Cortical Network Reorganization in Lower-Limb Amputees

Lay Summary

Understanding how brain networks reorganize after leg amputation may inform rehabilitation approaches

Investigators will use a novel combination of functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to study how the functional connections between brain regions change in amputees who have lost a lower leg. These studies may lead to new rehabilitation strategies that target altered brain connections to improve functional outcomes in lower-limb amputees.

Nearly two million people in this country have suffered major or minor limb loss. In major limb loss cases, 90 percent involve leg amputation below the knee. Research shows that after a leg is amputated structural and functional changes occur in the part of the brain that previously supported the leg’s motor and sensory functions. Scientists do not yet know how connections between brain regions might change following limb loss, and how disruptions in the communication patterns between brain areas might relate to clinical outcomes.

The investigators will test two main hypotheses: 1) The connections between brain regions that support the lost and intact limbs will be disrupted; and the degree of disruption in these connections will correspond to the degree of difficulties in walking and balance. 2) Connections between the brain regions that support the lost limb and regions that are involved in self-oriented thoughts (called the “default mode network”), such as “How do I feel?” will be disrupted; the degree of disruption in these connections will correlate with individuals’ experiences of phantom limb sensations and pain. Investigators will test these hypotheses in 25 people with a lower leg amputation and 25 control volunteers without limb loss. Participants will complete a resting state functional MRI scan, in which they will lay in the scanner without doing any tasks. Activity patterns throughout the brain will be analyzed for similarity, and those regions that fluctuate together will be identified as a network. Comparing the brain network organization in individuals with limb loss and control subjects will reveal how limb loss alters brain networks. Researchers will also determine how brain areas interact by evaluating how activity in different brain regions changes as a result of direct and targeted modulation of the deprived cortex. This will be determined by having all participants undergo fMRI while they simultaneously receive TMS, a form of magnetic stimulation that safely induces electrical activity in a small area of the brain.

Understanding how brain areas are organized and functionally connected in amputees will enable the investigators to relate brain connectivity patterns in the amputees to clinical measurements of their motor function (walking, balance) and phantom limb sensations. The investigators hope to identify patterns of brain network disruption in lower limb amputees that fundamentally affects rehabilitation outcomes. A long-term goal would be the development of novel rehabilitation strategies that are tailored to these disrupted connections.

Significance: This research could identify disrupted network connections that could be targeted in new rehabilitation strategies to improve outcomes for people with a lower-limb amputation.

Abstract

Cortical Network Reorganization in Lower-Limb Amputees

Sensorimotor functions are supported by the activity of neural populations distributed over networks of brain regions. Sensorimotor function can be impaired acutely by diseases or traumatic injuries that affect our limbs, as in the case of limb amputation. The vast majority of major limb loss occurs in the lower limb. Rehabilitation, which often includes the prescription of a prosthetic limb, can result in variable outcomes. Limited recovery of function and quality of life may be related to maladaptive plasticity involving the cortical sensorimotor system. Indeed, lower limb loss is associated with structural and functional brain changes. However, previous characterizations of the cortical changes associated with lower limb loss have focused on region-specific alterations; little is known regarding how lower limb loss impacts brain function and processing at the network level. In the experiments proposed here, we will adopt a network-level perspective in characterizing cortical reorganization in transtibial amputees. In particular, we will focus on the connectivity patterns of the deprived sensorimotor cortex, the area that represents the residual (amputated) limb. We will employ multiple network discovery approaches, including causal interventions that pair transcranial magnetic stimulation with fMRI (in simultaneous TMS-fMRI experiments), to characterize sensorimotor networks in amputees and control subjects. We hypothesize that limb loss will substantially alter the relationship between the deprived cortex and its homologous sensorimotor region that represents the intact limb. We also hypothesize that the functional relationship between the deprived cortex and distributed brain regions beyond the sensorimotor system (e.g., the default mode network) will be altered and that these changes will be associated with prosthetic limb use and amputees’ experience of phantom sensations and pain. In Aim 1, we will use resting-state fMRI methods to characterize changes in the intrinsic architecture of the sensorimotor cortical system in lower limb amputees compared to control participants. In Aim 2, we will use simultaneous TMS-fMRI to causally probe inter-regional interactions between the deprived cortex and distributed cortical regions. In these experiments, we will deliver TMS to the deprived cortex as subjects undergo fMRI scanning and we will infer that brain regions showing significant TMS-related BOLD signal changes are functionally connected to the deprived cortex. We will compare TMS-related activation patterns in amputees to activation patterns in control subjects receiving TMS to analogous sensorimotor cortex targets. In Aim 3, we will relate intrinsic connectivity measurements and inter-regional interactions to clinical outcome measurements that describe amputees’ gait function and experience of phantom limb sensations. These experiments will enhance our understanding of how network organization relates to sensorimotor function. Identifying relationships between network organization and clinical outcomes can also inform clinical interventions for normalizing aberrant connectivity in amputees.