Limitations of available frameless stereotactic systems include the fact that they project the main vector of the induced current from the TMS coil assuming a homogenous spheric field of distribution. This oversimplified model may introduce an error in the current distribution and thus overestimate the focality of stimulation (Wagner, et al., 2004). In addition, differences in conductivity between brain tissue and cerebro-spinal fluid (CSF) result in the potential shunting of induced current by CSF collection (Wagner, et al., 2004). This might affect the focality of rTMS stimulation in the area of the inferior frontal gyrus, adjacent to the Sylvian fissure.

These limitations, however, do not detract from the functional resolution of our findings that demonstrate consistent differential effects of rTMS to suppress the right PTr versus the right POp. Although there is inter-individual variability in the effects, and the mechanisms of action remain unclear, local cortical effects are associated with specific distant effects on cortical and subcortical regions that depend on the strength of the anatomical projections (Valero-Cabre, et al., 2005). The effects of rTMS are not limited to the directly targeted brain region, but spread along functional neural networks (Chouinard, Van Der Werf, Leonard, & Paus, 2003; Siebner, Hartwigsen, Kassuba, & Rothwell, 2009; Valero-Cabre, et al., 2005). Our results suggest that the two portions of right Broca's homologue are integrated in neural networks with fundamentally different effects on residual speech in nonfluent aphasia.

This differential effect was observed across the range of severity of the cases studied. The greatest effect on picture naming accuracy was observed after suppression of the right PTr, where the increase was 4 pictures in mild-moderate cases and 1–2 pictures in the three more severe cases. After suppression of right PTr, a decrease in RT was observed across the mild, moderate and severe cases, but there was no pattern in relationship to degree of severity. Following suppression of right POp a significant increase in RT was observed across the mild, moderate and severe cases; again, there was no clear-cut pattern in relationship to degree of severity. P8, the most severe aphasia case, however, did show the greatest decrease in accuracy and increase in RT following suppression of right POp. Thus, suppression of right POp in more severe aphasia cases could have an especially detrimental effect. These cases may have weaker or fewer remaining neural-network, anatomical projections to access. For the remaining two ROIs, right M1 and right STG, there was no consistent effect on accuracy or RT in relationship to degree of severity.

Lesion size had no effect on the degree of improved accuracy after suppression of the right PTr. P8 (severe patient), who improved by only 1.55 pictures, had the smallest lesion size of all cases (Figure 1). Her lesion was in subcortical white matter areas only, and located in the two lesion site areas adjacent to ventricle, that are associated with severe nonfluent speech (Naeser, Palumbo, Helm-Estabrooks, Stiassny-Eder, & Albert, 1989). Paradoxically, P7 (another severe patient), with the largest lesion size of all cases, also improved by only 1 picture. This latter patient had large cortical-subcortical lesion, that extended from the cortex, deeper into the two lesion site areas adjacent to ventricle, associated with severe nonfluent speech (Figure 1).

The differential effects of rTMS suppression of PTr versus POp were not unique to patients with long-standing nonfluent aphasia because they were also demonstrated in the normal controls. The normal controls named all pictures correctly, but RT was significantly longer following rTMS suppression of left versus right ROIs. The longest RT followed rTMS suppression of left POp. Similar to findings in the aphasia patients, RT was longer compared to baseline, following rTMS suppression of right POp, but RT was shorter compared to baseline, following suppression of right PTr. Therefore, in patients with aphasia, in whom the observed effects of rTMS are much more prominent, existing interhemispheric and cortico-cortical interactions might simply be modified or exaggerated in the attempt to recover function (Pascual-Leone, et al., 2005).

The differential effect was observed in the aphasia patients regardless of the method of statistical analysis used to analyze their pre- versus post- rTMS naming data for each ROI. These two methods included: 1) using the S&V baseline mean and SD, as the pre- rTMS naming measure; or 2) using the pre- rTMS naming data obtained immediately before rTMS suppression of each ROI, as the pre- rTMS naming measure for that ROI. Thus, the absence of any significant difference between S&V baseline measures and pre- rTMS performance measures for any ROI, mitigates the possibility of day-to-day variability or practice effects accounting for improvement.

