Técnicas de neuromodulación no invasivas en sujetos sanos adaptadas para modelos de dolor crónico y neuropático

Resumen

Introduction The treatment of pain and its wide range of symptoms is in most of cases a complex procedure that requires prior knowledge of the underlying pathophysiological mechanisms. In the last two decades, non-invasive brain stimulation techniques have begun to be used clinically as an alternative therapy for the treatment of pain. To date, techniques, such as “direct current stimulation” (DCS), have produced changes in outcome measures related to pain and to pain evoked by mechanical and thermal stimuli. General objective The main objective of this thesis was to examine whether “direct current stimulation” could modulate pain control by modulating the endogenous pain modulation system, organised at the level of the brainstem, following suboccipital stimulation in healthy participants. In addition, a pilot study was performed to evaluate the effect of evaluating endogenous pain modulation at the level of at the level of trigeminal system to be adapted for patients with high spinal cord injury. Methods Three studies were made in this thesis work: firstly a systematic review and meta-analysis of the effect of non-invasive direct current stimulation, applied at cortical and subcortical sites, to evaluate the efficacy of this technique to modulate pain outcome measures and mechanical or thermal-evoked sensory measures in healthy participants; secondly a randomized clinical trial to evaluate the effect of transcranial motor cortex and suboccipital DCS on different modalities of evoked pain in healthy participants; thirdly an observational cross-sectional pilot study to evaluate the efficacy of a new conditioned pain modulation protocol applied at the trigeminal level in healthy participants to be adapted for patients with high spinal cord injury. The following methodological tools were used: - Systematic review analysis tools such as the “PEDro scale” and the “review manager” program (Revman version 5.4) to characterise the quality and effectiveness of studies screened for the systematic review and meta-analysis of direct current stimulation on pain and sensory function in healthy participants (Study 1). - Quantitative sensory tests to measure the effect of direct current stimulation intervention on different sensory modalities of evoked pain, in the randomized clinical trial (Study 2) and the observational cross-sectional pilot study (Study 3), including Pressure Pain Thresholds (PPTs), Thermal Pain Thresholds (TPT), Temporal Summation (TS), Conditioned Pain Modulation (CPM) and rated using the Visual Analogue Scale (VAS). - Questionnaires to measure mood, such as the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory Spanish version (STAI-ES). Results In the first study that performed a systematic review and meta-analysis of the effect of direct current stimulation on pain and sensory outcome measures in healthy subjects, the following relevant findings were found: 1) meta-analysis of studies related to the intensity of pain rated with the visual analogue scale (VAS), found statistically significant differences in the reduction of pain intensity following active transcranial motor cortex DCS compared to control intervention (n=158; SMD=0.79, 95% CI: 0.56 to 1.02); 2) meta-analysis of studies that measured pressure pain thresholds (PPTs) failed to observe statistically significant differences related to an increase in PPTs following active transcranial DCS compared to control intervention (n=82; SMD=0.06, 95% CI: -0.25 to 0.36); 3) meta-analysis of studies which measured heat pain thresholds (HPT), found statistically significant differences in the increase of heat pain threshold following active transcranial DCS compared to control intervention (n=222; SMD=1.16, 95% CI: 0.95 to 1.37); 4) meta-analysis of the studies that measured cold pain thresholds (CPT) found statistically significant differences in the increase of CPT for active transcranial DCS compared to control intervention (n=155; SMD=0.77, 95% CI: 0.53 to 1.01). In the second study, a randomized clinical trial showed the following relevant findings: 1) a statistically significant decrease in tonic cold pain intensity following active direct current stimulation applied at the suboccipital level (SO-DCS, p=0.011, mean [SD]: -0.76 ± 0.88 points) and active direct current stimulation applied at the primary motor cortex level (M1-DCS, p<0.002: -0.84 ± 0.82 points). Nevertheless, no interaction was found between active or control stimulation with the site of stimulation at M1 or SO. 2) The heterotopic conditioned pain modulation (CPM) protocol was not affected by either application of M1-DCS or SO-DCS (p > 0.05). 3) No significant differences were found in PPTs after the application of active M1-DCS or SO-DCS (p > 0.05). Finally in the third observational cross-sectional pilot study the following findings were found: 1) PPTs were significantly increased 12.5% just after the application of the tonic heat pain conditioning stimulus (mean difference = - 2.48 N, CI = - 4.1 to - 0.9 N, p <0.01) in the homotopic CPM group. 2) No significant change in PPT was detected with in the heterotopic CPM group following application of the cold pressor test as the conditioning stimulus (mean difference=1.5 N, CI = - 0.2 to 3.2 N, p > 0.05). Conclusions The results presented in this thesis suggest that transcranial motor cortex and suboccipital DCS can modulate the perception of painful thermal sensory stimuli and the intensity of pain perceived as rated with the VAS. However, both the systematic review and clinical trial failed to show modulation of PPT, TS and CPM. In addition, the pilot CPM protocol developed in in healthy participants could be now adapted for patients with high spinal cord injury and trigeminal disorders, which will be useful in future research studies that evaluate the state of endogenous pain modulation system in pathological conditions.