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Periodic Report Summary 2 - EPIONE (Natural sensory feedback for phantom limb pain modulation and therapy)

Project Context and Objectives:
EPIONE offers new solutions to understand and treat phantom limb pain.
Phantom limb pain (PLP) is a frequent consequence of amputation, and it is notoriously difficult to treat. Despite isolated reports of success, no medical/non-medical treatments have been beneficial on more than a temporary basis. Today it is known that the cause of phantom limb pain is likely related to changes in the cortex of the brain. Most of the treatments that are offered to patients today seek to actively suppress the pain through e.g. medication. In EPIONE, we oppositely believe to actively create natural, meaningful sensations that will restore the neuroplastic changes in the cortex and thereby control and alleviate pain. We believe that dedicated, technological solutions as offered by the EPIONE consortium will be the cornerstone needed to translate research results into clinical applications and provide long-term, patient-specific solutions to a large group of patients.

Why and when does phantom limb pain occur?
Amputation usually follows traumatic injuries or surgery following vascular diseases, diabetes, osteomyelitis or tumours in cases where the loss of the limb is required for the survival of the patient. The loss of a limb or other body parts is usually followed by the sensation that the lost body part is still present and can be felt. These phenomena are called, respectively, phantom awareness and phantom sensation. In 50-80% of amputees neuropathic pain develops in the lost limb also referred to as phantom limb pain (PLP). PLP is more frequent when the amputation occurs in adults; it is less frequent in child amputees and virtually non-existent in congenital amputees. Moreover, PLP can be related to a certain position or movement of the phantom limb, and might be elicited or worsened by a range of physical factors (e.g. changes in the weather or pressure on the residual limb) and psychological factors (e.g. emotional stress). It is well known that most treatments available for PLP today, such as pharmacological, surgical, anaesthetic, psychological and other, are ineffective.

What are the challenges that we need to address?
The first challenge; There is emerging evidence that neuroplastic changes in the cortex following amputation may be modulated by providing sensory input to the stump or amputation zone. For example, cortical reorganization and alleviation of phantom limb pain has been seen observed in patients following intense use of a hand prosthesis. However, the mechanisms underlying the painful perception of a missing body part are still unclear. In addition, there is no consistent knowledge on which type of sensations may be effective in affecting the cortical plasticity, and the strategy for applying sensory feedback.
The second challenge: There are no dedicated medical technologies available on the market with the aim to provide sensory feedback to control and alleviate pain.

Our specific objectives to overcome the current challenges and problems.
Objective 1: Through coordinated multi-centre clinical trials, we aim to assess the effectiveness of providing invasive/non-invasive sensory feedback (direct peripheral nerve stimulation/mechanical pressure or electrical stimulation) with or without simultaneous operation of hand prosthesis device for controlling phantom limb pain. Objective 2: We aim to assess the associated cortical neuroplastic, psychological and cognitive components of pain. Objective 3: We aim to provide clinical guidelines. Objective 4: We aim to build novel innovative technological pre-industrial systems for delivering invasive/non-invasive sensory feedback based on existing solutions emerging from previous funded EU research.

Project Results:
permanent therapies for amputees suffering from phantom limb pain.

Route 1: Direct peripheral nerve sensory feedback.
The invasive technology have been will be tested at three hospitals in Europe. Multiple transverse, intrafascicular electrodes (TIME-4H) are implanted in the median and or ulnar nerves of volunteer amputee subjects. Electrical stimulation is delivered through the active sites by the multi-channel, miniaturized electrical stimulator placed outside the body. Different strategies for delivering electrical stimulation will be tested. The TIME-4H electrodes will be surgically removed after completion of the study – the implant duration may be up to one year. To deliver the electrical stimulation sequences and also to obtain quantitative and qualitative measures on the effect of the microstimulation, a semi-automatic and computerized platform is used (Psychophysical Testing Platform).

