Cerebellar Direct Current Stimulation (ctDCS) for the treatment of phantom limb pain Bocci Tommaso 1,2, De Carolis G.3, Mansani F.1, De Rosa A.1, Ferrucci R. 2, Priori A. 2, Valeriani M. 4, Sartucci F.1,5 1 Department of Health Sciences, University of Milan, Milan, Italy; 2 Department of Clinical and Experimental Medicine, University of Pisa; 3 Pain Therapy Unit, University of Pisa, Pisa, Italy; 4 Division of Neurology, Ospedale Bambino Gesù, Rome, Italy; 5 Neuroscience Institute, National Research Council, Pisa, Italy 1 1

From bench to bedside: putative pathways What did we learn from MRI studies? Moulton et al., Brain Res Rev 2010 Borsook et al., Cerebellum 2008; Dimitrova et al., J Neurophysiol 2003; Plogahus, Science 1999

A new target for pain treatment in humans: the cerebellum Parazzini et al., Clin Neurophysiol 2013 Bocci et al., Restor Neurol Neurosci 2015 Bocci et al., Cerebellum 2016

Supra-spinal mechanisms: Central sensitization and chronic pain syndromes: the “red flags” for putative therapies Supra-spinal mechanisms: Reorganization of sensorimotor maps Thalamocortical Dysrhythmia Spinal mechanisms: Phenotipic switch in the expression of neuropeptides here was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Hsieh et al., Pain 2015 Suzuki&Dickenson, Neurosignals 2006

tDCS and phantom limb pain (PLP) Is it really effective? tDCS over the primary motor cortex (Bolognini et al., J Pain 2015)

Experimental Protocol 1. Clinical Scales 2. LEPs (nociceptive threshold, N1 and N2/P2 amplitude/latency) 3. fMRI 1. Clinical Scales 2. LEPs (nociceptive threshold, N1 and N2/P2 amplitude/latency) 3. fMRI 1. Clinical Scales 2. LEPs (nociceptive threshold, N1 and N2/P2 amplitude/latency) 3. fMRI T0 T1 (immediately after ctDCS) T2 and T3 (after two and three weeks ctDCS completion) Cerebellar tDCS (sham or anodal), five days a week (2.0 mA, 20’ per day).

Clinical scores Bocci et al., Cerebellum 2019

Neurophysiological outcome Bocci et al., Cerebellum 2019

Conclusions Anodal stimulation significantly improves both painful and non painful phantom limb sensations, dampening LEP amplitudes over time; Cerebellar polarization may be useful for the treatment of pain syndromes; it may act not only on spinal nociceptive neurons, but also on wide-range cortical networks of the pain matrix, thus influencing pain experience through top-down and bottom-up mechanisms.