Jorge Ortega-Márquez

Background/Objectives: Needle procedures cause acute pain through mechanical, chemical, sensory, and affective processes. We synthesized human and animal evidence and developed a framework spanning peripheral nociception, spinal/trigeminal modulation, central processing, and clinical outcomes. Methods: This PRISMA 2020 review was registered in PROSPERO (CRD420261477391). PubMed/MEDLINE, Embase, and Web of Science were searched from inception through June 2026. Eligible studies examined pain or mechanistic outcomes during needle procedures. Evidence was classified as peripheral, central, or mixed. Human comparisons were pooled as Hedges’ g using random-effects models. Results: Thirty-five studies were included: 18 peripheral (51.4%), 13 mixed central peripheral (37.1%), and four central (11.4%). Larger-diameter needles increased pain (painful insertions: 63% with 23-gauge versus 31% with 32-gauge; p < 0.001), while bevel geometry, injection pressure, and volume further modulated pain. A 1600 µL volume produced 7.2 mm more pain on a 100 mm scale than smaller volumes (p < 0.001). Warming local anesthetic reduced pain from 35.3 to 15.0 mm (p < 0.001). Counter stimulation, vibration, cold, distraction, virtual reality, and controlled or automated delivery reduced pain, anxiety, and autonomic responses. Across seven comparisons (625 participants), interventions reduced pain overall (Hedges’ g, −0.86; 95% CI, −1.71 to −0.02; I² = 77.5%), with differences by nervous-system level (central, −1.65 [−2.60 to −0.70]; peripheral, −1.46 [−4.92 to 1.99]; mixed, −0.36 [−0.99 to 0.28]; subgroup p = 0.018). Most studies had moderate risk of bias (62.5%). Conclusions: Needle-related pain is a multilevel process. Mechanism-informed interventions reduce pain, although effects vary by mechanism and context. Future studies should integrate peripheral, behavioral, and central measures and adopt standardized outcomes to identify modifiable targets and support mechanism-informed, patient-centered pain reduction.

Background: Life expectancy for cancer patients has improved due to new therapies, but many survivors experience long-lasting side effects, including cancer-related cognitive impairment (CRCI). CRCI symptoms—such as difficulties with attention, memory, processing speed, fatigue, and concentration—can persist for years post-treatment. While clinical evidence of CRCI exists, its underlying mechanisms and neural correlates remain unclear. This study aimed to identify functional brain networks associated with CRCI in breast cancer (BC) patients using structural and functional neuroimaging data. Methods: We reviewed studies on CRCI-related brain changes assessed via diffusion tensor imaging (DTI, n = 282), voxel-based morphometry (VBM, n = 177), and functional MRI (fMRI, n = 328). Using the Yeo 7-network resting-state functional atlas, we evaluated the overlap between CRCI-related brain alterations and known functional networks. Overlapping percentages were calculated, and statistical independence tests assessed associations between CRCI and specific networks. Results: Based on inclusion criteria, six DTI, six VBM, and ten fMRI studies were selected. Chi-square analyses revealed significant associations between CRCI-related changes and several networks: the Dorsal Attention Network (DAN, χ2 = 17.71, P = .0001), Default Mode Network (DMN, χ2 = 21.08, P = .0000002), Frontoparietal Network (FPN, χ2 = 110.63, P = .000002), and Ventral Attention Network (VAN, χ2 = 8.203, P = .01). Conclusions: Findings highlight network-specific alterations linked to CRCI symptoms in breast cancer survivors. These results enhance understanding of CRCI and may guide targeted therapeutic strategies.

Introduction: Stroke stands as one of the worldwide leading causes of disability, highlighting the need to develop new therapies. Although placebo effects in motor recovery have been reported to produce clinically meaningful improvements, the neural substrates underlying these effects, particularly across different modalities such as open-label and hidden placebo, remain unclear. This study aims to characterise the neurophysiological signatures of hidden and open placebo during motor-cortex stimulation in chronic stroke survivors and its correlation to motor recovery. Methods and analysis: This single-centre, parallel-group, controlled, randomised clinical trial will enrol 56 adults (≥6 months post-stroke) with upper-limb hemiparesis. Participants are block-randomised (2:2:2:1) to (i) open-label placebo tablets, (ii) hidden sham repetitive transcranial magnetic stimulation (rTMS), (iii) no intervention or (iv) active low-frequency (1 Hz) rTMS over the contra lesional primary motor cortex. The primary endpoint is change in frontal alpha asymmetry (FAA) on high-density electroencephalogram from baseline to 2 weeks. Secondary endpoints include β-band premotor-to-M1 coherence and Fugl–Meyer Upper Extremity scores. Exploratory outcomes include additional motor performance measures (Jebsen–Taylor Hand Function Test and Nine-Hole Peg Test), corticospinal excitability (single-pulse and paired-pulse TMS) and patient-reported measures (mood, expectancy and behavioural activation–inhibition), all assessed from baseline to 2 weeks. Analyses will follow an intention-to-treat framework with multivariable regression adjusting for age, sex, stroke severity, lesion location and time since stroke. Ethics and dissemination: The study was conducted in accordance with the Declaration of Helsinki and approved by the Mass General Brigham Institutional Review Board (protocol #2023P000884). All participants will be required to provide informed consent before enrolling in the study. An open-label phase will be offered to participants allocated to any of the groups that received no active intervention (sham rTMS stimulation, open-label placebo or no-intervention groups). This phase will consist of a task-specific, upper-limb, home-based rehabilitation programme. The results of this study will be shared in peer-reviewed journals and presented at scientific conferences. Trial registration number: NCT05832567 .

