A systematic review of studies using rTMS for lower limb stroke rehabilitation found it can improve walking speed.
Since it was first developed in the late 1990s, repetitive transcranial magnetic stimulation (rTMS) has been thought to be a promising treatment for stroke rehabilitation. That’s been especially true for upper limb rehabilitation, since motor areas controlling the upper limbs lie on the brain’s surface, where they are easy to affect by placing a stimulation coil against the scalp. In contrast, the lower limb motor control areas are within the intracerebral fissure and are thus harder to stimulate; as a consequence, there are fewer studies, and less evidence, supporting the efficacy of rTMS for improvements in post-stroke walking and balance.
Now, a systematic review of studies using rTMS for lower limb stroke rehabilitation, published online May 3 in the American Journal of Physical Medicine and Rehabilitation, indicates it can improve walking speed. The review may increase interest in further studies of rTMS for this application, according to experts, but whether the technique will move beyond the experimental stage any time soon is still in question.
HOW TMS WORKS
TMS delivers a strong electrical current to a copper coil to generate an oscillating, high-intensity magnetic field. Placed against the scalp, the field induces perpendicular currents in the tissue below, said the lead study author Yi Li, MD, of the department of rehabilitation medicine at the West China Hospital of Sichuan University in Chengdu, People’s Republic of China. “At the right strength, it can depolarize the targeted neurons and influence cortical excitability, which may facilitate motor function after stroke,” Dr. Li said.
There are many variables that determine the effect of the treatment, including shape of the coil, current strength, frequency, and duration of stimulation. Low-frequency stimulation, below 1 Hz, decreases cortical excitability, while higher frequency stimulation increases it. The mechanism or mechanisms involved in altering excitability remain a subject of study, Dr. Li noted.
“rTMS is presumed to be related to the activity of GABA-ergic neurons. Moreover, depending on the intrinsic properties and geometrical orientation of fibers within the cortical region stimulated, the magnetic stimulus not only activates local interneuronal circuits, but also those fibers projecting ortho- or antidromically to distant structures. However, why they are susceptible to this intervention is unclear.”
Despite this theoretical uncertainty, clinical benefit has been shown in stroke patients. In the lower limbs, studies have generally been small, and so Dr. Li and colleagues decided to look at them collectively to see what patterns emerged. They analyzed randomized controlled trials of more than five patients, performed in adults more than one month post-stroke, in which walking speed and balance were included among the outcomes.
They identified nine studies meeting these criteria, involving a total of 220 patients. The studies were published between 2012 and 2017, and included both hemorrhagic and ischemic stroke patients, several months to several years after their stroke.
Frequency and site of delivery differed among the studies. Seven studies used high-frequency stimulation to the affected hemisphere, while two delivered low-frequency stimulation to the primary motor area of the unaffected hemisphere, based on the interhemispheric competition model, which posits that lowering activity in the unaffected hemisphere can enhance functional recovery in the other side. On the affected side, stimulation was delivered to the primary motor area in four studies, the bilateral leg area in two studies, and the trunk motor spot in one study.
STUDY RESULTS
Among the six studies that included complete information on walking speed, with a combined 139 patients, ipsilesional stimulation, but not contralesional or bilateral stimulation, significantly improved walking speed. The standardized mean difference between treated and control groups was 0.80 (95% CI: 0.36 to 1.24, p=0.0003). (The standardized mean difference is defined as the difference in mean outcome between groups divided by the standard deviation of outcome among all participants, and is a method to summarize results from studies that use a variety of methods to address the same outcome. It is a unitless number, and is not simply convertible to a difference in speed.)
No effect was seen on balance in the three studies, comprising 77 patients, for which complete information was available.
While there was no detectable effect of contralesional stimulation on walking speed, Dr. Li said, only one study using the technique was included, and so it would be premature to rule out this approach to improving ambulation. Dr. Li also noted that the two studies using bilateral stimulation were also the two to attempt to reach the leg motor area, using custom-designed coils whose fields penetrate deeper than the standard figure-eight coil used in the other studies.
“In theory, customized coils such as these have a better ability to stimulate deeper leg-related cortical motor areas,” he said, but more trials will be needed to test their efficacy in stroke rehabilitation.
“We believe that rTMS is likely to be considered a standard option for treatment in the future,” Dr. Li said, either alone or in combination with other rehabilitation modalities. “However, more high-quality trials are needed to provide more powerful evidence.”
EXPERT COMMENTARY
“I was excited by this meta-analysis, because it addresses a patient-centered need, namely walking speed,” commented A.M. Barrett, MD, FAAN, director of Stroke Rehabilitation Research at the Kessler Foundation in East Hanover, NJ. Walking speed predicts community mobility and health, and in some studies correlates with post-stroke lifespan, she noted. “One of the most important concerns of stroke patients is that they can’t walk rapidly enough.”
However, she noted, studies of rTMS need to include its potential effects on multiple brain systems, to determine whether stimulation-related improvements in walking may be accompanied by unintended effects on cognition, for example. “We need to look at networks within the brain. We may be making walking better, but memory could be worse.”
Finally, she said, rTMS needs to be compared to other, lower-tech rehabilitation approaches. She noted that a 2010 multi-center, randomized study that provided daily verbal feedback about performance improved walking speed by about 25 percent. “Behavioral techniques are some of the best ones for stroke rehabilitation,” Dr. Barrett said.
“I think this review is a valuable contribution, because it analyzed a number of studies on the lower extremities, whereas most previous work has been focused on the upper extremities,” said Randie Black-Schaffer, MD, medical director of the stroke program at Spaulding Rehabilitation Hospital, affiliated with Massachusetts General Hospital in Boston. Seeing the potential for benefit on walking may encourage people to solve the problems of access to the cortical areas for the lower extremities, she said.
There are still challenges ahead for more widespread use of rTMS in stroke, Dr. Black-Schaffer noted. “I think it has a lot of promise, but one of the difficulties is using the technique consistently. The equipment is not easy to use, and it’s not easy to get consistent results. Currently it requires quite a bit of training and experience to be good at it, to make sure you are delivering an effective stimulus repeatedly to the patient.”
The leg areas within the fissure are not only deeper, but also directly apposed, “so you are quite likely stimulating both hemispheres at once, which can complicate your perception of what the results are,” she said. And older patients present a special challenge, because brain shrinkage means the target tissue is that much further away from the scalp, and that much harder to reach.
“Nonetheless, this is an exciting time, with the number of studies on rTMS increasing exponentially. I am hopeful that some of these challenges will be solved over the next five years or so.”