Sham interventions in randomized clinical trials (RCTs) of physical, psychological, and self-management (PPS) therapies for pain are highly variable in design and believed to contribute to poor internal validity. However, it has not been formally tested whether the extent to which sham controls resemble the treatment under investigation consistently affects trial outcomes, such as effect sizes, differential attrition, participant expectancy, and blinding effectiveness. Placebo- or sham-controlled RCTs of PPS interventions of clinical pain populations were searched in 12 databases. The similarity of control interventions to the experimental treatment was rated across 25 features. Meta-regression analyses assessed putative links between employed control interventions, observed effect sizes in pain-related outcomes, attrition, and blinding success. The sample included 198 unique control interventions, dominated by manual therapy and chronic musculoskeletal pain research. Meta-analyses indicated small-to-moderate benefits of active treatments over control interventions, across subgroups of manual therapies, exercise, and rehabilitation, and psychological intervention trials. Multiple meta-regression modelling demonstrated that similarity between sham control and tested interventions predicted variability in pain-related outcomes, attrition, and blinding effectiveness. Influential variables were differences relating to the extent of intervention exposure, participant experience, and treatment environments. The results support the supposed link between blinding methods and effect sizes, based on a large and systematically sourced overview of methods. However, challenges to effective blinding are complex and often difficult to discern from trial reports. Nonetheless, these insights have the potential to change trial design, conduct, and reporting and will inform guideline development.

Blinding is challenging in randomised controlled trials of physical, psychological, and self-management therapies for pain, mainly because of their complex and participatory nature. To develop standards for the design, implementation, and reporting of control interventions in efficacy and mechanistic trials, a systematic overview of currently used sham interventions and other blinding methods was required. Twelve databases were searched for placebo or sham-controlled randomised clinical trials of physical, psychological, and self-management treatments in a clinical pain population. Screening and data extraction were performed in duplicate, and trial features, description of control methods, and their similarity to the active intervention under investigation were extracted (protocol registration ID: CRD42020206590). The review included 198 unique control interventions, published between 2008 and December 2021. Most trials studied people with chronic pain, and more than half were manual therapy trials. The described control interventions ranged from clearly modelled based on the active treatment to largely dissimilar control interventions. Similarity between control and active interventions was more frequent for certain aspects (eg, duration and frequency of treatments) than others (eg, physical treatment procedures and patient sensory experiences). We also provide an overview of additional, potentially useful methods to enhance blinding, as well as the reporting of processes involved in developing control interventions. A comprehensive picture of prevalent blinding methods is provided, including a detailed assessment of the resemblance between active and control interventions. These findings can inform future developments of control interventions in efficacy and mechanistic trials and best-practice recommendations.

Repetitive transcranial stimulation (rTMS) has been shown to produce an analgesic effect and therefore has a potential for treating chronic refractory pain. However, previous studies used various stimulation parameters (including cortical targets), and the best stimulation protocol is not yet identified. The present study investigated the effects of multi-session 20 Hz (2000 pulses) and 5 Hz (1800 pulses) rTMS stimulation of left motor cortex (M1-group) and left dorsolateral prefrontal cortex (DLPFC-group), respectively. The M1-group (n = 9) and DLPFC-group (n = 7) completed 13 sessions of neuronavigated stimulation, while a Sham-group (n = 8) completed seven sessions of placebo stimulation. The outcome was measured using the German Pain Questionnaire (GPQ), Depression, Anxiety and Stress Scale (DASS), and SF-12 questionnaire. Pain perception significantly decreased in the DLPFC-group (38.17%) compared to the M1-group (56.11%) (p ≤ 0.001) on the later sessions. Health-related quality of life also improved in the DLPFC-group (40.47) compared to the Sham-group (35.06) (p = 0.016), and mental composite summary (p = 0.001) in the DLPFC-group (49.12) compared to M1-group (39.46). Stimulation of the left DLPFC resulted in pain relief, while M1 stimulation was not effective. Nonetheless, further studies are needed to identify optimal cortical target sites and stimulation parameters.

