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What Can Predict the Benefit of Repetitive Transcranial Magnetic Stimulation for Post-Stroke Aphasia?

Article In Brief

In a study of post-stroke aphasia, investigators reported that repetive transcranial magnetic stimulation over the right pars was not associated with overall changes in naming accuracy, but they observed a small but marginally significant correlation between overall changes in naming accuracy and the degree of phonological impairment at baseline.

PHILADELPHIA—Speech-language therapy is the current mainstay for treating post-stroke aphasia, but its effects on long-term outcomes are only modestly beneficial. Can repetitive transcranial magnetic stimulation (rTMS) improve on that?

That was the question posed by Denise Y. Harvey, PhD, who presented results of new research she led to determine whether the benefit of rTMS might be influenced by the type of word retrieval error the patient displays—whether early in the process of choosing the right word, or later while bringing together the phonemes to form the word. Dr. Harvey, a post-doctoral research fellow at the University of Pennsylvania in the laboratory for cognition and neural stimulation, shared her findings here at the Contemporary Clinical Issues Plenary Session at the AAN Annual Meeting.

“Repetitive transcranial magnetic stimulation has shown promise in facilitating recovery of language ability in chronic aphasia,” Dr. Harvey said. Work at the University of Pennsylvania and elsewhere has shown that, at least for some patients, treatment improves over time.

“In our 2017 study [in Cognitive and Behavioral Neurology], we found a marginal improvement at two months, but a greater improvement at six months,” with patients stating the correct name of a pictured object about 55 percent of the time at baseline, rising to 60 percent at two months, and 70 percent at 12 months. “These changes were associated with bilateral changes in the language networks on fMRI.”

However, she noted, individuals vary in the degree to which they respond to rTMS therapy, “making it difficult to determine who would be a good candidate for this treatment approach.” Prior work has investigated whether aphasia severity predicts response to rTMS therapy, but the evidence is mixed.

“We hypothesized instead that the characteristics of word retrieval failure, or the different ways in which people with aphasia err, may be a better predictor of who is most likely to benefit from rTMS therapy, as it may represent a more sensitive approach than overall severity.”

Naming: The Three Stages

Naming—word retrieval in response to a visual image—is thought to proceed through three stages, she explained. In the semantic stage, the picture—for instance of a dog—is associated with multiple properties, such as having four legs and barking. That leads to the lexical stage, in which the word “dog” is associated with the image, and then the phonological stage, in which the sounds that make up the spoken word are associated with the lexical word, and then are brought together to speak the word “dog.”

At both the semantic-lexical transition and the lexical-phonological transitions, the brain maps one representation onto the next, and errors often occur in these mappings. For instance, in a semantic-lexical error, the patient might map the concept of “dog” onto the lexical word “cat,” which is then spoken correctly. In a lexical-phonological error, he might map the correct lexical word “dog” onto the sounds “duh” and “at,” and speak the work “dat.”

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“We believe these data have important implications for determining the best candidates for further rTMS treatment trials. Characterizing the nature of aphasic individuals' language impairment could inform the stratification of patients into other effective rTMS protocols, such as those involving stimulation to different brain regions.”

—DR. DENISE Y. HARVEY

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In the most current study, the patients maximal lesion overlap (in dark red) was localized to the left pars opercularis, or Brodmann area 44, extending medially (n=9).

A further aspect of retrieval, also of interest to the research team, was response consistency. “Successful word retrieval for a given item is not always predictive of future retrieval success,” Dr. Harvey noted.

Assessing Better Outcomes

Dr. Harvey's study, published in May in Brain and Language, was designed to assess whether better outcomes following rTMS were associated with either response consistency at baseline, or stage of word retrieval failure. She enrolled 11 participants, nine of whom were male, with chronic post-stroke aphasia of wide-ranging severity.

Subjects were shown a large selection of pictures, twice, and the mean percent correct— averaged across the two baseline sessions—served as the measure of naming impairment severity. She also recorded the type of error (semantic-lexical versus lexical-phonologic) and the response consistency. Items named incorrectly twice were judged “wrong,” while those named once right and once wrong were “inconsistent.”

Subjects then received rTMS stimulation—of a type known as theta burst—over the right pars triangularis (rPTr), contralateral to the lesion, inhibiting the intact cortex in order to stimulate activity in the lesioned cortex. Stimulation over the cranial vertex served as a control.

Subjects were shown 40 items before stimulation, then another 40 items afterward, and the difference between percent correct response, and error type, before and after treatment was determined.

Dr. Harvey found that at the group level, there was no significant effect of stimulation on change in the number of either inconsistent or wrong items, a result she did not find surprising, given that past studies have shown that response to rTMS varies considerably among individuals.

Subjects whose baseline naming ability was above the median did not improve with stimulation, she found, but subjects below the median—those with the worst performance at baseline—did have a modest improvement in consistency after rPTr stimulation. There was no effect on the number of wrong items in either group.

“We then asked whether the improvement might be specific to one of the stages of the production system,” Dr. Harvey said. “For this, we looked at whether there was a relationship between the degree of semantic or phonological accuracy at baseline, and changes in performance overall, as well as changes in the specific types of error.”

“We found that the degree of lexical-semantic impairment at baseline did not relate to overall changes in naming accuracy following rTMS,” she said. In contrast, she did observe a small but marginally significant correlation between overall changes in naming accuracy and the degree of phonological impairment at baseline (p=0.057). “Individuals who have a higher degree of phonological access impairment at baseline were making fewer phonological errors following stimulation.”

Together, the results suggest that the level of noise in the system—as indicated by inconsistency in response at baseline—may be improved by rTMS of the rPTr, “however the benefit seems specific to the phonological access phase of production,” Dr. Harvey concluded.

She acknowledged that the study was small. But, she said, “We believe these data have important implications for determining the best candidates for further rTMS treatment trials. Characterizing the nature of aphasic individuals' language impairment could inform the stratification of patients into other effective rTMS protocols, such as those involving stimulation to different brain regions.”

Expert Commentary

There are many possible ways to optimize rTMS for post-stroke aphasia, commented Eric Wassermann, MD, chief of the behavioral neurology unit at the National Institute of Neurological Disorders and Stroke in Bethesda, MD. These include varying the targeted site and altering the frequency, intensity, duration, and other parameters of the stimulation.

One challenge in the field is that rTMS doesn't have translatable effects in animal models. “It doesn't behave the same way,” he said. This means that the mechanisms are still largely unknown, “and we can't use behavioral effects to validate mechanistic assumptions”—that is, even if it works, it may not be for the reason the researcher assumes it does.

The current study was “intriguing,” he said, “but we as a community should be looking for a definitive trial, one that is adequately powered” to uncover significant differences, if there are any, between subgroups. Admittedly, “that is difficult in cognitive neurology. It is a long pathway, but I think we are making progress.”

Disclosures

Drs. Harvey and Wassermann had no disclosures.

Link Up for More Information

•. Harvey DY, Podell J, Turkeltaub PE, et al. Functional reorganization of right prefrontal cortex underlies sustained naming improvements in chronic aphasia via repetitive transcranial magnetic stimulation https://journals.lww.com/cogbehavneurol/Abstract/2017/12000/Functional_Reorganization_of_Right_Prefrontal.1.aspx. Cogn Behav Neurol 2017;30(44):133–144.
•. Harvey DY, Mass JA, Shah-Basak PP, et al. Continuous theta burst stimulation over right pars triangularis facilitates naming abilities in chronic post-stroke aphasia by enhancing phonological access https://www.sciencedirect.com/science/article/abs/pii/S0093934X18301718. Brain Lang 2019; 192:25–34.