Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia

Summary

We explore the use of repetitive transcranial magnetic stimulation (rTMS) to improve language abilities in patients with chronic stroke and non-fluent aphasia. After identifying a site in the right frontal gyrus for each patient that responds optimally to stimulation, we target this site during ten days of rTMS treatment.

Abstract

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia¹. In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six-month post-stimulation language testing.

Introduction

Aphasia-an acquired deficit of language ability-is a common and often debilitating consequence of stroke². Although some degree of recovery from aphasia after acute stroke is typical, many patients experience at least some degree of persistent deficits, and existing language therapies are generally considered to be only modestly effective in facilitating recovery^3-5. Recent years have seen the emergence of noninvasive stimulation techniques such as transcranial magnetic stimulation (TMS) as promising potential treatment approaches for a variety of deficits after stroke, including aphasia. TMS employs the principle of electromagnetic induction and involves the generation of a rapidly fluxing magnetic field in a coil of wire. When the coil is placed adjacent to the head of a subject, the magnetic field penetrates the scalp and skull, inducing a current in underlying cortical neurons that is sufficient to depolarize neuronal membranes and generate action potentials³. TMS parameters such as frequency, intensity, and number of pulses can be varied in order elicit different neurophysiologic, behavioral, and perceptual effects^4,5. Repetitive TMS (rTMS) entails the administration of a series of pulses at a predetermined frequency and produces effects that can outlast the application of the stimulation. Germane to the current experiment, evidence shows that rTMS delivered at a low frequency (0.5-2 Hz) tends to focally decrease cortical excitability, while high-frequency stimulation has been associated with cortical excitation³. rTMS has been explored as a treatment for various neurologic and psychiatric disorders, most notably depression⁶.

A growing body of evidence suggests that low frequency rTMS may be used to enhance language recovery in persons with chronic stroke-induced aphasia. Naeser and colleagues^7,8 were the first to apply 1 Hz inhibitory rTMS to the right inferior frontal gyrus for 20 min five days a week for two weeks in four right-handed patients with chronic non-fluent aphasia. Significant improvements in naming were observed, which persisted for at least eight months following completion of stimulation⁸. We subsequently replicated and extended these results, and have demonstrated that 1 Hz stimulation resulted in persistent improvements in both naming and spontaneous elicited speech in chronic non-fluent aphasic patients^9-11. Encouragingly, the results of small studies such as these have been replicated in further investigations in patients with chronic stroke¹², as well as in patients with subacute stroke and aphasia¹³.

One important and nearly ubiquitous feature of prior TMS studies in patients with non-fluent aphasia is that the salutary effects of stimulation appear to be site-specific. Adopting the approach initially employed by Naeser and colleagues, most investigations in which rTMS has been used to facilitate language recovery have targeted the right pars triangularis¹ (Brodmann area 45). In fact, recent evidence has suggested that stimulation of other regions of the right inferior frontal gyrus may be ineffective, or may even have deleterious effects on language performance¹⁴, underscoring the need for careful individual identification of optimal stimulation sites.

Building upon the approach established by Naeser and colleagues⁸, our ongoing investigation explores the effects of inhibitory rTMS in the inferior frontal gyrus on language ability, and also examines the topographic specificity of rTMS effects in the right frontal lobe. In this article, we provide a detailed description of how an optimal site for stimulation can be identified in patients with chronic non-fluent aphasia. We then describe the administration of therapeutic rTMS and explain our techniques for assessing the efficacy of stimulation in enhancing language recovery in this population.

Protocol

1. Pre-Treatment Evaluation

1. Recruit patients who meet the eligibility requirements for the study. These criteria include a single, unilateral, left hemisphere ischemic stroke that spares the supplementary motor area (SMA), mild to moderate non-fluent speech (defined as the ability to produce meaningful words and at least a 2-4 word length string), between the ages of 18 and 75 and at least six months post-stroke.
2. Additionally, all potential patients must be able to name at least three of the first 30 items on the Boston Naming Test¹⁵, an average of at least three pictures out of 20 when presented with ten sets of picture-naming stimuli taken from the Snodgrass and Vanderwart corpus¹⁶, and score at or above the 25^th percentile on the subtests for word comprehension and commands on the Boston Diagnostic Aphasic Examination¹⁷.
3. Conduct a medical screening examination to ensure patients are healthy enough to participate in the study, and that there are no contraindications to undergoing a Magnetic Resonance Imaging (MRI) scan or TMS.

2. Baseline Testing

1. Administer a battery of standardized tests on three separate days to assess the extent of each patient's language impairment and deficits in other cognitive domains. The tests include the Cookie Theft picture description subtest of the BDAE¹⁸, BDAE (2^nd Ed.) Subtests for Word Comprehension (Basic Word Discrimination) and Commands, Boston Naming Test¹⁵, sets of 40 line drawing stimuli taken from the Snodgrass and Vanderwart picture database¹⁶, and the Cognitive Linguistic Quick Test¹⁹ (CLQT).
2. Initiate a baseline BOLD-fMRI study in which the patient performs a picture-naming task with oral response. Collect high resolution whole-brain T1-weighted images with a MPRAGE sequence (RT = 1,620 msec, TE = 3.87 msec, FA = 15, FOV = 192 x 256, slices = 160, voxel sizes = 1 mm³). Acquire functional volumes using a whole-brain T2*-weighted BOLD echoplanar sequence (TR = 3,000 sec, TE = 35 msec, FA = 90, FOV = 128 x 128, slices = 31, voxel sizes = 1.875 mm², slice thickness = 4 mm).
3. Randomize patients into either a group receiving real repetitive TMS (rTMS) or a group receiving initial sham stimulation (sTMS), followed by rTMS (Figure 1).

