Transcranial Magnetic Stimulation (TMS)
Repetitive TMS (rTMS) allows painless, noninvasive stimulation of human cortex (approximately 1 cc in size), from outside of the skull. It utilizes magnetic fields to create electrical currents in cortical regions of interest (ROIs). Repetitive TMS can be used to produce changes in cortical excitability [32
]. When delivered to the same cortical region, slow (1 Hz) rTMS appears to decrease excitability
in the targeted cortical ROI that lasts beyond the duration of the train itself [34
] leading to measurable behavioral effects. Conversely, rapid rTMS (≥5 Hz) increases cortical excitability [35
]. Repetitive TMS has been observed to effect language, ranging from facilitation of naming [36
] to speech arrest [37s] depending on rTMS parameters and location of the coil.
As reviewed in Part 1, several functional imaging studies with chronic, nonfluent aphasia patients have observed high activation, possibly “over-activation” during language tasks, in parts of R Broca’s area and other R perisylvian language homologues which may be ‘maladaptive’ [6
]. When applied to a specific ROI in the undamaged hemisphere, low-frequency (1 Hz) rTMS may suppress the inhibitory process of that ROI, permitting reactivation of some areas within the damaged hemisphere, promoting some functional recovery [32
]. This is similar to the phenomenon of ‘Paradoxical Functional Facilitation’ or PFF [38
]. The phenomenon of PFF suggests that direct or indirect neural ‘damage’ to a specific area in the central nervous system may result in facilitation of behavior [38
]. Thus, suppressing a cortical ROI in the RH of a nonfluent aphasia patient using 1 Hz rTMS may result in a decrease in over-activation of that ROI, thus promoting less inhibition exerted by that ROI on other adjacent or distant areas resulting in an overall modulation of the bilateral neural network for naming.
Review of our rTMS Treatment Protocol with Nonfluent Aphasia Patients Inclusion Criteria
Our studies have included chronic aphasia patients who were at least 6 months post- single, unilateral LH stroke. They were R-handed, native English speakers, ranging in age from 40–80. They had not had a seizure for at least one year. Patients had nonfluent speech, with a 1–4 word phrase length as measured with elicited propositional speech on the Cookie Theft Picture, Boston Diagnostic Aphasia Exam (BDAE). Patients named at least 3 pictures from the first 20 pictures on the Boston Naming Test (BNT). Patients were requested not to receive any individualized speech therapy throughout their first year of participation in our rTMS studies.
Baseline Naming Testing
At Entry, the baseline naming ability for Snodgrass & Vanderwart (S&V) (1980) pictures was established for each patient. This baseline S&V naming score was used during Phase 1 rTMS sessions (explained below), to establish the best RH cortical ROI to suppress with rTMS, in order to improve naming. Ten, 20 item S&V lists were administered across three separate testing sessions during baseline testing. For each patient, the baseline mean and SD for response time (RT) and for number of S&V pictures named correctly across the ten lists were calculated.
rTMS Treatment (Two Phases)
Each patient participated in two phases of rTMS treatment. The intensity of rTMS was adjusted for each TMS session and applied at 90% of motor threshold (MT). Motor threshold is the intensity of magnetic stimulation needed to elicit a muscle twitch in the thumb, L first dorsal interosseus muscle (L FDI), in 5 out of 10 trials when using single-pulse TMS applied to the primary motor cortex of the contralateral hemisphere. Published guidelines for safety parameters of rTMS are based on stimulation intensities expressed as a percent of the individual’s MT [40
Phase 1 rTMS, Establish Location of Best RH Cortical ROI to Suppress
The location of the single, best RH cortical ROI to suppress with rTMS to improve picture naming was determined individually for each patient during Phase 1, where 1 Hz rTMS was applied at 90% MT for 10 min (600 pulses). A figure 8-shaped TMS coil (7 cm diameter) was used with the Super-Rapid High Frequency MagStim Magnetic Stimulator (MagStim, NY). This rTMS protocol was applied in separate sessions, to different RH cortical ROIs. ROIs examined have included the M1, mouth (orbicularis oris, verified with motor evoked potential), superior temporal gyrus (STG) and subregions within Broca’s area: PTr posterior, and Pop (see ). Immediately post-10 minutes of rTMS to suppress an ROI, picture naming was assessed by administering an S&V 20-item picture list. The single RH cortical ROI associated with at least a 2 SD improvement above baseline S&V naming (obtained at Entry) was considered to be the “Best Response” RH cortical ROI for that patient.
Figure 1 RH cortical ROIs examined during Phase 1 rTMS treatment protocol including M1, mouth (orbicularis oris, verified with motor evoked potential), superior temporal gyrus (STG) and subregions within Broca’s area: PTr posterior, and POp. Phase 1 establishes (more ...)
Phase 2 rTMS, Suppressing the Best Response RH ROI Longer, over More Sessions
During Phase 2, the Best Response RH ROI determined for each individual during Phase 1, was suppressed with 1 Hz rTMS (90% MT) for 20 min, 5 days per week, across 2 weeks. On each day of treatment, rTMS was applied using the same MagStim device as in Phase 1. A frameless stereotaxic system (Brainsight, Rogue Industries, Montreal) was used to guide the position of the TMS coil on the patient’s scalp. This enabled on-line monitoring of the specified brain area on the patient’s MRI scan throughout the rTMS session, and from day-to-day. Coil orientation was monitored and held constant across sessions, at approximately 45 degrees. One purpose of Phase 2 was to investigate the long-term effects on naming, following a series of 10 rTMS treatments. Each patient received follow-up language testing at 2 months and up to 8 months following the 10th rTMS treatment. There were no negative side effects.
