**5. Laser evoked potentials (LEPs) as a valuable outcome measure: setting and method**

Laser evoked potentials (LEPs) allow to evaluate both the lateral and the medial pain pathways, two different, parallel and partially segregated spinal "highways," targeting cortical areas differently involved in nociceptive experience and pain processing. In particular, the two main LEP components, formally named N1 and N2/ P2 potentials, correspond, respectively, to the activation of the secondary somatosensory cortex (SII) and of the insular region; from a functional perspective, N1 reflects the sensory-discriminative, whereas N2/P2 complex the affective-emotional dimension of pain [32, 33].

A solid-state laser is commonly used in clinical trials (neodymium: yttriumaluminum-perovskite, Nd: YAP; wavelength 1.04 mm, pulse duration 2–20 ms, maximum energy 7J: Stimul 1340VR, Electronical Engineering®, Florence, Italy). The laser beam was transmitted from the generator to the stimulating probe via a 10 m length optical fiber; signals were amplified, band pass filtered (0.1–200 Hz, time analysis 1000 ms) and fed to a computer for analysis [30, 63, 64]. Compared to CO2 laser, Nd: YAP uses pulses with a shorter duration and lower wavelengths, thus resulting in a better synchronization of afferent inputs, reducing at the same time the possibility of tissue damage (**Figure 5**).

#### **Figure 5.**

*Non-painful (top row) phantom limb phenomena: changes in VAS scores overtime. Note that anodal ctDCS (black circles) significantly improved phantom movements and sensations compared to the sham condition (white squares). Data are given as percentage of baseline value ±1 S.D. At each time interval, the statistical significance refers to the comparison between anodal (active) and sham (placebo) stimulation (\*\*\*p < 0.001, Bonferroni post-hoc comparison; modified from [51], with permission).*

In our paper [51], the stump was stimulated by laser pulses (individual variability: 15.75–24.91 J/cm2 ) with short duration (5 ms) and small diameter spots (5 mm), inducing pinprick sensations. Twenty stimuli, whose intensity was established on the basis of the perceptive threshold of each patient, were delivered: we used a fixed intensity set at two times the individual sensory threshold, defined as the lower stimulus intensity that elicited a distinct painful pinprick sensation. In order to reduce both skin lesions and fatigue of peripheral nociceptors, the laser beam was shifted slightly by ~10 mm in a random direction between consecutive pulses [64]. Patients were reclined on a couch, wore protective goggles, and were instructed to keep their eyes open and gaze slightly downwards; they were requested to mentally count the number of stimuli, to keep their attention level constant. The interstimulus interval varied randomly between 15 and 30 s.

The main Aδ-LEP complex, N2/P2, and the earlier lateralized N1 component were recorded through standard disc, nonpolarizable Ag/AgCl surface electrodes (diameter 10 mm; BiomedVR, Florence, Italy). N2 and P2 components were recorded from the vertex (Cz), referenced to the earlobes; the N1 component was recorded from the contralateral temporal leads (T3 or T4), referenced to Fz [63]. The baseline-to-peak and the peak-to-peak amplitudes of N1 and N2/P2 components, respectively, were evaluated. Blinks and saccades were recorded with an EOG electrode placed on the supero-lateral right canthus connected to the system reference. Ground was placed on the mid-forehead.

Skin impedance was kept below 5 kΩ. An automatic artifact rejection system excluded all trials contaminated by transient signals exceeding the average value by ±65 μV on each recording channel, including the EOG.

### **6. Theoretical limitations to tDCS for cerebellar stimulation**

Cerebellar tDCS has still some limitations. First, the variability in outcome measures as well as the applied stimulation parameters across studies prompts further research about montage, duration, intensity of stimulation, electrodes number, and placement.

Second, direct current stimulation may exert different, sometimes opposite, effects on motor and non-motor cerebellar functions; in this view, while studies exploring cognitive and emotional domains have used a classical monopolar configuration, others focusing on motor functions have adopted a different montage, in which the return electrode is positioned over the ipsilateral face. Only in the second case, tDCS has demonstrated long-lasting polarity-specific effects.

**185**

*Cerebellar Transcranial Direct Current Stimulation (ctDCS) Effect in Perception…*

That could be critically depend also on the cerebellar somatotopy: the motor cerebellum is mainly represented within the anterior areas, whereas non-motor functions are likely located in the posterior regions. In this connection, only few studies have demonstrated to date the "reverse effect" between anodal and cathodal

Third, tDCS effects critically depend on the structure orientation relative to the electric field direction: neurons of the cerebellum are not identically orientated and follow complex anatomical distributions over folia. That might cause a hyperpolarization in some cells, while others are depolarized at the same time [66, 67].

Cerebellar current stimulation represents an emerging, safe, and effective neuromodulation strategy for pain treatment. The possibility to interfere with cerebellar activity is particularly fascinating in the field of chronic pain syndromes, given that the cerebellum itself regulates both ascending and descending pathways involved in pain processing and nociception. However, the exact mechanisms of action are not fully understood, and some stimulation parameters have to be clearly defined, comprising duration, intensity, and charge density. Moreover, more attention will be deserved to combine and integrate different NIBS techniques, as well as different targets at the same time; for instance, by using the same device, cerebellar tDCS may be associate to spinal direct current polarization, in order to improve the

1 "Aldo Ravelli" Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan and ASST Santi Paolo e Carlo,

4 Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark

5 Section of Neurophysiopathology, Department of Clinical and Experimental

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Alberto Priori1,2, Massimiliano Valeriani3,4

clinical outcome and possibly extend putative effects over time.

*DOI: http://dx.doi.org/10.5772/intechopen.89805*

polarization [45, 52, 65].

**7. Conclusions**

**Author details**

Milan, Italy

and Ferdinando Sartucci5

Tommaso Bocci1,2, Roberta Ferrucci1

Medicine, University of Pisa, Italy

provided the original work is properly cited.

\*

2 III Neurology Clinic, ASST Santi Paolo e Carlo, Milan, Italy

3 Division of Neurology, Ospedale Bambino Gesù, Rome, Italy

\*Address all correspondence to: ferdinando.sartucci@med.unipi.it

*Cerebellar Transcranial Direct Current Stimulation (ctDCS) Effect in Perception… DOI: http://dx.doi.org/10.5772/intechopen.89805*

That could be critically depend also on the cerebellar somatotopy: the motor cerebellum is mainly represented within the anterior areas, whereas non-motor functions are likely located in the posterior regions. In this connection, only few studies have demonstrated to date the "reverse effect" between anodal and cathodal polarization [45, 52, 65].

Third, tDCS effects critically depend on the structure orientation relative to the electric field direction: neurons of the cerebellum are not identically orientated and follow complex anatomical distributions over folia. That might cause a hyperpolarization in some cells, while others are depolarized at the same time [66, 67].
