This study reported results for overt naming fMRI scans, pre- and post- ten, 20-minute, 1 Hz rTMS treatments to suppress part of R PTr, in two chronic nonfluent aphasia patients. 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.
We had hypothesized that in chronic nonfluent aphasia, after rTMS treatment to suppress R PTr, fMRI would show a shift in activation from RH frontal areas to new activation in LH perilesional, perisylvian areas and L SMA, if there was good response with improved naming. For P1, who was a ‘good responder’, at 16 mo. post- TMS, there was significant activity in LH perilesional sensorimotor cortex activation. For P1, significant activation in L sensorimotor cortex continued to be present at 46 mo. post- TMS, with continued improved naming.
In addition, at 16 mo. post- TMS, there was a significant increase in activation in the L SMA compared to pre- and 3 mo. post- TMS (p<.02; p<.05, respectively). There was also greater activation in L SMA than R SMA at 16 mo. post- TMS, whereas 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 LH activation occurred for this patient during overt naming, however, it was first observed at 16 mo. post- TMS. There were no intervening overt speech fMRI scans between 3 and 16 mo. post- TMS. The new LH activation remained, however, even at 46 mo. post- TMS (nearly 4 years post- TMS) when the patient was 13 yr. 11 mo. poststroke.
Overt story-telling fMRI obtained for P1 only, at 16 and 46 mo. post- TMS, showed significant activation in L and R sensorimotor cortex mouth and significant activation in L and R SMA. However, at 46 mo. post- TMS, ROI analyses showed activation in the SMA remained significant for the L SMA only. Data showing greater R than L SMA activation had been obtained for P1 during overt story-telling DSC fMRI, 6 years prior to any TMS. These DSC-fMRI data suggest that this patient had greater RH activation at least as early as 4 yr. poststroke.
For P2, who was a ‘poor responder’, suppression of R PTr with rTMS resulted in no lasting change in LH activation during overt naming fMRI, corresponding with no change in naming or propositional speech post- TMS. Pre- TMS, P2 showed activation in R IFG and R sensorimotor cortex, mouth. At 3 and 6 mo. post- TMS, there was continued activation in these ROIs. However, ROI analyses showed there was no difference across sessions in the activation of the R IFG, or R sensorimotor cortex.
On all three fMRI scans (pre- TMS, and at 3 and 6 mo. post- TMS), ROI analyses also showed no difference across sessions in the L or R SMA activation. P2 had severe damage to parts of the neural network important for propositional speech, as well as damage to parts of the neural network important for naming. A discussion of lesion sites in both patients, follows below.
Each patient had extensive lesion in Broca’s area (), however, presence of lesion in Broca’s area, alone, would not have accounted for the lasting nonfluent speech in each case, nor for the discrepancy in severity of nonfluent speech between the two cases.
P2 continued to name only 1 picture on the BNT, post- TMS. He had an unusually high, frontal lobe lesion, which is important to consider regarding his severe impairment in picture naming. First, this high frontal lobe lesion may have interrupted MScF pathways close to their origin, the SMA, contributing to his limited speech output.
Second, P2 had lesion in an ‘epicenter’ for naming at the junction of the superior frontal sulcus with the precentral sulcus (Duffau et al., 2003
) which may have interrupted connections in the neural network for naming to and from this region.
