Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) is moderately effective for depression when applied by trained staff. It is not known whether self-applied tDCS, combined or not with a digital psychological intervention, is also effective. Objective: To determine whether fully unsupervised home-use tDCS, combined with a digital psychological intervention or digital placebo, is effective for a major depressive episode. Design, Setting, and Participants: This was a double-blinded, sham-controlled, randomized clinical trial with 3 arms: (1) home-use tDCS plus a digital psychological intervention (double active); (2) home-use tDCS plus digital placebo (tDCS only), and (3) sham home-use tDCS plus digital placebo (double sham). The study was conducted between April 2021 and October 2022 at participants' homes and at Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Included participants were aged 18 to 59 years with major depression and a Hamilton Depression Rating Scale, 17-item version (HDRS-17), score above 16, a minimum of 8 years of education, and access to a smartphone and internet at home. Exclusion criteria were other psychiatric disorders, except for anxiety; neurologic or clinical disorders; and tDCS contraindications. Interventions: tDCS was administered in 2-mA, 30-minute prefrontal sessions for 15 consecutive weekdays (1-mA, 90-second duration for sham) and twice-weekly sessions for 3 weeks. The digital intervention consisted of 46 sessions based on behavioral therapy. Digital placebo was internet browsing. Main Outcomes and Measures: Change in HDRS-17 score at week 6. Results: Of 837 volunteers screened, 210 participants were enrolled (180 [86%] female; mean [SD] age, 38.9 [9.3] years) and allocated to double active (n = 64), tDCS only (n = 73), or double sham (n = 73). Of the 210 participants enrolled, 199 finished the trial. Linear mixed-effects models did not reveal statistically significant group differences in treatment by time interactions for HDRS-17 scores, and the estimated effect sizes between groups were as follows: double active vs tDCS only (Cohen d, 0.05; 95% CI, -0.48 to 0.58; P = .86), double active vs double sham (Cohen d, -0.20; 95% CI, -0.73 to 0.34; P = .47), and tDCS only vs double sham (Cohen d, -0.25; 95% CI, -0.76 to 0.27; P = .35). Skin redness and heat or burning sensations were more frequent in the double active and tDCS only groups. One nonfatal suicide attempt occurred in the tDCS only group. Conclusions and Relevance: Unsupervised home-use tDCS combined with a digital psychological intervention or digital placebo was not found to be superior to sham for treatment of a major depressive episode in this trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04889976.

Dissecting neuropathic from poststroke pain: the white matter within.

ABSTRACT: Poststroke pain (PSP) is a heterogeneous term encompassing both central neuropathic (ie, central poststroke pain [CPSP]) and nonneuropathic poststroke pain (CNNP) syndromes. Central poststroke pain is classically related to damage in the lateral brainstem, posterior thalamus, and parietoinsular areas, whereas the role of white matter connecting these structures is frequently ignored. In addition, the relationship between stroke topography and CNNP is not completely understood. In this study, we address these issues comparing stroke location in a CPSP group of 35 patients with 2 control groups: 27 patients with CNNP and 27 patients with stroke without pain. Brain MRI images were analyzed by 2 complementary approaches: an exploratory analysis using voxel-wise lesion symptom mapping, to detect significant voxels damaged in CPSP across the whole brain, and a hypothesis-driven, region of interest-based analysis, to replicate previously reported sites involved in CPSP. Odds ratio maps were also calculated to demonstrate the risk for CPSP in each damaged voxel. Our exploratory analysis showed that, besides known thalamic and parietoinsular areas, significant voxels carrying a high risk for CPSP were located in the white matter encompassing thalamoinsular connections (one-tailed threshold Z > 3.96, corrected P value <0.05, odds ratio = 39.7). These results show that the interruption of thalamocortical white matter connections is an important component of CPSP, which is in contrast with findings from nonneuropathic PSP and from strokes without pain. These data can aid in the selection of patients at risk to develop CPSP who could be candidates to pre-emptive or therapeutic interventions.

Sorting pain out of salience: assessment of pain facial expressions in the human fetus.