Route 2: Non-invasive sensory feedback.
The non-invasive technology will be tested at five universities in Europe and the USA. Either we will apply mechanical sensory feedback (i.e. air pressure) through silicone pads, or electrical stimulation will be applied through of-the-shelf electrodes. Two steps will be performed; 1) use of the psychophysical testing platform to deliver stimuli and obtain the patient’s response, 2) following a period with receiving non-invasive sensory feedback, the patient will be asked to perform a series of functional tasks including a hand prosthesis while simultaneously receiving sensory feedback. Different strategies for delivering the non-invasive sensory feedback are tested.

Results so far
All technology development has been completed, and all clinical partners have obtained ethical approval and/or approval by the national competent authorities. One volunteer has participated in to receive ‘direct’ peripheral sensory feedback, and 8 volunteer subjects have participated in the non-invasive trials. Of the subjects, one subject did not appear to respond to sensory feedback therapy. We found an indication that despite the wide differences in routes, modes, intensity and dosage of sensory feedback therapy, the therapy showed to have a large effect on pain if the subject responded to the therapy. The highest pain reduction was found at the end of the therapy phase. The experiments in the last phase of the project will seek to establish the necessary dosage and to establish if the pain reduction was correlated with cortical reorganization and changes in the psychological state.

Potential Impact:
We expect that EPIONE will deepen our knowledge of how pain is generated and quenched.
Through the multi-modal/multi-disciplinary quantitative assessment measures planned, we aim to establish a more comprehensive picture of the nature of phantom limb pain and the influence of electro-mechanical sensory feedback than what is currently available/known and which will bring our understanding of the neuroplastic, psychological and cognitive components of pain beyond the state-of-the-art.

We expect that EPIONE will identify more effective treatment approaches.
No effective, long-term treatments are currently available for PLP. EPIONE will directly compare two routes for providing a more long-term or permanent solution for the amputees, i.e. a non-invasive sensory feedback solution that may be integrated with the operation of a hand prosthesis which many patients already use on a daily basis and an invasive sensory feedback solution that in the future will offer the ultimate, permanent, invisible and cosmetically acceptable interface. While the majority of the treatments currently offered seek to actively suppress the pain, we believe in challenging the status-quo of PLP treatment by actively creating natural, meaningful sensations that will restore the neuroplastic changes in the cortex and thereby control and alleviate pain. In addition we will directly compare two routes for delivering sensory feedback and provide clinical guideline which has not been accomplished before for the treatment of phantom limb pain.

We expect to translate basic discoveries and validate new therapies.
There is a number of potential areas and markets of application for the technologies developed by EPIONE. The incidence of peripheral nerve injuries is about 360,000 cases in the USA and 300,000 cases in Europe. There are approximately 400,000 amputees within the EU, with an incidence of 2/100,000 persons-year described for hand amputations in Northern Europe. Successful clinical evaluations proposed in this project will significantly improve exploration possibilities for the developed technology. With the participation of two industrial partners we expect to pave the way to rapid exploitation of the technologies.
For therapeutic use, devices have to stay in the body for years. Devices have to be optimized to prove long-term stability under stimulation conditions. For translational research towards medical device approval, a multi-centre clinical trial is therefore mandatory to investigate in several patients. We expect that EPIONE is the next step on the way to commercialize these non-implantable and implantable devices and deliver a new therapy for PLP that is currently not available. The EPIONE specific technologies are presently only available as experimental units and have only been tested on very few subjects. In EPIONE we will directly translate our results into the clinic to be validated and this is in particular important for the invasive sensory feedback system, where large-scale clinical work is high-risk and high-cost for a company to commit to or engage in.
In addition, the advantage of the proposed therapies is that they can be performed continuously. The sensory feedback system could be integrated in the socket of the prosthesis or implanted for the invasive technology, and thus generating continuous treatment. In addition, the feedback will be related to specific actions and coming from the nerves that originally innervated the missing hand.

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