Prosthesis embodiment induced by multimodal sensory feedback: neural correlates and its potential for the treatment of phantom limb pain in lower-limb amputees

After the amputation of a limb, most amputees complain of phantom limb pain (PLP) which is accompanied by reorganization of somatotopically structured brain areas. Prosthesis use not only restitutes the patients’ autonomy but is further negatively related to the presence of PLP as well as dysfunctional brain changes. Embodiment of the prosthesis, phenomenologically reflected in perceived ownership for the device, might represent an important modulator variable in this process. In the present project, we aim to identify the neural correlates of prosthesis embodiment in lower limb amputees and its association with PLP. We will use the PHANTOMMIND data base, composed of more than 2,200 prosthesis-using lower-limb amputees, and will include participants complaining of chronic PLP. In study 1, we will implement a recently developed paradigm to experimentally manipulate the sense of ownership for an artificial leg and will assess associated brain activity using functional magnetic resonance imaging. Crucially, we will search for functional relationships between brain areas involved in bodily self-processing and key areas associated with pain processing. Based on subjective and neural responses, we will select a sub sample of participants who will undergo an innovative two-week training trial (study 2) in which they are repeatedly induced to perceive ownership for an artificial leg by multimodal sensory feedback. We expect that induced ownership for an artificial limb by multimodal sensory input is associated with activity in a network associated with conscious body perception whose activity correlates with those in key regions associated with pain processing. Over a course of two weeks, we expect that the repeated induction of ownership for an artificial body part significantly reduces PLP intensity. The results of the proposed project are likely to have noteworthy impact on existing theories of neuroplasticity after amputation and might yield important implications for the treatment of PLP.



Investigating the pathophysiology of SPTLC1 mutations that cause painful hereditary sensory neuropathy type 1 using human iPSC-derived sensory neurons

Hereditary sensory and autonomic neuropathy type 1 (HSN1) is an exemplar of a monogenic neuropathic pain disorder, associated with shooting pain and loss of peripheral sensation. The most common cause for HSN1 are mutations in SPTLC1, which result in the production of deoxy-sphingoid bases (DSBs). DSBs are unable to be processed into complex sphingolipids, nor can they be degraded. Therefore, they accumulate in HSN1 patients and have proven to be neurotoxic, although the pathophysiology remains unknown. I have promising preliminary data which suggests HSN1 human sensory neurons are hyperexcitable. Therefore I intend to perform further electrophysiology and RNA-sequencing to fully investigate the pathophysiology of DSB accumulation. I also plan to assess ion channel transport and localisation in HSN1 human sensory neurons. Once validated, we intend to use this system to assess the efficacy of neuropathic pain compounds to modulate excitability, and test novel therapeutics such as modulating enzyme substrate availability.

Disclosing mechanisms underlying painful diabetic neuropathy. A clinical and skin biopsy study with new emerging sensory biomarkers

Patients with diabetic neuropathy frequently complain of different types of neuropathic pain, whose pathophysiological mechanisms are only partially known. Previous skin biopsy studies have raised the hypothesis that neuropathic pain in diabetes could depend on mechanisms other than fibers loss, such as the overactivity of irritable nociceptors and regenerating sprouts in ongoing burning pain, but few studies have investigated the expression of different skin biopsy biomarkers than the pan-axonal protein PGP 9.5, which could disclose alternative mechanisms for pain. Our study aims to verify if specific neuropathic pain subtypes and sensory profiles in diabetic neuropathy are conditioned by clinical variables and show different patterns of expression of emerging skin biopsy bio-markers (Gap 43, Voltage-Gated Sodium Channels, Transient Receptor Potentials, CGRP), improving our understanding on pain mechanisms. Data from 120 patients with painful and painless diabetic neuropathy and 50 healthy subjects will be collected through clinical examination, neuropathic pain and diabetes severity questionnaires, nerve conduction study, quantitative sensory testing and immunofluorescence analysis of skin samples.



What is the role of baroreceptors in descending pain modulation?

There is a strict interaction between the autonomic nervous system (ANS) and pain; where high blood pressure and greater heart rate variability (LF-HRV) are linked to higher pain tolerance. Nociception is also modulated by ‘top-down’ processes occurring in the brain, brainstem and spinal cord (i.e. the Diffuse noxious inhibitory control [DNIC]). Conditioned Pain Modulation (CPM) is a paradigm used to assess the DNIC in humans. An association has been described between ANS and CPM. Chronic pain patients exhibit both ANS dysregulation and deficient CPM. Here, a crucial role might be played by baroreceptors, involved in the regulation of blood pressure and HRV, and whose stimulation reduces pain. The involvement of baroreceptors in DNIC and their functioning in chronic pain has not been explored. We want to combine baroreceptor stimulation with CPM to explore the role of baroreceptors in DNIC and the possibility to use baroreceptor stimulation to treat chronic pain.

The missing link between fear learning and pain levels: an investigation into sensory discrimination

Perceptual mechanisms modulating the relationship between fear learning and pain reports remain poorly understood, despite well-established behavioral effects of fear learning in the context of pain. This project aims to investigate the putative role of pain-related fear learning in perceptual alterations and its potential therapeutic implications for chronic pain. In a series of studies, we will investigate: (1) the impact of fear learning on the ability to discriminate between different bodily sensations, (2) the relationship between discrimination acuity and pain reports, (3) the role of avoidance within this context, and finally (3) whether the effectiveness of exposure therapies is mediated through improvements in tactile discrimination. The outcome of this project would extend contemporary pain models through the mapping of fear learning-perception pathways, and better inform clinical practices (e.g., extension of therapy with a somatosensory discrimination training) on the behavioral and perceptual effects of fear learning.