**3. Transcranial direct current stimulation (tDCS) and the cerebellum: an overview**

### **3.1 Putative mechanisms of action of cerebellar tDCS and implications for pain treatment**

Transcranial direct current stimulation (tDCS) has emerged in the past few years as a novel, noninvasive, inexpensive, and safe technique to modulate cortical excitability, both in health and disease. tDCS uses subthreshold currents (1.0–2.5 mA), too weak to induce neuronal activity independent from afferent input, but sufficient *per se* to alter both the excitability and spontaneous neuronal firing rate.

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

**178**

**Figure 2.**

**Figure 1.**

*pathways.*

*molecular pathways.*

*Rationale for the use of cerebellar tDCS (tcDCS) for pain treatment: possible mechanisms of action and* 

*"Red Flags" responsible for chronization of pain. Chronic pain is a multi-level and multi-step phenomenon, comprising changes at brain as well as spinal levels, and involves different neurotransmitters and neuronal* 

tDCS shows short- and long-term effects; the first ones outlast the end of stimulation for only a few minutes and involve non-synaptic mechanisms, comprising changes in membrane polarity, migration, and steric conformation of transmembrane proteins. Conversely, the long-term after-effects are mainly driven by synaptic modifications. In particular, anodal tDCS seems to have an overall excitatory effect, probably reducing intra-cortical GABA, whereas cathodal polarization dampens cortical excitability by reducing glutamate [34, 35]. Many studies reported the same polarity-specific effects for cerebellar tDCS, although they also depend on the position of the return electrode (namely, the "reference"), as well as on the size of electrodes and duration of the stimulation [36, 37].

Direct current polarization has both on-line and off-line effects on cerebellar excitability. This is in agreement with the effects elicited by tDCS in the cerebral cortex that are observable after both short-term and long-term delays and most likely interfering with long-term potentiation (LTP-like) phenomena [38]. From a cellular point of view, animal studies suggest that the electrical stimulation of Purkinje cells mediates on-line effects [39], whereas depolarization of Golgi inhibitory neurons is responsible for long-lasting changes [40]. Nonetheless, electrical fields induced by cerebellar tDCS in humans are much smaller than those used in animals, thus making it difficult to compare their mechanisms of action [41].

Purkinje cells represent the output from the cerebellar cortex, and their activation leads to the inhibition of cerebellar nuclei, ultimately dampening motor cortex excitability. Cerebellar tDCS (ctDCS) may interfere with this connectivity, influencing the so-called "Cerebellar-Brain Inhibition" (CBI); consequently, anodal ctDCS may reduce pain perception by increasing the inhibitory tone exerted by the cerebellum on different brain targets, whereas cathodal ctDCS could elicit opposite effects by inducing hyperalgesia. This tentative model has been recently confirmed by a clinical study of Ruscheweyh and co-workers [42], showing that patients with cerebellar infarctions have reduced pain thresholds, as concerns both placebo and offset analgesia.

Apart from non-synaptic and synaptic (neuroplastic) changes, tDCS may modulate pain experience and processing through different mechanisms. In recent years, a growing body of evidence has strengthen the importance of tDCS aftereffects on regional blood flow and immune responses. In particular, animal studies have proved that tDCS elicits neural stem cells (NSCs) activation in vivo, thus influencing the development and the distribution of microglia in the adult brain [43]. In addition, tDCS likely modulates inflammatory response by regulating proinflammatory cytokines and increasing glutathione levels [44].

### **3.2 Cerebellar tDCS: setting parameters**

Commonly, tDCS uses two electrodes, a cathode and an anode, but montages with multiple electrodes are possible. Their sizes vary among different studies and critically depend on the target; small electrodes (3 × 5 cm, 3 × 3 cm) are used for cerebellar polarization [36], whereas larger ones are commonly applied for direct spinal stimulation [45].

The return electrode (namely, the "reference") may be applied either over another cortical region or extra-cranially (e.g., the shoulder); the second choice should be preferred because cutaneous impedance is reduced and opposite effects of anodal and cathodal stimulation emerge more clearly.