In addition to differences in their frontal lobe lesion pattern, P1 and P2 had differences in temporal lobe lesion, which may further explain their disparity in picture naming ability. Although each case had lesion in Wernicke’s area (posterior STG), P2 had additional lesion extension inferior and posterior to Wernicke’s area, including parts of MTG (BA 21 and 37) whereas P1 did not. Several imaging studies have noted the importance of BA 21 and/or BA 37 for semantic aspects of naming in normals as well as aphasia patients (Abrahams et al., 2003
; Gold & Buckner, 2002
; Hillis et al., 2006
; Price, Warburton, Moore, Frackowiak, & Friston, 2001
Thus, for P2, the severe naming deficit (and poor response following TMS) may have been associated with lesion in two major ‘epicenters’ for naming, as described by Duffau et al., (2003
): 1) DLPFC in posterior MFG at the junction of the superior frontal sulcus and the precentral sulcus; and 2) the MTG (BA 21). In addition, Price et al. (2001)
described functional imaging co-activation between Broca’s area and the posterior MTG during naming. Thus, the severe anomia (and poor response to TMS) in P2 is likely associated with having lesion in Broca’s area plus the two areas described by Duffau et al., (2003
Connections from the temporal lobe to Broca’s area and precentral gyrus (BA 6) have been reported in recent DTI studies (Frey, Campbell, Pike, & Petrides, 2008
; Glasser & Rilling, 2008
). White matter lesion was also likely present in fiber bundles connecting these critical regions including the inferior fronto-occipital fasciculus and the arcuate fasciculus (Catani, Jones, & ffytche, 2005
; Duffau et al., 2005
). Further studies with DTI, particularly in aphasia patients, would be necessary to better understand these disconnections.
P1 had no lesion in the L MTG (BA 21 and 37), or the posterior MFG (a part of BA 8). Interestingly, P1 showed no consistent activation in these LH regions during overt naming fMRI. Although he showed no activation in the posterior portion of the L MFG, he did activate other parts of L BA 8 (perilesional) during all three overt naming fMRI scans post- TMS. He still had a moderate naming deficit post- TMS, where his scores ranged 42 to 58% correct during overt naming fMRI at 3 mo. to 46 mo. post- TMS. Perhaps increased activation in L posterior MFG or L posterior MTG would have been associated with better naming.
P1 had lesion only in the lowest portion of the L sensorimotor cortex area. Although there was a trend toward increasing activation in this region over time, which continues to increase even at 46 mo. post- TMS, the change was not significant. P2 had extensive lesion in the L sensorimotor cortex mouth area, thus could not activate this region during overt speech.
These fMRI data suggest additional studies with overt naming fMRI in nonfluent aphasia patients are warranted. Activation and presence of lesion in the above-mentioned DLPFC and MTG ‘epicenters’ for picture naming should be carefully examined.
Auditory Comprehension Post- TMS
P2 improved on auditory comprehension post- TMS, but P1 did not. For P2 pre- TMS, his mean auditory comprehension score for Commands was 8.67, and post- TMS, 11/15. Pre- TMS, his mean score for Complex Ideational Material was 2.33 and this improved to 4/12, at 6 mo. post- TMS. Although some improvements were made in auditory comprehension, a moderate-severe auditory comprehension deficit was still present post- TMS (overall, 51.7 percentile). Why P2 improved on auditory comprehension post- TMS is unknown. Improvement in auditory comprehension lasting out to 6 or 8 months post- TMS has not been an area where significant change was noted in our previous TMS studies with nonfluent aphasia patients (Naeser, Martin, Nicholas, Baker, Seekins, Helm-Estabrooks et al., 2005
; Naeser, Martin, Nicholas, Baker, Seekins, Kobayashi et al., 2005
). Our fMRI scans only examined overt speech in the present study (not auditory comprehension), therefore no fMRI data are available for auditory comprehension, pre- and post- TMS.
Revision of TMS Entry Criteria
We have studied three other severe, nonfluent aphasia patients with 1-word phrase length, who did not improve post- TMS (data not published, personal observation). We have observed that if, on pre- TMS language testing across three sessions, a patient did not have a mean of at least 3 pictures named correctly (on the first 20 pictures) of the BNT, then there was no improvement in naming, post- TMS. Overt naming fMRI scans are not available for these other cases.
