Cortical correlates of TMS-induced phantom hand movements revealed with concurrent TMS-fMRI

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Abstract

We studied an amputee patient who experiences a conscious sense of movement (SoM) in her phantom hand, without significant activity in remaining muscles, when transcranial magnetic stimulation (TMS) is applied at appropriate intensity over the corresponding sector of contralateral motor cortex. We used the novel methodological combination of TMS during fMRI to reveal the neural correlates of her phantom SoM. A critical contrast concerned trials at intermediate TMS intensities: low enough not to produce overt activity in remaining muscles; but high enough to produce a phantom SoM on approximately half such trials. Comparing trials with versus without a phantom SoM reported phenomenally, for the same intermediate TMS intensities, factored out any non-specific TMS effects on brain activity to reveal neural correlates of the phantom SoM itself. Areas activated included primary motor cortex, dorsal premotor cortex, anterior intraparietal sulcus, and caudal supplementary motor area, regions that are also involved in some hand movement illusions and motor imagery in normals. This adds support to proposals that a conscious sense of movement for the hand can be conveyed by activity within corresponding motor-related cortical structures.

Introduction

A special situation that may potentially shed unique light on the neural basis of conscious sense of movement (SoM) arises in cases of phantom-limb perceptions after arm amputation. These phantoms correspond to the experience of persisting perceptions for the amputated (and hence now non-existent) extremity (Ramachandran, 1998; Ramachandran & Hirstein, 1998; Woodhouse, 2005). Many amputees experience some form of phantom, sometimes even retaining a degree of apparent voluntary control over this. Several neuroimaging studies of phantom-limb phenomena have suggested that active imagery of phantom movements may engage some similar brain regions as actual voluntary movement (or illusory movement) of an intact limb (Brugger et al., 2000; Ersland et al., 1996; Lotze, Flor, Grodd, Larbig, & Birbaumer, 2001; Rosen et al., 2001; Roux et al., 2003; Willoch et al., 2000), as may perception of supernumerary phantoms (McGonigle et al., 2002). Active imagery of limb movements can also engage a network of cortical brain regions, that includes cortical motor areas, in normals with no phantoms (Dechent, Merboldt, & Frahm, 2004; Jeannerod & Frak, 1999; Kuhtz-Buschbeck et al., 2003; Lotze, Montoya et al., 1999; Porro et al., 1996).

An alternative approach for studying the neural basis of phantom SoM is to try and induce phantom experiences in amputees in an event-related manner, without requiring them to engage in active, continuous self-produced imagery. Transcranial magnetic stimulation (TMS) over contralateral M1 has been used in this way to induce conscious phantom movements (Cohen, Bandinelli, Findley, & Hallett, 1991) or a sense of movement during transient deafferentation in normals (Amassian, Cracco, & Maccabee, 1989). In some amputee cases, the TMS-induced phantom SoM will be accompanied by TMS-induced twitches in remaining proximal muscles, and thereby with associated reafferent feedback. But TMS-induced phantom SoMs without muscular twitches have been reported in at least one case who had congenitally absent limbs (Brugger et al., 2000). Moreover, the possibility that conscious SoM in humans might be elicited by central cortical activity, even in the absence of any input from the periphery, could be consistent with studies of TMS-evoked leg paresthesias in patients with complete thoracic spinal cord injury (Cohen, Bandinelli et al., 1991; Cohen, Topka, Cole, & Hallett, 1991). Thus, for some patients experiencing phantoms, the phantom SoM might in principle have an origin in motor-related cortical regions, rather than requiring reafferent feedback from remaining proximal muscles.

