Auricular vagal nerve stimulation combined with rehabilitation to enhance functional outcome in cerebral palsy patients with upper extremity deficits (AVANS study) Part1

Most children with Cerebral Palsy (CP) experience impaired hand function,
resulting in difficulties performing daily activities. Intensive physical
rehabilitation programs, using variants of bimanual training (BIMT) or
constraint-induced movement therapy (CIMT), positively affect functional
outcomes and have been shown to result in beneficial structural neuroplastic
changes including the reorganization of the sensorimotor network. Such
neuroplastic changes may also be induced by means of neuromodulation
technologies. Functional outcomes could therefore be enhanced by combining
physical rehabilitation with concomitant non-invasive neuromodulation.
Non-invasive auricular vagal nerve stimulation (aVNS) is already used in this
way with promising results for rehabilitation of adult stroke patients. In
these studies the focus was functional improvement after the training program,
none of these studies focused on the underlying neuroplastic changes. To this
date, no studies have investigated the use in children suffering from CP.
However, before testing such a combination therapy in children, further
research into mechanisms underlying neuroplastic changes is necessary.

The ultimate goal is to investigate whether aVNS can enhance cortical
plasticity and improve functional outcomes during intensive rehabilitation
programs in children with cerebral palsy. First, we aim to establish the extent
of cortical plasticity changes after aVNS in healthy adult volunteers (part 1).
Secondly, we aim to establish the proof of principle in combining aVNS and
rehabilitation for enhanced functional outcomes in adult stroke patients (part
2) and in children with cerebral palsy (part 3); a separate research proposal
will be submitted. We hypothesize that medium-intensity aVNS induces cortical
plasticity and enhances functional recovery.

Randomized controlled trial

It is unknown which aVNS stimulation intensity is the most effective in
inducing cortical plasticity and improving the performance of a simple motor
task. Therefore, the group will be divided into three subgroups, testing
different stimulation intensities both during a simple motor task and at rest.
To account for individual differences in the primary outcome measure, i.e.
motor evoked potential (MEP), each participant will act as their own control
and will receive both sham and stimulation, with and without a motor task at
the allocated intensity during four visits. The order of the tested conditions
will be randomized. The aVNS stimulation (sham/stimulation) will last 30
minutes.

Part 1: the sham-controlled study in healthy adult volunteers will consist of
four visits. During these visits, first MEP, SSEP and stacking test are
performed, followed by one of the conditions below:
30 min sham stimulation during rest
30 min sham stimulation during performance of a simple motor task
30 min aVNS stimulation at the allocated intensity during rest
30 min aVNS stimulation at the allocated intensity during performance of a
simple motor task
At each visit a repeated MEP, SSEP and stacking test are performed pre and post
aVNS stimulation/sham. We ask the participants not to practice between the
visits, they will not be required to perform other tasks.
A literature search of side effects of aVNS showed no severe adverse events
during the treatment of children with epilepsy. Among 229 adult stroke patients
using aVNS, only one patient with a local skin reaction(redness) was reported.
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