Final Report Summary - PLASTICITYINAMPUTEES (Multimodal plasticity in the human brain following hand amputation: Bridging the gap between neuronal reorganization and rehabilitation) Executive Summary:What happens to the brain cells responsible for operating the hand following arm amputation? You might expect that they will become unemployed, or even die. Alternatively, it has been thought that when brain cells are deprived of their usual inputs and outputs, they will now be “recruited” to work for other body parts. This ability to dynamically reassign jobs to brain cells, based on changing circumstances (termed ‘plasticity’), is key for our basic ability to adapt to new situations. Amputation is a particularly powerful model for studying plasticity as it combines two major drivers for reorganisation – sensory deprivation and adaptive motor behaviour: Following hand amputation, simple daily tasks, such as lacing your shoes, become a challenge which individuals have to learn to overcome. Despite this, most accounts of plasticity following hand amputation have focused on the apparently passive remapping of the adjacent face or arm representation into the deprived cortex, due to sensory deprivation. Such changes have been previously related to a mysterious phenomenon termed “phantom limb pain” – pain that is perceived to be arising from the missing hand. We looked into the brains of amputees, using sophisticated brain imaging techniques, in order to study the flexibility of their brains. We also wanted to learn whether such changes are beneficial (adaptive), or rather harmful (maladaptive), to the amputee. In the first study, we studied the relationship between brain plasticity and phantom pain. Following arm amputation, individuals report that they still perceive their missing limb. This “phantom” sensation often manifests as unpleasant or painful, and has been estimated to occur in up to 80% of amputees, and therefore poses a significant medical problem. We found that amputees suffering from more phantom pain show apparently more normal (i.e. less deprived) brain structure and activity in the former hand area: in amputees that have suffered long-term phantom pain, the brain’s response to phantom hand movements was indistinguishable from that seen in people with intact limbs. This was despite the fact that our participants typically lost their hand many years prior to the experiment. Furthermore, while amputees tended to have degeneration of this cortex compared to intact participants, we found less degeneration in amputees who experienced more pain. In fact, the hand-area in the brain of a typical amputee suffering from chronic phantom pain looked indistinguishable from that of a typical intact participant. However, the apparent preservation of the hand area does not indicate that the brain is functioning normally. People with more phantom pain had disrupted communication between the hand are and other brain areas, responsible for interaction with our external environment. In other words, the dissociation between phantom sensations and the physical world resulted in a functional detachment between the phantom cortex and the rest of the movement cortex. Therefore, our results may encourage rehabilitation approaches aimed at re-coupling the representation of the phantom hand with the external sensory environment. In the second study, we studied two separate populations, which are facing a similar challenge – how to adapt to a world designed for people with two hands, when you only have one hand? We studied adaptive limb-usage patterns in individuals who were born without one hand (congenital deprivation) and individuals who have lost one hand due to injury later in life (acquired deprivation). We show that congenitally deprived participants tended to use their stump more frequently in daily tasks, whereas amputees with acquired deprivation exhibited stronger reliance on their intact hand. These different strategies for adaptive behaviour mapped onto corresponding distinct patterns of plasticity in the missing hand brain area: in congenitally deprived individuals, the deprived cortex showed increased representation of the stump, whereas acquired amputees showed increased representation of the intact hand. This finding demonstrates that the deprived cortex is recruited to support adaptive use, irrespective of the utilised body part. Importantly, we find that plasticity in hand amputees does not depend solely on the age at deprivation, but instead reflects the limb-use strategy adopted by individuals: individuals from both groups that rely more on their intact hands (and report less frequent stump usage) showed increased representation of the intact hand in the deprived cortex. This result shows that adaptive plasticity is contingent upon the limb-use strategy adopted by individuals, rather than the age at which they were injured, suggesting that rehabilitation could be extremely beneficial to amputees. In a third study, we examined the ‘domino-effect’ of this local reorganization on the entire brain. Using a novel approach, we demonstrated that the representations of body parts that are not directly affected by the amputation (or the rehabilitation process) but are nevertheless neighbouring the missing hand in the brain (the face) migrate towards the missing hand area in amputees. This was previously shown in other species, but in humans previous techniques were not suitable to reliably replicate this phenomena. Most importantly, we also showed how such local remapping relates to large-scale network-level reorganization: we discovered that as years go by following amputation, the deprived hand area of amputees becomes functionally decoupled from its network of origin (responsible for movement of touch). Instead, the missing hand area becomes coupled with a different network, named ‘ the default mode network’. This network is in charge of processing internal sensations (such as what you see in your mind’s eye when you are day dreaming). Individuals showing more dramatic shifts in face representation (local remapping) also showed greater global network-level reorganisation, suggesting that the local changes associated with adaptive and maladaptive plasticity have long-range consequences. It still remains unclear how these global changes affect the daily lives and rehabilitation of amputees, but we suggest that they might be related to phantom sensations. Benefiting from this new knowledge, we designed a new study aiming at using a non-invasive brain stimulation technique (transcranial direct brain stimulation), concurrently with behavioural therapy, to abolish maladaptive phantom pain representation. Phantom pain is recognised as one of the pain syndromes most difficult to treat. The unusual challenge that medical staff face in treating phantom limb pain is that the pain arises from a part of the body that no longer exist. Indeed, conventional pain management mostly results in incomplete relief. Based on our previous research, which identified the structural and functional brain correlates of phantom pain, we tested the benefit of three potential brain-stimulation treatments, in a double-blind placebo-controlled trial. Our aim was to reinstate the representation of the phantom hand into its network of origin. A battery of behavioural and imaging tests, as well as pain ratings, was collected before and after each treatment. Using this approach we were able to induce significant pain relief in a group of 12 amputees, however further data needs to be collected to confirm this potential treatment. Overall, the project showed us that the adult brain is much more flexible than we previously assumed. The study will enable scientists to guide amputees to take advantage of the benefits of these remarkable brain changes, rather than to suffer from their adverse effects.
