RICARDO GALHARDONI
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- Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression(2016) VERONEZI, B. P.; MOFFA, A. H.; CARVALHO, A. F.; GALHARDONI, R.; SIMIS, M.; BENSENOR, I. M.; LOTUFO, P. A.; MACHADO-VIEIRA, R.; DASKALAKIS, Z. J.; BRUNONI, A. R.Objective: Major depressive disorder (MDD) is a clinically heterogeneous condition. However, the role of cortical glutamate and gamma-aminobutyric acid (GABA) receptor-mediated activity, implicated in MDD pathophysiology, has not been explored in different MDD subtypes. Our aim was to assess the atypical and melancholic depression subtypes regarding potential differences in GABA and glutamate receptor-mediated activity through established transcranial magnetic stimulation (TMS) neurophysiological measures from the motor cortex. Method: We evaluated 81 subjects free of antidepressant medication, including 21 healthy controls and 20 patients with atypical, 20 with melancholic, and 20 with undifferentiated MDD. Single and paired-pulse TMS paradigms were used to evaluate intracortical facilitation (ICF), cortical silent period (CSP), and short intracortical inhibition (SICI), which index glutamate, GABA(B) receptor-, and GABA(A) receptor-mediated activity respectively. Results: Patients with MDD demonstrated significantly decreased mean CSP values than healthy controls (Cohen's d = 0.22-0.3, P < 0.01 for all comparisons). Atypical depression presented a distinct cortical excitability pattern of decreased cortical inhibition and increased cortical facilitation, that is, an increased mean ICF and SICI ratios than other depression subtypes (d = 0.22-0.33, P < 0.01 for all comparisons). Conclusion: Different MDD subtypes may demonstrate different neurophysiology in relation to GABA(A) and glutamatergic activity. TMS as an investigational tool might be useful to distinguish between different MDD subtypes.
- Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial(2016) ATTAL, Nadine; ANDRADE, Daniel C. de; ADAM, Frederic; RANOUX, Daniele; TEIXEIRA, Manoel J.; GALHARDONI, Ricardo; RAICHER, Irina; UECEYLER, Nurcan; SOMMER, Claudia; BOUHASSIRA, DidierBackground Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain. Methods We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Pare Hospital, APHP, Boulogne-Billancourt, and Neurological Centre, Hopital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clinicas da FMUSP, Sao Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211. Findings Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0.77, 95% CI -0.95 to -0.59; p<0.0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1.0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0.8). Interpretation Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further.
- Subthalamic deep brain stimulation modulates conscious perception of sensory function in Parkinson's disease(2016) CURY, Rubens G.; GALHARDONI, Ricardo; TEIXEIRA, Manoel J.; GHILARDI, Maria G. dos Santos; SILVA, Valquiria; MYCZKOWSKI, Martin L.; MARCOLIN, Marco A.; BARBOSA, Egberto R.; FONOFF, Erich T.; ANDRADE, Daniel Ciampi deSubthalamic deep brain stimulation (STN-DBS) is used to treat refractory motor complications in Parkinson disease (PD), but its effects on nonmotor symptoms remain uncertain. Up to 80% of patients with PD may have pain relief after STN-DBS, but it is unknown whether its analgesic properties are related to potential effects on sensory thresholds or secondary to motor improvement. We have previously reported significant and long-lasting pain relief after DBS, which did not correlate with motor symptomatic control. Here we present secondary data exploring the effects of DBS on sensory thresholds in a controlled way and have explored the relationship between these changes and clinical pain and motor improvement after surgery. Thirty-seven patients were prospectively evaluated before STN-DBS and 12 months after the procedure compared with healthy controls. Compared with baseline, patients with PD showed lower thermal and mechanical detection and higher cold pain thresholds after surgery. There were no changes in heat and mechanical pain thresholds. Compared with baseline values in healthy controls, patients with PD had higher thermal and mechanical detection thresholds, which decreased after surgery toward normalization. These sensory changes had no correlation with motor or clinical pain improvement after surgery. These data confirm the existence of sensory abnormalities in PD and suggest that STN-DBS mainly influenced the detection thresholds rather than painful sensations. However, these changes may depend on the specific effects of DBS on somatosensory loops with no correlation to motor or clinical pain improvement.