In the left inferior frontal gyrus, POp is generally occupied by Brodmann Area 44 (BA 44), while PTr tends to correspond to BA 45 (Amunts, et al., 2004). Both of these areas are critical for verbal fluency, but consistent with their cytoarchitectonic differences, their linguistic contributions appear to be distinct. Left BA 45 is preferentially involved in semantic aspects of language processing while left BA 44 contributes primarily to phonological processing (Devlin, Matthews, & Rushworth, 2003; Gold & Buckner, 2002; Nixon, Lazarova, Hodinott-Hill, Gough, & Passingham, 2004; Poldrack, et al., 1999; Gough et al., 2005; Hartwigsen, et al., 2010). In recent DTI studies, different primary, white matter pathways have been observed between different parts of Broca’s area (PTr versus POp), and different parts of posterior language zones. For example, LH pathways between the PTr and the posterior language zone (superior or middle temporal gyrus) have been observed to be primarily via the extreme capsule (Frey et al., 2008; Saur et al., 2008). However, LH pathways between the POp and the posterior language zone (anterior supramarginal gyrus) have been observed to be primarily via the arcuate fasciculus (Frey et al., 2008; Saur et al., 2008; Kaplan et al., 2010). Kaplan et al. (2010) observed similar white matter pathway differences for PTr versus POp, in the RH, as well as in the LH. Thus, the connections between parts of Broca’s area and parts of the posterior language zones have been observed to be similar in the RH and in the LH. However, it is unknown if, or how, these differences in connection pathways for PTr and POp with posterior areas may support aphasia recovery. A possibly greater role for the right POp is discussed below.

A role for the right POp and right ventral premotor cortex (vPMC) was posited in promoting recovery of speech in nonfluent aphasia by Barlow (1877), in a detailed anatomical study. A 10 year-old boy lost speech for only 10 days following a first stroke restricted to L POp and L vPMC. One month later, however, a second stroke occurred, located in the homologous RH areas (R POp and R vPMC). Following the second stroke, he lost all speech again, and there was “loss of voluntary motor power over the muscles concerned in articulation.” The boy died two months later, without any recovery of speech, despite intact left and right PTr. The results from this early post-mortem study suggest that the intact right POp may be more important than intact right PTr in aphasia cases with left frontal lesion.

The potential contribution of the mirror neuron system to recovery in aphasia is unknown. The POp (BA 44) is thought to be the human equivalent of the primates’ F5, a primary locus of visuomotor (mirror) neurons (Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti and Craighero, 2004). The mirror neuron system is bilateral, important in child language acquisition and activates during both production and perception of similar actions (Rizzolatti and Craighero, 2004; Wilson et al., 2004; Iacoboni, 2008 for review). The POp has been observed to mediate “observation-execution matching for the goals of arm/hand actions” (Kemmerer and Gonzalez-Castille, 2010, for review). The POp also participates in non-language related motor functions (Binkofski, et al., 2003), and is part of a parieto-premotor network that integrates sensory (visual and auditory) inputs with related motor representations for hand- and face-related actions, possibly including articulation and language. Such a sensory input to an action matching system bears similarity to the implementation system that includes Wernicke's and Broca’s areas in an audio-phonological-articulatory loop (A. R. Damasio, 1992). In our other rTMS treatment studies where the right PTr was suppressed with rTMS for longer rTMS treatments (20 minutes, 1200 pulses) and over more days (10), long-term follow-up showed significant improvement in naming of “Tools/Implements” at 8 months post-rTMS (Naeser et al. 2005a,b), and with naming Actions at 6 months post-rTMS (Hamilton et al., 2010). While unknown, these improvements could be associated with the mirror neuron system.

A recent rTMS study (Meister, Wilson, Deblieck, Wu, & Iacoboni, 2007) has supported the role of ventral premotor cortex as necessary for phonemic categorization in speech perception, within the “motor theory of speech perception” (Liberman & Mattingly, 1985). Suppression of right POp in our aphasia patients could have interrupted these functional phonological circuits, slowing picture naming.

Another possible mechanism could involve u-fiber connections between PTr and POp. DTI tractography has been used to show the presence of u-fibers between PTr and POp (Naeser et al., 2010). Neurons in BA 45 with rich prefrontal connections, might serve to modulate activity of neurons in BA 44 through inhibitory interaction. If so, possible hyperactivity of neurons in right BA 45, could excessively suppress right BA 44 and hinder recovery in nonfluent aphasia patients. Suppression of this hyperactivity in right BA 45 with 1 Hz rTMS might permit better modulation of right BA 44 (in part, via u-fibers), and consequently promote better modulation of other right and left temporo-parietal regions important for naming (H. Damasio, Tranel, Grabowski, Adolphs, & Damasio, 2004; Price, Warburton, Moore, Frackowiak, & Friston, 2001). Longer rTMS sessions (20 minutes) to suppress right PTr, repeated over 10 days can lead to sustained improvements in naming and phrase length for several months in chronic nonfluent aphasia patients, and warrant careful clinical trial evaluation (Martin, et al., 2009; Naeser, Martin, Nicholas, Baker, Seekins, Helm-Estabrooks, et al., 2005; Naeser, Martin, Nicholas, Baker, Seekins, Kobayashi, et al., 2005; Barwood et al., 2011; Weiduschat et al., 2011).

The present study demonstrates the critical importance of the focality of a TMS target area to suppress in the RH with chronic, nonfluent aphasia patients in order to improve naming. Future studies are important to investigate the focality of TMS target areas, in order to promote optimal language recovery in additional types of aphasia with different lesion site patterns.

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