Background: Placebo effects are well documented in Parkinson’s disease (PD) clinical trials and represent a major methodological challenge in interpreting neuromodulation studies. Although sham stimulation has been associated with clinical improvement, the magnitude, durability, and outcome specificity of placebo-related effects across non-invasive neuromodulation trials remain incompletely characterized. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD1272381). PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library were searched from inception through September 2025. Randomized, sham-controlled trials of non-invasive neuromodulation in adults with PD were included. Results: Seventeen randomized sham-controlled trials (n = 654 participants) involving repetitive transcranial magnetic stimulation and transcranial direct current stimulation were included. Sham stimulation was associated with small but statistically significant improvements in UPDRS Part III (motor examination) at post-intervention and follow-up, whereas no significant placebo-related improvement was observed for UPDRS Total score. Placebo effects were modest and did not increase over time. In contrast, active neuromodulation produced larger and more durable improvements in both UPDRS Total and Part III, with statistically significant effects maintained at follow-up. Conclusions: Placebo effects contribute to short-term clinical improvement in non-invasive neuromodulation trials for PD, particularly for motor examination outcomes, but do not fully account for the sustained benefits observed with active stimulation. Placebo responsiveness is outcome- and time-dependent, underscoring the importance of rigorous trial design, including careful outcome selection, assessment timing, expectancy management, and comparator structures, to accurately estimate neuromodulation efficacy and support clinical translation.

Neuroimaging research depends on registration, the alignment of patients’ brains to a template or standard space, to enable accurate comparisons across individuals. Decades of work have advanced our ability to accurately register typical brains, but registering atypical brains, such as those with injury or highly distorted anatomy, remains a challenge. In particular, registration of perinatal stroke imaging is often complicated by delayed injury identification, which results in imaging obtained during the chronic stage where secondary structural impacts are evident. While analyses in native space can be valuable for subject-specific investigations, group-level studies require registration to a common template space, which enables between-subject comparisons of lesion locations and their network correlates. Although many registration algorithms exist, as do various compensation techniques for focal lesions, it is unclear how effective they are when applied to the highly distorted anatomy often present in this chronic perinatal stroke imaging. Here, we quantitatively and qualitatively compared the performance of three registration algorithms (FNIRT, ANTs, EasyReg) in registering eleven variably distorted brains with perinatal stroke to a standard template using their default lesion-compensation techniques. We also assessed the impact of “brain grafting”, that is, inserting a healthy tissue mask in place of the defined lesion area prior to registration. Our findings show that ANTs and EasyReg are significantly more accurate than FNIRT for chronic perinatal stroke imaging, although all three software packages have marked difficulty with large lesions. Notably, brain grafting significantly improved the lesion mask normalization performance of FNIRT. In light of these comparisons, the recently released EasyReg appears to be an appropriate starting point for registering cohorts with chronic perinatal strokes, but we still emphasize the necessity of consistent visual inspection of registered brains.

Background/Objectives: Haptic technology has transformed interactions between humans and both tangible and virtual environments. Despite its widespread adoption across various industries, the potential therapeutic applications of this technology have yet to be fully explored. Methods: A systematic review of randomized controlled trials (RCTs) and randomized crossover trials was conducted, utilizing databases such as PubMed, Embase, Cochrane Library, and Web of Science. This review included studies reporting clinical applications of haptic technology in rehabilitation, cognition, wellness, and mental health among adult subjects. Results: This systematic review included 34 studies, of which 20 focused on clinical outcomes and 14 on learning clinical skills. The results showed that haptic devices, both robotic and non-robotic, enhance sensorimotor performance and motor function in rehabilitation settings, especially in post-stroke recovery, with reported effect sizes ranging from 0.2 to 0.7. The majority of the haptic technologies reported were integrated into robotic systems (40%). Haptic devices were also reported to improve clinical skills training by providing tactile feedback that enhances procedural performance and trainee self-efficacy. In fact, surgical simulations accounted for 79% of all the modalities used for medical training. Conclusions: This review underscores the potential yet underexplored applications of haptic technology in healthcare, including medical education, rehabilitation, cognition, and mental health. The key limitations of this review include heterogeneity across studies, small sample sizes, and a scarcity of comprehensive, long-term investigations. Therefore, future research should aim to validate these findings further and expand the applications of haptic technology to maximize its utility in the healthcare industry and clinical practice.

Background: Phantom limb pain (PLP) is highly prevalent after amputation. However, the influence of non-painful sensations (PLS) remains unclear. This study examines the PLP-PLS index as a novel tool to differentiate PLP from PLS and explores the association of clinical factors with the index. Methods: We conducted a cross-sectional analysis of baseline data from 112 participants in a previous factorial trial in patients with unilateral traumatic lower limb amputation. Linear regression models were used to examine the associations between the index and various demographic, psychological and clinical factors. Logistic and Poisson regression, and e-value calculation were utilized for sensitivity analyses. Results: Adjusted multivariable linear regression models demonstrated significant associations of phantom movement sensation (β: −1.532; 95% CI: −2.615 to −0.449; p = 0.006) and time since amputation (β: 0.005; 95% CI: 0.0006 to 0.0101; p = 0.026) with the PLP-PLS index. These findings were confirmed by multivariable logistic regression (phantom movement sensation OR: 0.469; 95% CI: 0.200 to 1.099, p = 0.082; time since amputation OR: 1.003; 95% CI: 1.00003 to 1.007; p = 0.048) and sensitivity analyses. Conclusions: Time since amputation and phantom movement sensation likely reflect distinct phenotypes and potential mechanisms for PLP and PLS. The PLP-PLS index is a promising clinical tool for selecting therapies to prevent/treat PLP and for measuring treatment effects to modulate phantom pain. These findings emphasize the importance of understanding the mechanisms underlying PLP and PLS for improving clinical management and guiding future research.