conferenceObject Deep brain stimulation of the dentate nucleus improves ataxia and modulates cortical excitability(2016) FRANCA, C. C.; TEIXEIRA, M. J.; ANDRADE, D. Ciampi de; GALHARDONI, R.; BARBOZA, V. R.; SILVA, V.; LEPSKI, G.; BARBOSA, E. R.; CURY, R. G.- Sensory abnormalities and pain in Parkinson disease and its modulation by treatment of motor symptoms(2016) CURY, R. G.; GALHARDONI, R.; FONOFF, E. T.; LLORET, S. Perez; GHILARDI, M. G. dos Santos; BARBOSA, E. R.; TEIXEIRA, M. J.; ANDRADE, D. Ciampi dePain and sensory abnormalities are present in a large proportion of Parkinson disease (PD) patients and have a significant negative impact in quality of life. It remains undetermined whether pain occurs secondary to motor impairment and to which extent it can be relieved by improvement of motor symptoms. The aim of this review was to examine the current knowledge on the mechanisms behind sensory changes and pain in PD and to assess the modulatory effects of motor treatment on these sensory abnormalities. A comprehensive literature search was performed. We selected studies investigating sensory changes and pain in PD and the effects of levodopa administration and deep brain stimulation (DBS) on these symptoms. PD patients have altered sensory and pain thresholds in the off-medication state. Both levodopa and DBS improve motor symptoms (i.e.: bradykinesia, tremor) and change sensory abnormalities towards normal levels. However, there is no direct correlation between sensory/pain changes and motor improvement, suggesting that motor and non-motor symptoms do not necessarily share the same mechanisms. Whether dopamine and DBS have a real antinociceptive effect or simply a modulatory effect in pain perception remain uncertain. These data may provide useful insights into a mechanism-based approach to pain in PD, pointing out the role of the dopaminergic system in pain perception and the importance of the characterization of different pain syndromes related to PD before specific treatment can be instituted.
- Normative data of cortical excitability measurements obtained by transcranial magnetic stimulation in healthy subjects(2016) CUEVA, Ana Sofia; GALHARDONI, Ricardo; CURY, Rubens Gisbert; PARRAVANO, Daniella Cardoso; CORREA, Guilherme; ARAUJO, Haniel; CECILIO, Sofia Barros; RAICHER, Irina; TOLEDO, Diego; SILVA, Valquiria; MARCOLIN, Marco Antonio; TEIXEIRA, Manoel Jacobsen; ANDRADE, Daniel Ciampi deObjectives. - To obtain normative data for CE measurements by transcranial magnetic stimulation, to assess inter- /intra-investigator variability and the influence of sex, age and oral contraception use. Methods. - A sample of 216 healthy volunteers matched according to age and gender was evaluated. Bilateral rest motor thresholds, motor evoked potentials (MEP), intracortical inhibition and facilitation were measured in the first dorsal interosseous muscle area representation of the primary motor cortex with a circular transcranial magnetic stimulation coil delivering biphasic pulses. Normative data were obtained for 200 participants (in a 1:1 male:female ratio) in a balanced proportion between five age groups (18-30; 31-40; 41-50; 51-60; > 60 years). Inter/intra-investigator variability was assessed in 20 healthy volunteers in two sessions performed within a 30-minute interval. Measurements were also performed in a subgroup of 16 healthy female volunteers, using oral contraception and during the menstrual phase. Results. - Age had a dichotomous effect on CE measurements, providing significantly different normative data for subjects < 50 and > 50 years old, with smaller MEP's and intracortical inhibition in older individuals. There were no differences between genders or between left and right hemispheres. Also, CE parameters did not significantly differ with use of contraceptive treatment compared to the menstrual phase of the cycle. The inter-/intra-investigator reliability assessment showed some variability that may not be clinically significant. Conclusions. - Age had a non-linear effect on CE. There were non-significant differences between genders, hemispheres or with use of oral contraceptives. There was good inter- /intra-investigator correlation for rest motor thresholds and motor evoked potentials while intracortical inhibition and facilitation had low correlations but acceptable reliability. 2016 Elsevier Masson SAS. All rights reserved.