3. Identification of Optimal Sites of Stimulation

1. In order to target rTMS to cortical sites in a precise and accurate manner, use a neuronavigational system (e.g. Brainsight, Rogue Research, Montreal) to co-register high-resolution whole-brain T1-weighted images (see 2.2 above) with the location of the patient and coil. For the rTMS group, determine resting motor threshold (RMT) via stimulation to right motor cortex and subsequent visual inspection²⁰.
2. During real rTMS, orient the coil with the handle in a posterior and inferior direction approximately 45° clockwise from the downward position. For the sham group, administer sTMS with the coil perpendicular to the head so that only the outer rim of the lateral wing of the coil contacts the head. In this orientation, the peak magnetic field runs parallel to the skull and thus does not produce cortical stimulation.
3. In six separate sessions conducted over five days (two sessions conducted on final day, with a 45-minute break in between sessions), administer ten minutes of either rTMS (600 pulses of 1 Hz at an intensity of 90% RMT) or sTMS to different sites in the right inferior frontal lobe: the primary motor cortex (M1) corresponding to the mouth, pars opercularis (BA 44), anterior pars triangularis (BA 45), dorsal posterior pars triangularis (BA 45), ventral posterior pars triangularis (BA 45), and pars orbitalis (BA 47; Figure 2). Randomize stimulation site order between patients.
4. Have patients perform a 40-item picture-naming task immediately before and after each TMS session. Picture stimuli are taken from the Snodgrass and Vanderwart¹⁶ item set, the Peabody Picture Vocabulary Test²¹, and the International Picture Naming Project (IPNP) database²². The 40-item lists must be matched with respect to word length, frequency, and semantic category; in our item lists 20 items were novel while 20 were repeated throughout the testing sessions to assess for practice effects. Utterances should be counted as correct if they differ from the target by no more than one phoneme⁸. Word list order should be randomized across subjects and each subject should receive different word lists at every visit.
5. Determine the optimal site of stimulation by performing one-sample t-tests comparing the change in picture-naming performance at each site to the mean change in naming performance for all other sites. Next, compare the change in performance at the optimal site to the variance of performance across all six pre-rTMS sessions; if the change in performance after rTMS is greater than two times the standard deviation of mean pre-TMS performance, it is unlikely that the benefit in naming performance is attributable to test-retest variability⁹.
6. For sham site-finding, administer sTMS over the pars triangularis. This location acts as the "optimal site" for the sham arm of the treatment phase, as described in Protocol section 4.

4. Treatment Phase

1. Administer rTMS or sTMS to the optimal stimulation site for ten days in a twelve-day period (stimulation on every weekday with weekends off).
2. On the first day of stimulation, the order of events is as follows: have the patient undergo an fMRI (with concurrent picture-naming, as in baseline), administer the 40-item naming task, stimulate the optimal site using 20 min of either 1 Hz rTMS at 90% RMT or sTMS, administer the naming task again, and finally have the patient undergo a second fMRI with concurrent picture-naming.
3. On days two through nine, the protocol consists of a 20-minute rTMS session (1,200 pulses), using 1 Hz rTMS at 90% RMT or sTMS.
4. On day ten, stimulate the optimal site for 20 min with 1 Hz rTMS, preceded and followed by the picture-naming task. Of note, picture item lists shown on days one and ten should be different, but matched for frequency, word length, and semantic category as noted above.

5. Two- and Six-month Follow-up Visits

1. Two months following day ten of either rTMS or sTMS, repeat baseline testing (step 2.1), as well as fMRI with concurrent picture-naming.
2. Patients in the sham condition should then cross over to real TMS condition, beginning with the optimal site-finding phase (Figure 1).
3. Six months following day ten of real rTMS stimulation, repeat baseline testing (as in step 2.1), and also have patients undergo another fMRI with a concurrent picture-naming task.

Results

In the site-finding phase of this investigation, most but not all patients respond optimally on the picture-naming task to stimulation of the right pars triangularis¹⁴. In our experience, patients' performance on picture naming is most consistently facilitated by stimulation of the ventral posterior aspect of the pars triangularis (Figure 3).

Long-term improvement in performance on standardized language assessments is illustrated in Figure 4. This ...

Discussion

The goal of this article is to detail the steps for identifying a responsive target site in the right hemisphere in patients with chronic non-fluent aphasia. By doing so, we are able to stimulate that target region therapeutically, assess the effects of stimulation on language ability, and use low-frequency rTMS to elicit long-term improvements in naming and fluency in patients with chronic non-fluent aphasia. Our approach replicates and extends methods used by prior investigators, most notably Naeser and colleagues^...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Rapid transcranial magnetic stimulator	Magstim
3.0 Trio Scanner	Siemens
8 channel head coil	Siemens
Brainsight neuronavigational system	Rogue Research