Both electrodes are connected to a standard tDCS stimulator, delivering currents for 15–25 min, at an intensity ranging from 1 to 2 mA. This stimulation intensity

**181**

**Figure 3.**

*[49], with permission].*

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

*Current density generated by cerebellar transcranial direct current stimulation (cerebellar tDCS) in humans. Examples of segmented tissues in two human realistic virtual family models (Ella and Duke) undergoing cerebellar tDCS. The spread of the current density (J) over the occipital cortex—quantified as the percentage of occipital volume where the amplitude of J-field is greater than 70% of the peak of J in the cerebellum—was only 4% for "Duke" and much less than 1% for "Ella" [modified from Parazzini et al.* 

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

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

### **Figure 3.**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

of electrodes and duration of the stimulation [36, 37].

it difficult to compare their mechanisms of action [41].

tDCS shows short- and long-term effects; the first ones outlast the end of stimulation for only a few minutes and involve non-synaptic mechanisms, comprising changes in membrane polarity, migration, and steric conformation of transmembrane proteins. Conversely, the long-term after-effects are mainly driven by synaptic modifications. In particular, anodal tDCS seems to have an overall excitatory effect, probably reducing intra-cortical GABA, whereas cathodal polarization dampens cortical excitability by reducing glutamate [34, 35]. Many studies reported the same polarity-specific effects for cerebellar tDCS, although they also depend on the position of the return electrode (namely, the "reference"), as well as on the size

Direct current polarization has both on-line and off-line effects on cerebellar excitability. This is in agreement with the effects elicited by tDCS in the cerebral cortex that are observable after both short-term and long-term delays and most likely interfering with long-term potentiation (LTP-like) phenomena [38]. From a cellular point of view, animal studies suggest that the electrical stimulation of Purkinje cells mediates on-line effects [39], whereas depolarization of Golgi inhibitory neurons is responsible for long-lasting changes [40]. Nonetheless, electrical fields induced by cerebellar tDCS in humans are much smaller than those used in animals, thus making

Purkinje cells represent the output from the cerebellar cortex, and their activation leads to the inhibition of cerebellar nuclei, ultimately dampening motor cortex excitability. Cerebellar tDCS (ctDCS) may interfere with this connectivity, influencing the so-called "Cerebellar-Brain Inhibition" (CBI); consequently, anodal ctDCS may reduce pain perception by increasing the inhibitory tone exerted by the cerebellum on different brain targets, whereas cathodal ctDCS could elicit opposite effects by inducing hyperalgesia. This tentative model has been recently confirmed by a clinical study of Ruscheweyh and co-workers [42], showing that patients with cerebellar infarctions have reduced pain thresholds, as concerns both placebo and

Apart from non-synaptic and synaptic (neuroplastic) changes, tDCS may modulate pain experience and processing through different mechanisms. In recent years, a growing body of evidence has strengthen the importance of tDCS aftereffects on regional blood flow and immune responses. In particular, animal studies have proved that tDCS elicits neural stem cells (NSCs) activation in vivo, thus influencing the development and the distribution of microglia in the adult brain [43]. In addition, tDCS likely modulates inflammatory response by regulating pro-

Commonly, tDCS uses two electrodes, a cathode and an anode, but montages with multiple electrodes are possible. Their sizes vary among different studies and critically depend on the target; small electrodes (3 × 5 cm, 3 × 3 cm) are used for cerebellar polarization [36], whereas larger ones are commonly applied for direct

The return electrode (namely, the "reference") may be applied either over another cortical region or extra-cranially (e.g., the shoulder); the second choice should be preferred because cutaneous impedance is reduced and opposite effects

Both electrodes are connected to a standard tDCS stimulator, delivering currents for 15–25 min, at an intensity ranging from 1 to 2 mA. This stimulation intensity

inflammatory cytokines and increasing glutathione levels [44].

of anodal and cathodal stimulation emerge more clearly.

**3.2 Cerebellar tDCS: setting parameters**

spinal stimulation [45].

**180**

offset analgesia.

*Current density generated by cerebellar transcranial direct current stimulation (cerebellar tDCS) in humans. Examples of segmented tissues in two human realistic virtual family models (Ella and Duke) undergoing cerebellar tDCS. The spread of the current density (J) over the occipital cortex—quantified as the percentage of occipital volume where the amplitude of J-field is greater than 70% of the peak of J in the cerebellum—was only 4% for "Duke" and much less than 1% for "Ella" [modified from Parazzini et al. [49], with permission].*

induces an electric field of the same order of magnitude as that influencing the cerebellar neuron activity in animal experiments [37].