We have now developed a minimum criterion for Entry into the TMS study — i.e., the patient must have a mean score of at least 3 pictures named correctly (on the first 20 items of the BNT) as tested across three test sessions pre- TMS. P2 would not have met this minimum criterion for Entry, as his mean BNT score across three testing sessions pre- TMS was only 1.67 (SD=1.15, range, 1-3). We have entered into the TMS protocol, one severe nonfluent aphasia patient (1-word phrase length) who was a good responder. She named 4 pictures on the BNT pre- TMS; 7 pictures, 2 mo. post- TMS; and 12 pictures, 8 mo. post- TMS. She had primarily a subcortical lesion, and no lesion was present in the DLPFC or the posterior MTG areas (Naeser, Martin, Nicholas, Baker, Seekins, Helm-Estabrooks et al., 2005
The application of the findings in the present study to a more general population of nonfluent aphasia patients may be limited by the following: First, there were only two patients examined with fMRI. Second, P1 entered at 10 yr. poststroke, whereas P2 entered at 2 yr. poststroke. The effect of time poststroke at entry, and potential for increased recovery before entry into the TMS study is a factor that could not be controlled for. Third, the long-term effect of the handheld, augmentative speech device used on a daily basis by P2 (starting about 4 mo. post- TMS) on the language testing and on the fMRI scan performed at 6 mo. post- TMS, is unknown. Patients had been requested not to have individualized speech therapy intervention during the first year of participation in the study. Additionally, for P1, who showed a significant increase in verb production during narrative speech after 2 mo. of Constraint-Induced Aphasia Treatment (CIAT), the effect of CIAT (Goral & Kempler, 2008
) on the fMRI activation between 16 mo. and 46 mo. post- TMS is unknown. However, at 16 mo. post- TMS this patient had already shown a shift to his left hemisphere, which continued at 46 mo. post- TMS.
Although physiologically, TMS may have a modulating effect on the bilateral neural network for language, the TMS treatment alone, the change in performance level, or both could have influenced the observed changes in activation patterns for P1.
Future studies may want to include the use of an event-related design, which would allow analysis of responses in greater depth, particularly examination of activation patterns for correct versus incorrect responses or responses within specific categories. Recent studies have demonstrated the use of overt naming fMRI paradigms in longitudinal studies in normal controls (Meltzer, Postman-Caucheteux, McArdle, & Braun, 2009
). However, the use of an event-related design, is particularly problematic due to the multiple hesitations and false-starts during overt speech in aphasia patients. Sensitivity is also an issue, particularly with more severe nonfluent aphasia patients, who may only correctly name fewer than 3 or 4 items.
Suppression of R PTr with rTMS in the good responder may have promoted inhibition there, permitting better modulation of regions within the bilateral premotor, sensorimotor and temporo-parietal network important for naming (Damasio, Tranel, Grabowski, Adolphs, & Damasio, 2004
; Gold & Buckner, 2002
; Price, Warburton, Moore, Frackowiak, & Friston, 2001
). The role of the L SMA in conjunction with this shift was associated with sustained, improved naming up to almost 4 yr. post- TMS in P1. These results for the good responder are compatible with other functional imaging studies where activation of remaining LH language regions were associated with better recovery (Heiss, Kessler, Thiel, Ghaemi, & Karbe, 1999
; Heiss & Thiel, 2006
; Perani et al., 2003
; Warburton, Price, Swinburn, & Wise, 1999
) and with studies that show new LH activation after speech therapy is associated with language improvement (Cornelissen et al., 2003
; Leger et al., 2002
; Meinzer et al., 2008
; Small, Flores, & Noll, 1998
For P2, extensive lesion in Broca’s area, along with subcortical white matter lesion, lesion extension into the DLPFC, plus Wernicke’s area and posterior MTG lesion may have created a lesion distribution where TMS could not promote enough bilateral modulation to permit activation of any remaining portions of the neural network for naming, especially in the LH. The consistent, high L SMA activation in P2 may not be working in conjunction with the other parts of the bilateral network for naming, due to extensive DLPFC and white matter lesion. It is possible that not enough of the major phonological or lexical-semantic regions in the LH important for naming were spared in order to promote naming.
These two patients each contribute information toward understanding which nonfluent aphasia cases are likely to improve post- TMS and which cases may not. The overt speech fMRI data with our single nonfluent patient with good response to TMS support the hypothesis that restoration of the LH language network is linked, at least in part, to better recovery of naming and phrase length in propositional speech in nonfluent aphasia.