Results for 6 patients in Phase 1
We observed a site-specific effect of rTMS for number of pictures named correctly (F=14.63; df 3, 5; p=0.0001) and RT (F=5.63; df 3, 15; p=0.009), including a double dissociation within parts of Broca’s area. In 6 aphasia patients, suppression of R PTr with 1 Hz rTMS resulted in patients becoming more accurate, naming more pictures, and having a faster reaction time (RT). However, suppression of R POp with 1 Hz rTMS, resulted in patients becoming less accurate, naming fewer items, and showing an increased RT. Patients named significantly more items after 1 Hz rTMS to suppress R PTr than to R POp (Fisher’s PLSD post-hoc P<0.001), R M1, orbicularis oris (p<0.01), and R STG (p<0.005) [41
Results for 4 Patients in Phase 2
We observed in 4 aphasia patients at 2 months post- ten rTMS treatments to suppress R PTr, significant improvement on three naming tests: 1) the BNT, first 20 items (p=.003); 2) the BDAE subtest, Animals (p=.02); and 3) the BDAE subtest, Tools/Implements (p=.04) [42
]. At 8 months post-TMS, all three naming test scores continued to improve relative to pre-TMS testing, but only Tools/Implements was significant (p=.003). BNT and naming Animals failed to reach significance because of one patient.
Overt Naming Functional MRI Pre- and Post-TMS in Two Nonfluent Aphasia Patients
Functional MRI was utilized to examine brain activation during overt naming, pre- and post- ten, 20-minute, 1 Hz rTMS treatments to suppress part of R PTr, to improve naming, in two chronic nonfluent aphasia patients [9
]. One patient was a ‘good responder’ with improved naming and phrase length in propositional speech, lasting out to almost 4 years post-TMS. The other patient was a ‘poor responder’ with no change in naming or propositional speech post-TMS.
Overt Naming fMRI Block Design Paradigm
Overt naming fMRIs were obtained in the same manner as Martin et al., 2005. The continuous sample, block design, overt naming fMRI paradigm took advantage of the hemodynamic response delay where increased blood flow remains for 4–8 seconds after the task [44
]. Task-related information is obtained after the task, minimizing motion artifact [45
Functional Imaging Results for the ‘Good Responder’
We hypothesized that in chronic nonfluent aphasia, after rTMS treatment to suppress R PTr, a shift in activation from RH frontal areas to new activation in LH perilesional, perisylvian areas and L SMA would occur, if there were good response with improved naming. P1, who was a ‘good responder’, showed activation in R and L sensorimotor cortex (mouth area), R IFG, and in R and L SMA, pre-TMS as well as at 3 months and at 16 months post-TMS. At 16 mo. post-TMS, however, there was a significant change in SMA activation, where P1 showed significant increase in activation in the L SMA, compared to pre-, and to 3 mo. post-TMS (p<.02; p<.05, respectively). There was also a trend towards significantly greater activation in L SMA than R SMA at 16 mo. and 46 mo. post-TMS (p<.08; p<.09, respectively). Pre-TMS there had been no difference between L and R SMA activation. It is unknown exactly when, post-TMS, the shift to the stronger L SMA activation occurred for this patient during overt naming, however, it was first observed at 16 mo. post-TMS (his highest accuracy rate; 58% named). There were no intervening overt speech fMRI scans between 3 and 16 mo. post-TMS. The new LH activation remained present, even at 46 mo. post-TMS (nearly 4 years post-TMS) when the patient was 13 yr. 11 mo. poststroke. On the language outcome measures, P1 improved on the BNT from 11 pictures named pre-TMS, to scores ranging from 14–18 pictures, post-TMS (2 mo. to 43 mo. post-TMS). His longest phrase length improved from 3 words pre-TMS, to 5–6 words post-TMS.
Functional Imaging Results for the ‘Poor Responder’
Pre-TMS (1.5 yr. poststroke), P2 had significant activation in R IFG (3% pictures named). At 3 and 6 mo. post-TMS, there was no longer significant activation in R IFG, but significant activation was present in R sensorimotor cortex. Although P2 had significant activation in both the L and R SMA on all three fMRI scans (pre-TMS, and at 3 and 6 mo. post-TMS), ROI analyses showed no difference across sessions in the L or R SMA activation.
For P2, who was a ‘poor responder’, suppression of R PTr with rTMS resulted in no new, lasting perilesional LH activation across sessions. His naming remained only at 1–2 pictures during all three fMRI scans. His BNT score and longest phrase length remained at 1 word, post-TMS.
Lesion site may play a role in each patient’s fMRI activation pattern and response to TMS treatment. P2 had an atypical frontal lesion in the L motor and premotor cortex that extended high, near brain vertex, with deep white matter lesion near L SMA. P2 also had frontal lesion in the posterior middle frontal gyrus at the junction of the premotor cortex, an area important for naming [46
]. Additionally, P2 had lesion inferior and posterior to Wernicke’s area, in parts of BA 21 and 37. P1 had no lesion in these three areas.