### **3.3 Cerebellar tDCS: safety**

When the procedure is correctly delivered, according to the safety guidelines, no adverse effects occur, except for a transient itching of tingling sensation.

In most subjects, cerebellar tDCS evokes no sensation likely because cutaneous nerves in the occipital region show a higher threshold than those located in the frontal trigeminal dermatomes [46].

Researchers and therapists should keep in mind only few exclusion criteria, such as the presence of metallic implants in the skull or in the brain [47], and subjects' skin should be lightly cleaned with a swab. Second, electrode sponges should be soaked with saline solution to reduce skin impedance. Finally, a current density limit of 0.029–0.142 mA/cm2 , corresponding to a maximum of charge density of about 40 μC/cm2 at the stimulating electrode, has considered to be safe [48].

Notably, despite some inter-individual differences, recent modeling researches have revealed that the current spread to other structures outside the cerebellum is negligible and unlikely to produce functional effects (**Figure 3**) [49].

### **4. Cerebellar tDCS: emerging evidence for pain treatment**

In previous papers from our laboratory, we have demonstrated for the first time that cerebellar tDCS modulates pain processing in healthy humans, probably by interfering with the CBI network [50–52]. In particular, ctDCS exerts polarity-specific effects on the amplitude of laser evoked potentials (LEPs), thus modifying the perception of experimentally induced pain in young volunteers: anodal stimulation leads to analgesia, whereas cathodal polarization increases pain perception.

This is in line with the theory that cerebellum exerts an overall inhibitory effect on pain processing at a cortical level, similar to that induced within motor pathways.

Because tDCS is effective on the modulation of both N1 and N2/P2 components of LEPs and these responses are generated by parallel and partially segregated spinal pathways reaching different cortical targets [32], we argue that the cerebellum is involved in pain processing by modulating the activity of both somatosensory and cingulate cortices. Indeed, from a functional point of view, the cerebellum is engaged in the sensory-discriminative, as well as in the emotional and cognitive dimension of pain [53, 54]: therefore, non-invasive cerebellar current stimulation may modulate pain experience and the associated cortical activities through different, not mutually exclusive mechanisms. Moreover, our results indicate, for the first time in humans, that the cerebellum is also engaged in the primary sensorydiscriminative dimension of pain.

A recent paper by Pereira and co-workers [55] has confirmed our results, showing that anodal cerebellar tDCS reduces lower extremity pain perception in healthy humans.

However, in a previous study, Zunhammer and colleagues [56] failed to demonstrate analgesic effects of rTMS applied over the cerebellum; the discrepancy with our results, may be due to different factors: the authors evaluated changes in subjective pain thresholds, without any neurophysiological support, and used a different neuromodulation technique (rTMS vs. tDCS).

The efficacy of cerebellar tDCS on pain treatment has been recently confirmed also in patients suffered from "phantom limb pain" (PLP) [51].

**183**

respectively [59].

**Figure 4.**

**and method**

dimension of pain [32, 33].

the possibility of tissue damage (**Figure 5**).

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

PLP remains a challenge for clinicians and neuroscientists. The short and longterm effectiveness of pharmacological interventions is unclear; most of the studies were limited by their small sample sizes and by different pharmacological effects on either painful and non-painful phenomena; also invasive spinal cord stimulation (SCS), probably due to its poor somatotopic specificity, failed to demonstrate

*Painful (top row) phantom limb phenomena: changes in VAS scores overtime. Note that anodal ctDCS (black circles) significantly improved paroxysmal pain 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* 

Recent studies have shown that tDCS applied over the motor cortex represents a promising therapeutic tool in PLP, with effects likely arising from a transient restoration of the cortical representation of the phantom limb [59–62]. Based on this, we have recently shown that anodal ctDCS improves both paroxysmal pain and non-painful phantom limb sensations in subjects with upper limb amputations (**Figure 4**), as confirmed by changes observed in LEP amplitudes, with anodal tDCS significantly reducing the amplitude of both N1 and N2/P2 components [51]. We argue that, different from other brain targets and depending on the extent of anatomical connections between the cerebellum and the brain, ctDCS may reduce both painful and non-painful phantom limb sensations, which are induced by maladaptive changes in the sensorimotor network and posterior parietal cortex,

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

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

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

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

*comparison; modified from [51], with permission).*

significant and long-lasting effects specificity [57, 58].