INTRODUCTION: The question of whether the human fetus experiences pain has received substantial attention in recent times. With the advent of high-definition 4-dimensional ultrasound (4D-US), it is possible to record fetal body and facial expressions. OBJECTIVE: To determine whether human fetuses demonstrate discriminative acute behavioral responses to nociceptive input. METHODS: This cross-sectional study included 5 fetuses with diaphragmatic hernia with indication of intrauterine surgery (fetoscopic endoluminal tracheal occlusion) and 8 healthy fetuses, who were scanned with 4D-US in 1 of 3 conditions: (1) acute pain group: Fetuses undergoing intrauterine surgery were assessed in the preoperative period during the anesthetic injection into the thigh; (2) control group at rest: Facial expressions at rest were recorded during scheduled ultrasound examinations; and (3) control group acoustic startle: Fetal facial expressions were recorded during acoustic stimulus (500-4000 Hz; 60-115 dB). RESULTS: Raters blinded to the fetuses' groups scored 65 pictures of fetal facial expressions based on the presence of 12 items (facial movements). Analyses of redundancy and usefulness excluded 5 items for being of low discrimination capacity (P>0.2). The final version of the pain assessment tool consisted of a total of 7 items: brow lowering/eyes squeezed shut/deepening of the nasolabial furrow/open lips/horizontal mouth stretch/vertical mouth stretch/neck deflection. Odd ratios for a facial expression to be detected in acute pain compared with control conditions ranged from 11 (neck deflection) to 1,400 (horizontal mouth stretch). Using the seven-item final tool, we showed that 5 is the cutoff value discriminating pain from nonpainful startle and rest. CONCLUSIONS: This study inaugurates the possibility to study pain responses during the intrauterine life, which may have implications for the postoperative management of pain after intrauterine surgical interventions.

Balloon compression vs radiofrequency for primary trigeminal neuralgia: a randomized, controlled trial.

ABSTRACT: Surgical procedures are necessary in up to 50% of trigeminal neuralgia patients. Although radiofrequency (RF) is more widely used, it is associated with high intraprocedural costs and long technical learning time. Other simpler procedures such as balloon compression (BC) require a lower training period and have significant lower costs. We evaluated the effects of BC and RF in pain control in primary trigeminal neuralgia in a randomized, double-blinded, head-to-head trial. Individuals were randomly allocated in 1 of 2 groups: BC and RF. Throughout pain, psychological and quality of life measurements were performed at baseline and after surgery. The main outcome was the worst pain in the last 24 hours (0-10) at 6 months postoperatively. After the inclusion of half of the estimated sample, a preplanned interim analysis was performed when 33 patients (62.1 ± 9.4 y.) completed the study. Pain intensity (confidence interval [CI] 95% 0.6 to 3.8, and -0.6 to 2.2, for BC and RF) did not significantly differ. Complications, interference of pain in daily life (CI 95% -0.1 to 2.3 and -0.4 to 2.3, for BC and RF), neuropathic pain symptoms (CI 95% 1.7 to 3.6 and 3.0 to 5.7, for BC and RF), mood (CI 95% 4.8 to 11.5 and 5.5 to 15.1, BC and RF, respectively), medication use, and quality of life (CI 95% 80.4 to 93.1 and 83.9 to 94.2, for BC and RF) were also not different. Radiofrequency presented more paresthetic symptoms than BC at 30 days after intervention. Based on these results, the study was halted due to futility because BC was not superior to RF.

Posterior-superior insular deep transcranial magnetic stimulation alleviates peripheral neuropathic pain - A pilot double-blind, randomized cross-over study.

OBJECTIVES: Peripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief. METHODS: We explored the intensity and short-term duration of the analgesic effects produced in pNeP patients by 5 days of neuronavigated deep rTMS targeting the posterior superior insula (PSI) with a double-cone coil in a sham-controlled randomized cross-over trial. RESULTS: Thirty-one pNeP patients received induction series of five active or sham consecutive sessions of daily deep-rTMS to the PSI in a randomized sequence, with a washout period of at least 21 days between series. The primary outcome [number of responders (>50% pain intensity reduction from baseline in a numerical rating scale ranging from 0 to 10)] was significantly higher after real (58.1%) compared to sham (19.4%) stimulation (p = 0.002). The number needed to treat was 2.6, and the effect size was 0.97 [95% CI (0.6; 1.3)]. One week after the 5th stimulation day, pain scores were no longer different between groups, and no difference in neuropathic pain characteristics and interference with daily living were present. No major side effects occurred, and milder adverse events (i.e., short-lived headaches after stimulation) were reported in both groups. Blinding was effective, and analgesic effects were not affected by sequence of the stimulation series (active-first or sham-first), age, sex or pain duration of participants. DISCUSSION: PSI deep-rTMS was safe in refractory pNeP and was able to provide significant pain intensity reduction after a five-day induction series of treatments. Post-hoc assessment of neuronavigation targeting confirmed deep-rTMS was delivered within the boundaries of the PSI in all participants. CONCLUSION: PSI deep-rTMS provided significant pain relief during 5-day induction sessions compared to sham stimulation.

Sifting the wheat from the chaff? Evidence for the existence of an asymmetric fibromyalgia phenotype.

