo and 10.20 for active stimulation (P = .972).

The researchers found no significant differences in secondary endpoints. Both treatment groups had very good long-term recovery. At 12 months, UEFMA was 56.21 in the sham group and 55.76 in the active group. The intervention was well tolerated.

The strength of the current could have played a role in the apparent lack of treatment efficacy, the authors speculate. "We used 1 mA over 20 minutes because this has been shown to be effective for motor cortex modulation in prior studies," said Gerloff. "Maybe this was too weak, and 2 mA would have been better. More likely, we might face a ceiling effect."

In addition, the "thorough and intense" training protocol that guided rehabilitation in both arms might not have left additional room for tDCS-induced improvement, said Gerloff. The patients had mild to moderate strokes, which increases the likelihood of spontaneous recovery.

Moreover, previous data on tDCS were obtained mostly in the chronic phase after stroke. "We cannot exclude that tDCS exerts less effect in the acute phase because the molecular and cellular mechanisms of plasticity are already maximally upregulated, again leaving no room for additional tDCS-induced improvement," said Gerloff.

The researchers are testing other stimulation protocols and methods for future research. They also are performing an in-depth analysis of neural network patterns after stroke, and especially the interaction between the structural connectome, functional connectivity metrics, and recovery. "We are confident that 'smarter' stimulation protocols which effectively modulate network patterns might be more successful," said Gerloff.

Proof of Concept

The study's restricted patient population suggests "a proof-of-concept study rather than a viable approach for more widespread use," said Larry B. Goldstein, MD, Ruth L. Works professor and chairman of the Department of Neurology at the University of Kentucky in Lexington, who commented on the findings for Medscape Medical News.

The study's failure to find a benefit of the intervention is consistent with previous research. "Other small studies using this and other methods such as transcranial magnetic stimulation as a means of enhancing post-stroke motor recovery have also failed to find benefit," said Goldstein.

But the work that has been done to date is not necessarily grounds for abandoning this approach, he added. "There may be issues related to intensity, duration of treatment, timing in relation to the stroke, and targets that could be further explored."

The current findings provide "another example where it is difficult to translate findings from healthy populations or data showing an effect on outcomes such as motor learning into diseased populations," said Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow in Scotland, who also commented for Medscape Medical News.

"However, I think what is really important here is that the data suggests to us that using the stimulation technique early after stroke is acceptably safe, which should help facilitate future studies," he added.

The study was well conducted, and its results suggest that the method of stimulation used in the participants is not effective, said Dawson. "However, this does not mean that further attempts, perhaps even earlier after stroke or with higher stimulation amplitude, may not be effective."

Finally, the results highlight the importance of identifying participants who are unlikely to have good natural recovery, with the aim of targeting these interventions to the appropriate patients, said Dawson. "This might mean that people should be studied later, after there has been natural recovery."

The German Research Council funded the study. Gerloff, Goldstein, and Dawson have disclosed no relevant financial relationships.

European Stroke Organisation Conference 2021: Abstract PO0020A/#2133. Presented September 3, 2021.

Follow Erik Greb on Twitter: @MedscapeErik.

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