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

### **Figure 4.**

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

cerebellar neuron activity in animal experiments [37].

**3.3 Cerebellar tDCS: safety**

frontal trigeminal dermatomes [46].

limit of 0.029–0.142 mA/cm2

discriminative dimension of pain.

neuromodulation technique (rTMS vs. tDCS).

also in patients suffered from "phantom limb pain" (PLP) [51].

about 40 μC/cm2

pathways.

induces an electric field of the same order of magnitude as that influencing the

adverse effects occur, except for a transient itching of tingling sensation.

negligible and unlikely to produce functional effects (**Figure 3**) [49].

**4. Cerebellar tDCS: emerging evidence for pain treatment**

leads to analgesia, whereas cathodal polarization increases pain perception. This is in line with the theory that cerebellum exerts an overall inhibitory effect on pain processing at a cortical level, similar to that induced within motor

When the procedure is correctly delivered, according to the safety guidelines, no

In most subjects, cerebellar tDCS evokes no sensation likely because cutaneous nerves in the occipital region show a higher threshold than those located in the

Researchers and therapists should keep in mind only few exclusion criteria, such as the presence of metallic implants in the skull or in the brain [47], and subjects' skin should be lightly cleaned with a swab. Second, electrode sponges should be soaked with saline solution to reduce skin impedance. Finally, a current density

Notably, despite some inter-individual differences, recent modeling researches have revealed that the current spread to other structures outside the cerebellum is

In previous papers from our laboratory, we have demonstrated for the first time that cerebellar tDCS modulates pain processing in healthy humans, probably by interfering with the CBI network [50–52]. In particular, ctDCS exerts polarity-specific effects on the amplitude of laser evoked potentials (LEPs), thus modifying the perception of experimentally induced pain in young volunteers: anodal stimulation

Because tDCS is effective on the modulation of both N1 and N2/P2 components of LEPs and these responses are generated by parallel and partially segregated spinal pathways reaching different cortical targets [32], we argue that the cerebellum is involved in pain processing by modulating the activity of both somatosensory and cingulate cortices. Indeed, from a functional point of view, the cerebellum is engaged in the sensory-discriminative, as well as in the emotional and cognitive dimension of pain [53, 54]: therefore, non-invasive cerebellar current stimulation may modulate pain experience and the associated cortical activities through different, not mutually exclusive mechanisms. Moreover, our results indicate, for the first time in humans, that the cerebellum is also engaged in the primary sensory-

A recent paper by Pereira and co-workers [55] has confirmed our results, showing that anodal cerebellar tDCS reduces lower extremity pain perception in healthy

However, in a previous study, Zunhammer and colleagues [56] failed to demonstrate analgesic effects of rTMS applied over the cerebellum; the discrepancy with our results, may be due to different factors: the authors evaluated changes in subjective pain thresholds, without any neurophysiological support, and used a different

The efficacy of cerebellar tDCS on pain treatment has been recently confirmed

at the stimulating electrode, has considered to be safe [48].

, corresponding to a maximum of charge density of

**182**

humans.

*Painful (top row) phantom limb phenomena: changes in VAS scores overtime. Note that anodal ctDCS (black circles) significantly improved paroxysmal pain 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).*

PLP remains a challenge for clinicians and neuroscientists. The short and longterm effectiveness of pharmacological interventions is unclear; most of the studies were limited by their small sample sizes and by different pharmacological effects on either painful and non-painful phenomena; also invasive spinal cord stimulation (SCS), probably due to its poor somatotopic specificity, failed to demonstrate significant and long-lasting effects specificity [57, 58].

Recent studies have shown that tDCS applied over the motor cortex represents a promising therapeutic tool in PLP, with effects likely arising from a transient restoration of the cortical representation of the phantom limb [59–62]. Based on this, we have recently shown that anodal ctDCS improves both paroxysmal pain and non-painful phantom limb sensations in subjects with upper limb amputations (**Figure 4**), as confirmed by changes observed in LEP amplitudes, with anodal tDCS significantly reducing the amplitude of both N1 and N2/P2 components [51]. We argue that, different from other brain targets and depending on the extent of anatomical connections between the cerebellum and the brain, ctDCS may reduce both painful and non-painful phantom limb sensations, which are induced by maladaptive changes in the sensorimotor network and posterior parietal cortex, respectively [59].