Treatment refractory or recurrent trigeminal neuralgia (TN) is a severe chronic pain illness. Single-session repetitive transcranial magnetic stimulation (rTMS) has been shown to elicit analgesic effects in several craniofacial pain syndromes, including TN. However, the safety and long-term effect of multi-session rTMS for TN have yet to be fully explored. In this study, we present a case of a patient with medical treatment-refractory TN after microvascular decompression. The patient volunteered to undergo 73 sessions of 10 Hz rTMS over 23 months. Neurovagination was used for precise localization and stimulation of the hand and face representation at the left motor cortex. The numeric pain intensity scores derived using the visual analog scale served as a daily index of treatment efficacy. The patient experienced a significant weekly reduction in pain scores, cumulating in 70.89% overall pain relief. The medication dosages were reduced and then discontinued toward the end of the intervention period. No severe adverse events were reported. From our results, we can conclude that the longitudinal multi-session application of rTMS over the hand and face area of M1 is a safe and effective method for producing long-lasting pain relief in TN. Using rTMS may thus prove helpful as an adjunct to conventional methods for treating pain in TN.

Background: Chronic intracranial electrical stimulation is now widely used as treatment for drug resistant epilepsy. Subacute neocortical stimulation (SNCS) can also be performed during EEG recordings with intracranial electrodes (iEEG), but its diagnostic value remains largely unknown. Methods: We assessed the effects of SNCS on the frequency of seizures and epileptiform discharges (EDs) during 290 h of iEEG-from 12 patients (6 adults, 6 children) with epilepsy secondary to focal cortical dysplasia (FCD). Results: In 9/12 patients, SNCS periods showed decreased seizure-frequency (Median-73 %, p = 0.0093). At baseline, incidence of EDs were correlated with seizure-frequency (Spearman r = 0.59). However, this correlation disappeared during SNCS and a significant change in the incidence of EDs was observed. In addition, there was a trend towards greater reduction in seizure-frequency during SNCS in patients who underwent surgery. Conclusion: In summary, SNCS can reduce seizure-frequency and changes ED-frequency. The variability in ED changes may be explained by different effects of SNCS depending on electrode location. The magnitude of seizure reduction during SNCS suggests that this technique could contribute to preoperative assessment in epilepsy surgery.

Reasoning is the ability to formulate inferences or conclusions from available information. The two major types, deductive and inductive, are thought to rely on distinct cognitive mechanisms and recruit separate brain areas. Neuroimaging studies yield mixed results; some found the left inferior frontal gyrus (IFG) activations for deductive reasoning and the left dorsolateral prefrontal cortex (DLPFC) for inductive reasoning. This assumption was put to the test in the present study. In two double-blinded, sham-controlled experiments, high-definition transcranial direct current stimulation (HD-tDCS) was used to systematically explore the left IFG’s and DLPFC’s causal role in deductive and inductive reasoning. Participants with no formal training in logic judged deductive and inductive arguments before and after 10 minutes of anodal, cathodal, or sham tDCS of the left IFG (Experiment 1, n = 20) or left DLPFC (Experiment 2, n = 21). Left IFG anodal tDCS impairs reaction times (RTs) for easy categorical (p = < .001) and propositional (p = .025) deductive arguments and the accuracy for easy inductive propositional arguments (p = .003). Meanwhile, regardless of the active stimulation conditions, left DLPFC tDCS shortens RTs (anodal: p = < .001, cathodal: p = .014) and increases accuracy (anodal: p = .029, cathodal: p = .001) for difficult categorical inductive arguments, but decreases accuracy (anodal: p = .027, cathodal: p = < .001) for difficult propositional inductive arguments. The overall results showed a partial dissociation of the left frontal lobe areas subserving the two types of reasoning and argument difficulty-dependent stimulation effects. This study extends knowledge of the neural basis of reasoning and hopefully inspires interventions that could augment reasoning impairments associated with normal aging and brain lesions.