Reply: Persistent hand commands in the motor cortex of amputees' brain
1 Institut des Sciences Cognitives France 2 Université Claude Bernard Lyon 1, Lyon France 3 Department of Neurology, University of Rochester Rochester, NY, USA 4 Department of Neurobiology and Anatomy, University of Rochester Rochester, NY, USA
Correspondence to: Karen T. Reilly, Université Claude Bernard Lyon 1, Lyon, France E-mail: kreilly{at}cvs.rochester.edu
In his letter to the editor of Brain, Dr Levine challenges the main conclusion of our paper entitled ‘Persistent hand motor commands in the amputees' brain’, namely that the ability to voluntarily move a phantom limb reflects hand movement representations in the motor cortex that are maintained in part by retargeting cortical output to, and receiving afferent feedback from, stump muscles.
We agree with Dr Levine that the hand movement representation consists of the set of neurons in the motor cortex which, when activated, give rise to hand movements. But we must disagree with his statement that in amputees these neurons no longer exist. Recent work showing ‘invasion’ of cortical territory that had represented the amputated body part has fostered this widely held misapprehension. Although some spinal motoneurons certainly degenerate after amputation, many remain (Wu and Kaas, 1999
). Years after amputation, motor unit action potentials can be recorded from axons in the proximal stumps of amputated nerves, and these motor units are still under voluntary control (Dhillon et al., 2004). Years after shoulder disarticulation amputation, if the pectoralis muscles are denervated operatively, and then reinnervated with fascicles from the stump of the musculocutaenous, radial, median and ulnar nerves, the pectoralis subsequently contracts when the subject moves the phantom hand, and the patient feels touch in the phantom hand when the skin over pectoralis is stroked (Kuiken et al., 2004; Lipschutz et al., 2006). Hence many peripheral axons remain. Neurons remain in the cortex too. As long ago as 1905, Campbell described chromatolytic Betz cells in the somatotopically appropriate region of the human motor cortex years after amputation (Campbell, 1905). Other Betz cells in the same region were totally unaffected, however, as were (presumably) the smaller neurons of layer V and those of layers II and III. In our view, it is activation of these neurons and their corticocortical plus corticosubcortical connections that leads to the perception that the phantom hand moves upon transcranial magnetic stimulation (TMS) over the anatomically localized hand knob of the motor cortex (Mercier et al., 2006). Likewise, we suggest that activation of these neurons and their synaptic inputs and local outputs is what is visualized with functional MRI (fMRI) when amputees are asked to move their phantom hand (Lotze et al., 2001; Roux et al., 2001, 2003). Furthermore, Roux and colleagues have demonstrated that phantom hand movements and actual stump movements do not activate exactly the same motor cortical regions, indicating that some distinct hand representation is retained. All these observations indicate that the hand movement representation in the primary motor cortex persists years after amputation of the hand.
Levine goes on to argue that because phantom hand movements are most varied and vivid immediately after amputation, phantom movements cannot reflect the retargeting of cortical output from the hand area to stump muscle motoneurons. His argument assumes that the retargeting of motoneurons requires the gradual growth of new connections over time. While such sprouting certainly does occur (Florence and Kaas, 1995; Wu and Kaas, 1999) considerable reorganization of cortical output occurs rapidly as well. In normal subjects, ischaemic block of the peripheral nerves, which temporarily amputates an extremity from the nervous system, enlarges the territory from which TMS elicits output to proximal muscles in less than an hour (e.g. Merzenich et al., 1983; Calford and Tweedale, 1988; Donoghue et al., 1990; Brasil-Neto et al., 1992, 1993; Tinazzi et al., 2003; Weiss et al., 2004). In an actual amputee, somatosensory reorganization has been observed in <24 h (Borsook et al., 1998). Such rapid changes probably reflect unmasking of previously silent output connections due to changes in intracortical inhibition (Jacobs and Donoghue, 1991). In addition, spike triggered averaging of EMG in awake behaving monkeys has shown that many upper-limb corticomotoneuronal (CM) cells have branches to both proximal and distal forelimb muscles (McKiernan et al., 1998, 2000; Park et al., 2001). When peripheral axons to the distal muscles are severed, such CM cells still would provide cortical output to control proximal muscles. Hence much of the retargeting of stump muscles that we propose supports that phantom hand movements could occur rapidly after amputation.
Levine puts forward the thesis that the main reorganization occurring after amputation is in the periphery, where axotomized motoneurons undergo retrograde degeneration and find new muscle targets in proximal limb muscles. He states that our findings suggest ‘little or no reorganization of the central connectivities of the neurons in the hand areas of the motor and sensory cortex.’ Numerous studies, however, have shown reorganization of the intracortical and subcortical connections of cells in both motor and somatosensory cortex following amputation in experimental animals (Schieber and Deuel, 1997; Florence et al., 1998; Jones and Pons, 1998; Wu and Kaas, 1999; Florence et al., 2000; Jain et al., 2000). Similarly, fMRI studies in human amputees have shown central reorganization in both motor and sensory maps (Flor et al., 1995; Giraux et al., 2001; Lotze et al., 2001). Nevertheless we agree with Levine that much of the central connectivity of the hand areas of the motor and sensory cortex often is maintained long after amputation. Touching the face can be felt in the phantom fingers because peripheral afferents from the face activate the hand area of the somatosensory cortex, which still signals to other parts of the brain that the hand has been touched. We argue similarly that voluntary activation intended to make different movements of the fingers arriving from other regions of the brain still can elicit different patterns of output from the motor cortex hand area, which the amputee still perceives as phantom movements, but which we detect as different patterns of EMG activity retargeted to stump muscles (Reilly et al., 2006).
We suggested further that afferent activity from the stump muscles helps maintain the motor representations of different hand movements, based on our observations that ischaemic nerve block of the stump failed to eliminate the phantom, while rendering our amputees unable to move the phantom voluntarily (Reilly et al., 2006). Levine states that the experience of a mobile phantom limb arises when proprioceptive information from contracting stump muscles and long-standing body image expectations both supporting the presence of the limb prevail over visual feedback and cognitive knowledge that the limb is absent (page 3). This explanation falls short of accounting for our observation that TMS applied to the motor hand area of amputees elicited certain phantom finger and wrist movements which the amputees reported being unable to execute voluntarily (Mercier et al., 2006). Here, even though the amputee was making no voluntary effort, and had no expectation of being able to produce these movements voluntarily, such movements retained a cortical representation that could be activated artificially with TMS. Such artificially triggered phantom movements, we feel, reflect corticocortical output connections from representations of particular hand movements in the motor cortex that still have not been reorganized years after amputation, but which the subject no longer can access voluntarily, perhaps in part because of progressive reorganization of afferent inflow from the stump.
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