Brain activation for actual and imagined hand movement following bilateral hand transplantation.

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2025-12

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Abstract

Hand transplantation has been successful in restoring function in a select group of people, but the mechanisms by which the central nervous system integrates a new hand are unknown. We used event-related functional magnetic resonance imaging (fMRI) to assess brain activation related to actual and imagined hand movement, for a recipient (female, 60 years of age) of bilateral hand transplants. Investigation of a patient-specific network of sensorimotor cortical regions was conducted at a preoperative session, as well as at three assessments conducted over a 16-month, post-transplantation period. We detected significant activation for both actual and imagined hand movement, relative to a rest baseline, for both transplanted hands, at all three postoperative sessions. Activation was higher for actual movement than for imagined movement. Across the postoperative period, movement-related activation decreased in magnitude, relative to an imagined-movement baseline. Movement-related activation also became more focused, postoperatively, on hand-related brain regions, in contralateral sensorimotor cortex. Some movement-related brain activation was relatively stronger for the right hand, postoperatively, consistent with the fact that the patient had been right-handed, preoperatively. To our knowledge, this is the first hand-transplant recipient to exhibit more pronounced brain activation, post-transplantation, for actual movement relative to imagined movement. Overall, the findings suggest that, following hand transplantation, sensorimotor cortex returns to a more canonical functional organization, similar to that of healthy individuals.

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Hand, Brain, Humans, Magnetic Resonance Imaging, Brain Mapping, Imagination, Movement, Middle Aged, Female, Functional Laterality, Hand Transplantation, Sensorimotor Cortex

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Published Version (Please cite this version)

10.1016/j.cortex.2025.09.013

Publication Info

Madden, David J, Jenna L Merenstein, Todd B Harshbarger and Linda C Cendales (2025). Brain activation for actual and imagined hand movement following bilateral hand transplantation. Cortex; a journal devoted to the study of the nervous system and behavior, 193. pp. 57–73. 10.1016/j.cortex.2025.09.013 Retrieved from https://hdl.handle.net/10161/33995.

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Scholars@Duke

Madden

David Joseph Madden

Professor Emeritus in Psychiatry and Behavioral Sciences

My research focuses primarily on the cognitive neuroscience of aging: the investigation of age-related changes in perception, attention, and memory, using both behavioral measures and neuroimaging techniques, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI).

The behavioral measures have focused on reaction time, with the goal of distinguishing age-related changes in specific cognitive abilities from more general effects arising from a slowing in elementary perceptual processes. The cognitive abilities of interest include selective attention as measured in visual search tasks, semantic and episodic memory retrieval, and executive control processes.

The behavioral measures are necessary to define the cognitive abilities of interest, and the neuroimaging techniques help define the functional neuroanatomy of those abilities. The PET and fMRI measures provide information regarding neural activity during cognitive performance. DTI is a recently developed technique that images the structural integrity of white matter. The white matter tracts of the brain provide critical pathways linking the gray matter regions, and thus this work will complement the studies using PET and fMRI that focus on gray matter activation.

A current focus of the research program is the functional connectivity among regions, not only during cognitive task performance but also during rest. These latter measures, referred to as intrinsic functional connectivity, are beginning to show promise as an index of overall brain functional efficiency, which can be assessed without the implementation of a specific cognitive task. From DTI, information can be obtained regarding how anatomical connectivity constrains intrinsic functional connectivity. It will be important to determine the relative influence of white matter pathway integrity, intrinsic functional connectivity, and task-related functional connectivity, as mediators of age-related differences in behavioral measures of cognitive performance.

Ultimately, the research program can help link age-related changes in cognitive performance to changes in the structure and function of specific neural systems. The results also have implications for clinical translation, in terms of the identification of neural biomarkers for the diagnosis of neural pathology and targeting rehabilitation procedures.

Harshbarger

Todd B Harshbarger

Assistant Professor in Radiology
Cendales

Linda Carime Cendales

Professor of Surgery

Vascularized composite allotransplantation (VCA) refers to the transplantation of multiple tissues, such as skin, muscle, tendon, nerve, and/or bone, as a functional unit (e.g. a hand, an abdominal wall). Several recent advances in clinical organ transplant immunosuppression and experimental VCA have now made it feasible to consider clinical VCA for functional restoration in patients with the loss of one or both hands or large tissue defects that may not be reconstructed with autologous tissue. My research facilitates the translation of VCA from the bench to the bedside.

Our group has established preclinical models to understand VCA rejection in different tissues and to use that insight to minimize immunosuppression in VCA recipients who participate in clinical trials. We also organized the first public international consensus discussions conference in VCA at the Ninth Banff Conference on Allograft Pathology in Spain in 2007 resulting in the Banff VCA 2007 classification for skin allograft pathology. Additionally, we established a VCA Consortium to enable the comprehensive analysis of samples from patients in VCA clinical trials around the country.

Based on our studies of different immunosuppressive regimens in primates, we have been the first to show that belatacept prevents rejection in VCA in primates and controls rejection in humans. We are currently investigating this approach in a clinical trial of hand transplant recipients (NCT02310867). This clinical trial aims to determine the safety and efficacy of hand transplantation as a treatment for patients with limb loss. This study will also test the efficacy of belatacept to prevent rejection of the transplanted hand. We are also currently investigating in a clinical trial the efficacy of abdominal wall transplantation for the reconstruction of abdominal wall defects (NCT03310905).


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