Naoki Tani

Background: Neuropathic pain (NP) remains difficult to manage because conventional pharmacological therapies often have limited efficacy and intolerable side effects. Noninvasive neuromodulation techniques have emerged as potential alternatives with fewer adverse effects. Meta-analyses of randomized controlled trials suggest that high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex has analgesic effects; however, its efficacy is modest and restricted by the inability to stimulate deeper brain regions. Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel approach that enables precise targeting of deep brain structures and modulation of neural activity. Although promising in preclinical and preliminary human studies, its long-term therapeutic efficacy for NP remains unknown. Objective: This trial aims to explore the therapeutic effects and safety of repeated TUS sessions in patients with NP. Methods: This randomized, participant-blinded, placebo-controlled, 3-arm, parallel-group clinical trial will enroll 39 participants with NP (pain duration ≥3 months; pain intensity ≥4 on the numerical rating scale). Participants will be randomly allocated to one of three groups: (1) TUS targeting the primary motor cortex, (2) TUS targeting the posterior superior insula, or (3) sham stimulation. Each participant will undergo weekly sessions for 8 weeks. The primary outcome is change in weekly average pain intensity scores recorded in a pain diary. Secondary outcomes include additional pain scales, quality of life measures, psychological assessments, quantitative sensory testing, motor cortical excitability, and adverse events. Results: The first participant was enrolled on April 30, 2025, and 20 participants had been enrolled as of February 28, 2026, with enrollment ongoing. The final analysis will be conducted after completion of follow-up and data verification. Conclusions: To our knowledge, this will be the first randomized controlled trial to examine the long-term therapeutic effects of repeated low-intensity TUS for NP. It will provide exploratory proof-of-concept data regarding its clinical efficacy and safety.

Digger wasps are solitary apoid wasps that excavate ground nests and use venom to paralyze insect prey. Recent phylogenetic analyses suggest that digger wasps belong to an ancient lineage of aculeate Hymenoptera and share an evolutionary ancestry with other venomous hymenopterans, including bees and ants. Although the venoms of ants, bees, and social wasps have been extensively studied, those of digger wasps remain poorly characterized in terms of their composition, molecular diversity, and biological activity. In this study, we investigated the venom of the digger wasp Cerceris japonica using integrated transcriptomic and proteomic analyses. We identified 19 toxin-like proteins and peptides, 14 non-toxin-associated components, and 11 novel peptides and proteins with no detectable similarity to known peptides and proteins. Among these, peptide Cj 2 exhibited insecticidal activity but showed no antimicrobial, hemolytic, or nicotinic acetylcholine receptor-modulating activities. These findings provide new insights into the molecular diversity and biological activities of digger wasp venom, expand our understanding of venom evolution in venomous hymenopterans, and serve as a framework for elucidating the conserved and lineage-specific features of hymenopteran venoms.

BACKGROUND AND OBJECTIVES: Placement of stereotactic electroencephalography (SEEG) electrodes involves insertion of an obturator toward the target under image guidance without direct vision. Thus, tactile feedback during obturator manipulation is key to avoiding complications. Resistance encountered during advancement of the obturator that hinders planned electrode placement has prompted us to investigate the factors contributing to this resistance. METHODS: We analyzed 168 trajectories in 24 consecutive patients who underwent SEEG electrode placement between May 2019 and March 2023: 135 were placed using a 1.5-mm obturator and 33 were placed using a 0.86-mm obturator. The depth at which resistance was encountered was documented intraoperatively and compared with the preplanned trajectory to determine the structure where resistance occurred. Factors that may contribute to resistance were analyzed. RESULTS: Resistance was encountered in a total of 22 trajectories: 19 from the 1.5-mm obturator group and 3 from the 0.86-mm obturator group. Sulcal bank penetration was observed in 15 trajectories (68%) with resistance and in 42/146 trajectories (29%) without resistance. Sulcal bank penetration contributed most to resistance, more than lesion presence or trajectory length. In the 1.5-mm obturator group, insertion angles differed between trajectories with and without resistance (37.1° ± 19.0 vs 58.8° ± 15.5, 95% CI = 11.8-31.6, P = .000055). The difference remained significant when considering all pia penetrations, including at the cortical surface (37.6° ± 18.5 vs 66.1° ± 13.3, 95% CI = 21.3-35.5, P = 2.19 × 10 ⁻¹³ ). CONCLUSION: Sulcal bank penetration is the main factor contributing to resistance; resistance risk increases as the insertion angle decreases. Our findings guide forecasting resistance during sulci-traversing in SEEG electrode implantation, which may be unavoidable for optimal gray matter coverage, although forceful advancement against resistance should be avoided to minimize hemorrhagic risks.

