Article In Brief

A case report, involving a 49-year-old nurse who had lost her left, non-dominant arm below the elbow and underwent allotransplantation, uses both fMRI and transcranial magnetic stimulation to highlight how the brain works to restore cortical representation on a once amputated limb after a hand transplant.

A new paper sheds light on how the brain works to restore cortical representation of a previously amputated limb after a hand transplant.

The study, published online ahead of print in Neurology on August 13, is the first to combine fMRI and transcranial magnetic stimulation (TMS) to examine the neurophysiological changes in the somatosensory and primary motor cortices before and after surgery to transplant a human hand.

Prior to the surgery, cortical areas that had once represented the patient's hand were usurped by the biceps. Within a few months of the transplant surgery, howeverand before any restoration of functional capability was evidentthe study found that those cortical regions resumed representation of the hand. Moreover, cortical inhibition levels, which had been low prior to the transplant, gradually approached normal during the months following it.

The restoration of lost inhibition after [a] hand transplant is a sign of functional recovery after transplant, the paper concluded. The finding that cortical plastic changes occurred at early stages suggest that it may drive recovery and is an important factor in successful recovery of function in the transplanted hand.

The paper was coauthored by neurologists and surgeons at the University of Toronto, where the procedure was performed, as well as at the University of Michigan and the National Institute of Neurological Disorders and Stroke.

Reduction of cortical inhibition appears to be critical to enabling the plasticity necessary for the brain to shift somatosensory regions, said the senior author of the study Robert Chen, MD, professor of medicine at the University of Toronto and senior scientist at the Krembil Research Institute.

We assume this is a method of the brain to spread representation into the area not being used, Dr. Chen said.

Neuroscientists and surgeons who have previously led studies of cortical changes following hand transplantation said they welcomed the new findings, although some expressed disappointment at the brevity of the report.

I don't believe anyone has previously described imaging of the brain before and after the transplant, said Jon Kaas, PhD, the Gertrude Conaway Vanderbilt Chair and Distinguished Centennial Professor of Psychology at Vanderbilt University. But, he added, They're so brief about it. It would be much more interesting if they had elaborated more.

The case report involved a 49-year-old nurse who had lost her left, non-dominant arm below the elbow in an automobile accident in 2005. She underwent allotransplantation on January 7, 2016.

Dr. Chen and colleagues conducted a longitudinal study to evaluate cortical plastic changes beginning four months before and up to six months after the surgery. They performed somatosensory mapping using fMRI with electrical cutaneous over the upper arm and thumb. They also conducted TMS mapping to evaluate the changes in motor cortical representation.

The fMRI mapping showed that representation for [the] upper arm on the transplant side was located anterior-laterally compared to the intact side before surgery and moved posterior-medially at 6 months after surgery while that for the intact side was stable over time.

The resting motor threshold stimulus intensity for the biceps, the authors reported, were higher than those for abductor pollicis brevis muscle in the intact arm while the measurements for biceps muscle on the transplant side were similar to those for the intact abductor pollicis brevis muscle before surgery and gradually increased after surgery.

TMS of the biceps muscle on the transplant side showed that it was at a more anterior-lateral location before surgery and moved gradually in the posterior-medial direction after surgery, the study found.

The inhibition between hemispheres was absent before surgery but gradually increased afterward, the paper reported, from the symmetric position of motor hotspots for intact muscle on the transplant side (mirrored point) to the intact side. Short-interval intracortical inhibition on the transplant side was likewise absent before surgery and increased gradually after.

The restoration of lost interhemispheric interaction after surgery suggest that pyramidal neurons mediating transcallosal and corticospinal projections undergo plastic changes in a similar manner although the two groups of neurons located in different cortical layers, the paper concluded. Our finding that cortical inhibition was decreased in the amputated state was consistent with the opinion that gamma-aminobutyric-acid mediated cortical inhibitory circuit acts as a gate keeper in the induction of cortical plasticity.

The short length of the paper, Dr. Chen said, was due to the journal's length limit for the single case report; supplementary information is available at http://bit.ly/corticalSUP.

Steven McCabe, MD, one of the surgeons who performed the transplant, told Neurology Today that the patient has regained substantial use of the hand.

She has good motor recovery with grade 5/5 wrist extension and flexion, Dr. McCabe stated in an email. She has full finger flexion with the exception of the index which has reduced flexion of the metacarpophalangeal joint. She has full finger extension with no claw deformity. She has some sensory recovery with the ability to accurately localize light touch to each digit but no two-point discrimination.

His group is planning to write up a formal five-year report, Dr. McCabe added.

Decades of research have established the brain's plasticity in response to loss or restoration of limbs, first in animals and then in humans. In the 1980s, Dr. Kaas coauthored pioneering papers describing somatosensory reorganization in the non-human primate brain in response to the repair of peripheral nerves which had previously been severed.

In 2009, French researchers published one of the first papers to describe the restoration of hand-muscle representations in the human motor cortex following a hand allograft. A 2014 paper in Nature Communications reported that somatosensory reorganization following spinal cord injury is due not to cortical mechanisms but to changes at the level of the brainstem nuclei.

This new case report supports the growing body of literature on the ability of the brain to reverse plastic reorganization years later, said the senior author of the 2014 paper, Neeraj Jain, PhD, professor and director of the National Brain Research Centre in Manesar, India.

Vilayanur S. Ramachandran MD, PhD, professor of psychology and neurosciences and director of the Center for Brain and Cognition at the University of California, San Diego, said the new paper demonstrates yet again that there are no fixed connections in the brain.

The old model of the brain is fatally flawed, Dr. Ramachandran said. It was once generally assumed that the brain is made of highly specialized, task-specific autonomous modules arranged in a serial hierarchy starting from the sensory modules to the motor output. But in the last two decades it has become clear that we are dealing not with static maps but with dynamic, fluctuating mosaics of neural activitymore like a termite mound than a computer.

William Gaetz, PhD, research associate professor of radiology at the Perelman School of Medicine at the University of Pennsylvania, said the new paper was the first to establish a baseline of neural organization prior to the surgery.

That's the nicest part of the study, that they had a baseline and then followed up after, said Dr. Gaetz, who was the first author of a 2018 paper describing cortical reorganization following bilateral hand transplant in a child. It is an impressive demonstration of large-scale reorganization, and particularly interesting to see from someone in their late forties.

Dr. Gaetz expressed concern, however, about the risk-benefit ratio of performing an allotransplant on the non-dominant hand of a person who was not previously on anti-rejection drugs. The child described in his 2018 paper had lost both hands due to sepsis and was already on anti-rejection drugs following a kidney transplant.

You have to balance any benefit with the costs, which are not trivial, Dr. Gaetz said. Immunosuppressive drugs increase the risk of cancer and infection. And we know that transplanted organs tend to degrade after a decade or so. This recipient will likely outlive her transplant. She had been living with full function of her right, dominant hand, and so we have to think about the ethical justification of performing a procedure that may not significantly improve quality of life for this patient.

Dr. Chen said that the patient had been deeply troubled by the loss of her hand, was fully informed of all the risks, and is now very happy with the results. Press reports published six months after the surgery was performed quoted her as saying the surgery had made her feel whole again.

Dr. Chen has received honorarium from Allergen, Merz, and Ipsen. Drs. Gaetz, Kaas, and Jain had no relevant disclosures.

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