BACKGROUND: The different phenotypic presentations of fibromyalgia (FM) have been infrequently studied and may have diagnostic and therapeutic implications. The aim of this study was to explore differences between FM patients with classical symmetric (s-FM) presentation and FM patients with marked asymmetric (a-FM) pain. METHODS: We performed two consecutive cross-sectional studies on FM patients and matched healthy volunteers (HV). FM patients were divided into a-FM (and s-FM groups according to their score of pain intensity on each body side; patients with a difference of ≥40 mm in VAS between left and right sides were classified as a-FM, otherwise classified as s-FM. Participants (FM = 32; HV = 31) were assessed for clinical, cortical excitability (CE), quantitative sensory testing (QST; study 1), and intraepidermal nerve fibre density (IENFD) determinations (study 2). RESULTS: While pain intensity did not significantly differ between s-FM and a-FM patients, pain interference in daily activities was significantly higher in the a-FM as compared to the s-FM group (54.7 ± 8.9 and 37.6 ± 13.5; p < .0001). PPT was significantly lower in the more painful side of a-FM as compared to the HV (27.7 ± 7.9 and 49.9 ± 13.0; p < .0001), while PPT in the less painful side of a-FM was significantly higher than PPT values in the s-FM (35.8 ± 8.3 and 27.7 ± 5.5; p = .031). S-FM and a-FM had significantly abnormal intracortical inhibition values on CE measurements compared to HV. There were no significant differences in IENFD between groups. CONCLUSIONS: Within the current FM criteria, there exist different phenotypes with clinical, psychophysics, and neurophysiological findings that are not related to peripheral IENFD abnormalities. SIGNIFICANCE: Current fibromyalgia criteria may contain different phenotypes of fibromyalgia based on the lateralization of pain.

Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain.

OBJECTIVE: To compare the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) repetitive (r) transcranial magnetic stimulation (TMS) in patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. METHODS: Participants were randomly allocated into the active PSI-rTMS, ACC-rTMS, sham-PSI-rTMS, or sham-ACC-rTMS arms. Stimulations were performed for 12 weeks, and a comprehensive clinical and pain assessment, psychophysics, and cortical excitability measurements were performed at baseline and during treatment. The main outcome of the study was pain intensity (numeric rating scale [NRS]) after the last stimulation session. RESULTS: Ninety-eight patients (age 55.02 ± 12.13 years) completed the study. NRS score was not significantly different between groups at the end of the study. Active rTMS treatments had no significant effects on pain interference with daily activities, pain dimensions, neuropathic pain symptoms, mood, medication use, cortical excitability measurements, or quality of life. Heat pain threshold was significantly increased after treatment in the PSI-dTMS group from baseline (1.58, 95% confidence interval [CI] 0.09-3.06]) compared to sham-dTMS (-1.02, 95% CI -2.10 to 0.04, p = 0.014), and ACC-dTMS caused a significant decrease in anxiety scores (-2.96, 95% CI -4.1 to -1.7]) compared to sham-dTMS (-0.78, 95% CI -1.9 to 0.3; p = 0.018). CONCLUSIONS: ACC- and PSI-dTMS were not different from sham-dTMS for pain relief in CNP despite a significant antinociceptive effect after insular stimulation and anxiolytic effects of ACC-dTMS. These results showed that the different dimensions of pain can be modulated in humans noninvasively by directly stimulating deeper SNC cortical structures without necessarily affecting clinical pain per se. CLINICALTRIALSGOV IDENTIFIER: NCT01932905.

Not just a matter of pain intensity: Effects of three different conditioning stimuli on conditioned pain modulation effects.

INTRODUCTION: Heterotopic conditioned pain modulation (CPM) has provided potentially useful clinical information such as response to medication in neuropathic pain or the prediction of pain after surgical procedures. Despite these advances, several methodological aspects of CPM remain to be determined, such as the impact of the conditioning stimulus (CS) type upon CPM, if its evoked-pain intensity is controlled for [measured on a visual analogue scale (VAS: 0-100mm)]. OBJECTIVES: To explore potential differential effects of CPM using three distinct CS (having similar evoked-pain intensity) in the same individuals. METHODS: We conducted a cross-over randomized study in healthy volunteers (HV) and looked-for differences in the CPM effect evoked by three differing CS [cuff-pressure pain stimulation (CuPS), cold pressor test (CoPT), and thermode-based cold painful stimulation (TCPS)] on the same test stimulus [(TS)-supra-threshold heat pain stimulation with a contact-heat thermode). CPM was calculated as a ratio: [conditioned TS VAS - unconditioned TS VAS]/[unconditioned TS VAS]. Importantly, the range of pain evoked by the unconditioned-TS and by the CS was controlled for. Also, the unpleasantness evoked by the CS [visual analogue scale (VAS: 0-100mm)] was measured before the initiation of the conditioned-TS. RESULTS: Pain intensity VAS of the three unconditioned-TSs were similar between the three sessions. CPM was significantly different between the three types of CS (CoPT=-0.43±0.29; CuPS=-0.25±0.24; and TCPS=-0.23±0.35; P=.005): CoPT induced significantly more robust CPM compared to CuPS (P=.004) and TCPS (P=.005). CONCLUSIONS: Significantly different intensities of CPM can be evoked on the same individual according to the nature of the CS, even when controlling for the intensity of the unconditioned-TS, and the pain evoked by the CS. This may have implications for the design of future recommendations and may impact the translation of CPM from the laboratory to clinical practice.