Effects of long-term treatment with transcranial pulsed electromagnetic fields in Parkinson’s disease on kinematic and electrophysiological tremor

Parkinson’s disease (PD) is an asymmetric neurological disease characterized by severe loss of dopaminergic neurons resulting in motor symptoms including tremor. Tremor, defined as involuntary rhythmic oscillatory movements, is one of the clinical hallmarks of PD and is reported in approximately 2/3 of the patients at disease onset. The prevalence increases as the disease progresses (Gigante et al., 2017). The upper extremities are the most frequent site of tremor presentation at disease onset, and tremor tends to spread to other sites (Gigante et al., 2017). The classical Parkinsonian tremor occurs at a frequency of approximately 4–8 Hz and the underlying Parkinson electromyography (EMG) is characterized by tonic and/or alternating bursts (Helmich, 2018).

Tremor is influenced by central as well as peripheral factors. The central contribution has been described in the dimmer-switch model (Helmich, 2018) where oscillating activity is turned on/off and the amplitude can be modulated across time. Motor neuron activity in PD is characterized by reduced signal complexity, increased intermuscular coherence, and a regularly oscillating muscle activation pattern and/or alternating EMG bursts, which may result in rhythmic oscillations, a tremor activation pattern (Flood et al., 2019; Malling et al., 2019a; Rissanen et al., 2007). The peripheral contributions are mainly determined by the inertia of the extremity relative to gravity (i.e. mass, stiffness and geometry) but a reflex component is also thought to play a role, although to a lesser degree (Hess and Pullman, 2012).

Whether the oscillating motor neuron activity results in visible tremor or not depends on the internal net torque developed by the muscles relative to the external torque due to e.g. gravity. The internal net torque must exceed the external torque to elicit visible tremor. Thus, it is possible to register a regularly oscillating muscle activation pattern in the absence of visible tremor if agonist muscle activation level is low or if antagonists are activated synchronously. Consequently, electrophysiological and acceleration analysis represent to some extent different information about the mechanisms underlying tremor, although an association exists as the muscle activation pattern determines the exerted muscle force. Based on the literature, we expected that PD EMG and kinematic tremor measured during a low-level isometric contraction are sensitive to disease asymmetry, i.e., that the most affected side would have a more pronounced tremor EMG pattern and a higher tremor intensity.

Treatment with bipolar pulsed electromagnetic fields is a non-invasive rapidly emerging technique. The biophysical effects of pulsed electromagnetic fields are to depolarize the membrane potential slightly and to induce ion currents in the tissue (Rahbek et al., 2005). Stimulation with this technique in animal and in-vitro studies seems to enhance cellular activity and stimulate growth-related responses and regeneration (Rahbek et al., 2005). In short, different stimulation configurations of pulsed electromagnetic fields have been shown to stimulate nerve growth, attenuate nerve abnormalities, increase microvascular blood flow and tissue oxygenation, and to increase capillary density (Hei et al., 2016; Lei et al., 2013; Pan et al., 2013; Urnukhsaikhan et al., 2016), making the technique a potential therapy for certain neurodegenerative disorders. Applying 2 h of pulsed electromagnetic fields with the same stimulation configuration as in the present study to humane microglia cells enhanced the mRNA synthesis of VEGF and IL-8 as well as proglucagon and PC1/3 enzyme that cleaves the proglucagon protein to glucagon and GLP-1 proteins. In accordance, the microglial secretion of VEGF, IL-8, and GLP-1 increased (Hyldahl et al., 2023). Current evidence indicates that diverse VEGFs may influence PD progression and enhance survival of dopamine neurons in substantia nigra (Caballero et al., 2017; Ceci et al., 2024), and animal- and preclinical studies show that GLP1-receptor agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD (Kalinderi et al., 2024).

In vivo studies have shown indications of a positive effect of 8-weeks daily treatment with bipolar transcranial pulsed electromagnetic field stimulation (T-PEMF) on functional rate of force development and inter-hand acceleration coherence in patients with mild PD indicating an increased muscle contraction speed and an increasing inter-hemispheric inhibition as a result of T-PEMF treatment (Malling et al., 2018; Malling et al., 2019a). However, longer treatment periods are warranted. Previously published data from the present long-term T-PEMF treatment study showed improved movement speed and elevated cerebrospinal levels of the neuroprotective agent erythropoietin (Jensen et al., 2021) along with improved writing ability (case study) (Jensen et al., 2018).

Thus, long-term T-PEMF treatment improves motor control and function in persons with PD and therefore may also affect PD EMG and kinematic tremor. Based on the current knowledge, we hypothesize that long-term treatment with T-PEMF improves tremor and EMG characteristics in PD towards healthy reference values.

The present T-PEMF treatment system (Re5 Aps, Frederiksberg, Denmark) has recently been approved for treatment of PD in EU (G10 117853 0002 Rev. 01, 2024) and is to our knowledge the first antiparkinsonian treatment with neuroprotective perspectives. However, knowledge about the mechanisms of action in vivo is still lacking.

The present study aimed to investigate the effect of long-term treatment with T-PEMF on tremor intensity and EMG characteristics in PD. We analyzed relative surface EMG power in the theta-band (4–8 Hz) and tremor intensity (3–9 Hz) measured during a prolonged postural task performed with the arms extended, horizontal, and parallel with palms facing the floor.

Relative theta-band EMG results have, in part, been presented as an abstract at the ISEK-2020 Congress (Jensen et al., 2020).