BACKGROUND: Holmes tremor (HT) is a symptomatic tremor that develops weeks to years after stroke, traumatic brain injury, or brain tumor and is characterized by low-frequency, high-amplitude movements at rest, during posture, and with intentional movement. It is thought to result from lesions involving the dopaminergic nigrostriatal system, Guillain-Mollaret triangle, or dentato-rubro-thalamic tract. Because HT is often drug resistant, stereotactic procedures targeting the thalamus are considered. While deep brain stimulation for HT shows long-term efficacy, evidence for radiofrequency thalamotomy remains limited. OBSERVATIONS: An 18-year-old right-handed male developed a coarse tremor of the right hand 1 year after a severe traumatic brain injury at age 16. MRI revealed bilateral cerebellar dentate nucleus hemorrhage, diffuse axonal injury in the left thalamus, and multiple contusions. A diagnosis of posttraumatic HT due to right dentate and left thalamic lesions was made, and ventral intermediate nucleus (Vim) thalamotomy was performed because the tremor was refractory to medication. Tremor improvement was maintained for 18 months postoperatively, with marked enhancement of daily activities and an expansion of the ability to handle various daily tasks. LESSONS: This case illustrates that Vim thalamotomy remains a relevant and effective treatment option for HT. https://thejns.org/doi/10.3171/CASE2675

We investigated how subthalamic local field potentials evolve as the microlesion effect emerges and wanes after electrode implantation in Parkinson's disease. Thirteen patients underwent repeated resting recordings that were analyzed across six predefined postoperative periods (days 0-6, 7-30, 31-90, 91-180, 181-365, and ≥366). Power spectral density (1-50 Hz) was decomposed into periodic and aperiodic components. Period-wise changes were tested with nonparametric within-subject analyses, and spatial differences across sensing-electrode pairs were evaluated with population-averaged regression under multiplicity control. Total local field potential power and aperiodic parameters (offset and exponent) followed an inverted-U trajectory, peaking at 31-90 days and declining by ≥12 months. In contrast, periodic beta power (13-30 Hz) increased from approximately 1-3 months onward and remained elevated at 6-12 months, resulting in a higher periodic-to-total beta ratio in late windows. Spatially, periodic beta was maximal over more dorsal, putative sensorimotor territories, whereas the aperiodic exponent was relatively larger ventrally, indicating distinct topographies of oscillatory versus aperiodic activity. Clinically, Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III improved at 6 months with partial attenuation by 12 months; time-matched correlations with electrophysiological metrics did not survive multiple-comparison adjustment. These findings suggest that the microlesion initially suppresses oscillatory beta more than broadband activity, with a later relative prominence of the periodic component, and that spatial dissociation between periodic and aperiodic features may inform biomarker selection and contact targeting for adaptive stimulation.

The development of algorithms to accurately decode neural information has long been a research focus in the field of neuroscience. Brain decoding typically involves training machine learning models to map neural data onto a preestablished vector representation of stimulus features. These vectors are usually derived from image- and/or text-based feature spaces. Nonetheless, the intrinsic characteristics of these vectors might fundamentally differ from those that are encoded by the brain, limiting the ability of decoders to accurately learn this mapping. To address this issue, we propose a framework, called brain-aligning of semantic vectors, that fine-tunes pretrained feature vectors to better align with the structure of neural representations of visual stimuli in the brain. We trained this model with functional magnetic resonance imaging (fMRI) and then performed zero-shot brain decoding on fMRI, magnetoencephalography (MEG), and electrocorticography (ECoG) data. fMRI-based brain-aligned vectors improved decoding performance across all three neuroimaging datasets when accuracy was determined by calculating the correlation coefficients between true and predicted vectors. Additionally, when decoding accuracy was determined via stimulus identification, this accuracy increased in specific category types; improvements varied depending on the original vector space that was used for brain-alignment, and consistent improvements were observed across all neuroimaging modalities.

Introduction: Neuropathic pain (NP) remains difficult to manage because conventional pharmacological therapies often have limited efficacy and intolerable side effects. Non-invasive neuromodulation techniques have emerged as potential alternatives with fewer adverse effects. Meta-analyses of randomised controlled trials suggest that high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex has analgesic effects; however, its efficacy is modest and restricted by the inability to stimulate deeper brain regions. Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel approach that enables precise targeting of deep brain structures and modulation of neural activity. Although promising in preclinical and preliminary human studies, its long-term therapeutic efficacy for NP remains unknown. This trial aims to evaluate the therapeutic effects and safety of repeated TUS sessions in patients with NP. Methods and analysis: This randomised, participant-blinded, placebo-controlled, three-arm, parallel-group clinical trial will enrol 39 participants with NP (pain duration ≥ 3 months; pain intensity ≥ 4 on the Numerical Rating Scale). Participants will be randomly allocated to one of three groups: (1) TUS targeting the primary motor cortex, (2) TUS targeting the posterior superior insula, or (3) sham stimulation. Each participant will undergo weekly sessions for eight weeks. The primary outcome is change in weekly average pain intensity scores recorded in a pain diary. Secondary outcomes include additional pain scales, quality of life measures, psychological assessments, quantitative sensory testing, motor cortical excitability, and adverse events. Ethics and dissemination: The protocol has been approved by the University of Osaka Clinical Research Review Board. Written informed consent will be obtained from all participants. Findings will be disseminated via scientific presentations and peer-reviewed publications. Trial registration number: jRCTs052240227 STRENGTHS AND LIMITATIONS OF THIS STUDY: ⇒ This is the first randomised, participant-blinded, placebo-controlled clinical trial evaluating the long-term effects of transcranial focused ultrasound stimulation (TUS) for neuropathic pain. ⇒ TUS is a novel, non-invasive technique that can precisely target deep brain areas using a navigation system, offering the potential to modulate brain function. ⇒ The single-blind design (participants only) may introduce a risk of performance bias, as operators cannot be blinded owing to technical constraints. ⇒ The small sample size may limit statistical power to detect subtle between-group differences.