However, no previous study to date has been able to study the neural activations arising for a phantom SoM in an amputee, when evoking this in an event-related manner with a TMS input to motor cortex (rather than requiring sustained and active motor imagery). Fortunately, recent technical developments now permit the combination of TMS concurrently with fMRI, to allow direct study of the neural consequences of transcranial cortical stimulation, as in some recent studies of normals (Baudewig, Paulus, & Frahm, 2000; Bohning et al., 1998; Shastri, George, & Bohning, 1999). Several combined TMS-fMRI studies have now applied suprathreshold TMS to motor cortex, thereby evoking a SoM, but also a muscular twitch in the normal groups studied. Activity increases were observed in the stimulated M1 and also in secondary motor cortices (Baudewig et al., 2001; Bestmann, Baudewig, Siebner, Rothwell, & Frahm, 2004; Bohning et al., 1999; Bohning, Shastri, McGavin et al., 2000; Bohning, Shastri, Wassermann et al., 2000; Denslow, Lomarev, George, & Bohning, 2005). However, since suprathreshold motor TMS elicits an actual movement as well as a SoM in normals, the reported activity increases may have reflected not only the direct TMS effects, but also any brain activations resulting from the reafferent feedback caused by the TMS-evoked muscular twitch. By contrast, in a suitable amputee case, the phantom-limb situation might provide an ideal opportunity for inducing a conscious SoM via TMS without any overt twitch, while concurrently using fMRI to study the neural correlates of the TMS-induced purely phantom movements.

Here we implemented this by studying a patient with painless phantom sensations 3 years after amputation of the right arm, in whom a conscious SoM for the phantom hand could reliably be elicited when applying TMS to contralateral M1. Importantly, in this patient a TMS site over motor cortex could be located that reliably evoked a phantom SoM at TMS intensities much lower than those required to evoke significant motor responses in proximal muscles. This allowed us to study the neural basis of the phantom SoM in isolation from the substantial overt muscle movements that in normals are intimately linked and synchronous with TMS-induced movement. Moreover, the present event-related TMS approach also avoided requiring the amputee patient to engage in active, self-generated motor imagery in the absence of a phantom-triggering event (Brugger et al., 2000, Ersland et al., 1996, Lotze et al., 2001, Rosen et al., 2001, Roux et al., 2003, Willoch et al., 2000). Instead, we simply applied TMS while the patient reported any induced phantom SoM event. Finally, the critical comparison contrasted trials in which the patient experienced conscious phantom-limb movement against trials without any phantom SoM, but for identical intermediate TMS intensities. This factored out any non-specific effects of TMS per se. Thus, we applied TMS during fMRI scanning (Baudewig et al., 2001, Bestmann et al., 2004, Bohning et al., 1998), to a carefully selected and well-characterized amputee who experienced phantom movements. We also separated trials based on phenomenal report of phantom SoM versus its absence. In this way, we were able to show a direct relation of the evoked SoM to activity in cortical regions that govern motor control, including primary and secondary motor regions contralateral to the perceived phantom movement.

Section snippets

Case report

IM is a 19-year-old woman who lost her right arm from midway along the upper segment, with biceps and triceps cut ‘halfway’, following a traumatic injury during an accident at age 16. Voluntary control over the remaining proximal arm muscles is retained. Phantom-limb experiences started approximately 4 weeks after the incident, with the position of the phantom arm reported as being typically flexed and rigid with the phantom hand usually in a clenched fist. Voluntary control over the phantom

Motor and phantom SoM mapping with TMS before scanning

In the present patient we were able to evoke a conscious phantom SoM at intensities below the threshold for evoking consistent muscle responses in proximal arm muscles. We placed the TMS probe over specific sites to provide a well-specified input over left M1 (see schematic representation of site-grid in Fig. 1a, where phantom CoG is also marked, and then the actual site used during fMRI shown against the patient's anatomical scan in Fig. 1b). This revealed a clear separation of the

Discussion

We studied an amputee patient who experiences painless phantom movement, 3 years after amputation of the right lower arm. We found that in this patient, it was possible to induce phenomenal phantom movements reliably with TMS (see also Amassian et al., 1989; Cohen, Bandinelli et al., 1991), at a particular site over left motor cortex (see Fig. 1a and b), that was topographically distinct from the optimal sites for eliciting right deltoid or right face muscle activity (Fig. 1c). Moreover, in the

Acknowledgements

S.B. was supported by the Wellcome Trust. J.D. was supported by the Wellcome Trust and the Medical Research Council. J.B. and P.D. were supported by the Volkswagen Stiftung. M.V. was supported by the German Academic Exchange service and the James S. McDonnell Foundation. We thank the “Instituto de Ciencia de la Salud”, Junta de Comunidades de Castilla La Mancha, Ayudas (grant 03058-00) for financial support, and the patient for her participation.

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