Multisine Frequency Modulation of Intra-epidermal Electric Pulse Sequences to Study Nociceptive Processing: Methods and Limitations

  • Boudewijn van den Berg (Speaker)
  • Mana Manoochehri (Contributor)
  • Mindy Kasting (Contributor)
  • Schouten, A. C. (Contributor)
  • Frans C.T. van der Helm (Contributor)
  • Buitenweg, J. R. (Contributor)

Activity: Talk or presentationOral presentation


In the past decades, researchers have tried to study how the sensation of pain emerges from a peripheral nociceptive input. A frequent approach has been to study the evoked brain response to a single painful stimulus. However, such a stimulus is very different from the continuous pain sensation evoked by tissue damage. Brain responses to a continuous stimulus can be studied by adding a frequency tag to the stimulus. As such, the brain response evoked by such a stimulus can be identified based on its frequency content. By adding multiple frequency tags, also other properties such as the delay and nonlinearity of a system can be studied.

Recently, we developed a method to stimulate nociceptive skin afferents with a frequency modulated pulse sequence. Nociceptive afferent nerve fibers are targeted by using intra-epidermal electric pulses at twice the detection threshold. By modulating this pulse sequence with a multisine waveform, we add multiple frequencies to the signal, allowing us to study the brain response to intra-epidermal stimulation, and explore non-linearity of the nociceptive system.

In a proof-of-principle experiment, we demonstrated that multisine modulation of an intra-epidermal pulse sequence evokes significant brain activity at each of the three base frequencies. However, we also found significant stimulation artefact, which concentrates near the EEG ground electrode. Furthermore, lower frequencies (3 Hz and 7 Hz) were found to have a better signal-to-noise ratio than the higher frequency (13 Hz).

As such, we found that it is possible to study pain processing using multisine modulated intra-epidermal pulse sequences. When using this technique, stimulus artefacts should be minimized and mapped, in order to prevent any interference with stimulus-related brain activity. The signal-to-noise ratio of brain responses might be improved by a smart choice of modulation frequencies.
Period28 Jan 2021
Event title8th Dutch Bio-Medical Engineering Conference, BME 2021
Event typeConference
Conference number8
LocationVirtual ConferenceShow on map
Degree of RecognitionNational


  • Steady State Evoked Potential
  • Nociceptive Processing
  • Pain
  • Multisine