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The human primary motor cortex (Ml) undergoes considerable reorganization in response to traumatic upper limb amputation. The representations of the preserved arm muscles expand, invading portions of Ml previously dedicated to the hand, suggesting that former hand neurons are reassigned to the control of remaining proximal upper limb muscles. Hand allograft offers a unique opportunity to study the reversibility of such long-term cortical changes. We used transcranial magnetic stimulation in patient LB. who underwent bilateral hand transplantation 3 years after a traumatic amputation, to longitudinally track both the emergence of intrinsic (from the donor) hand muscles in Ml as well as changes in the representation of stump (upper arm and forearm) muscles. The same muscles were also mapped in patient CD, the first bilateral hand allograft recipient. Newly transplanted intrinsic muscles acquired a cortical representation in LB's Ml at 10 months postgraft for the left hand and at 26 months for the right hand. The appearance of a cortical representation of transplanted hand muscles in Ml coincided with the shrinkage of stump muscle representations for the left but not for the right side. In patient CD, transcranial magnetic stimulation performed at 51 months postgraft revealed a complete set of intrinsic hand-muscle representations for the left but not the right hand. Our findings show that newly transplanted muscles can be recognized and integrated into the patient's motor cortex. [ABSTRACT FROM AUTHOR]