Hui Ming Khoo

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.

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.

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.

Background: Patients' “pain attributions,” or their beliefs about chronic pain causes, critically affect pain experience and recovery, potentially modulating responses to analgesics and psychotropics. Since many pain‐mitigating drugs also impact psychological processes and brain functions underlying these attributions, such processes are relevant targets. The Chronic Pain Attribution Scale (CPAS) by Ashar et al. (2023) quantifies these beliefs. A Japanese version (CPAS‐J) is needed to assess this psychologically relevant construct in Japanese populations. This study aimed to develop and linguistically validate the CPAS‐J. Methods: The CPAS‐J was developed following International Society for Pharmacoeconomics and Outcomes Research guidelines, with permission from the original author. The process included forward translation by eight bilingual medical experts, reconciliation by a pain research team, back‐translation by an independent translator, review by the original author, and a final consensus discussion to establish the definitive CPAS‐J. Results: The linguistic validation identified challenges in distinguishing “cause” from “trigger” in Japanese. To enhance comprehensibility, the team combined “kikkake” (initiating factor) and “gen'in” (broader cause/origin). The finalized CPAS‐J assesses perceived causes of pain. Conclusions: The CPAS‐J was successfully developed through a rigorous process. This tool supports research on pain attributions in Japanese‐speaking populations and may improve our understanding of treatment responses by assessing a key psychological dimension of chronic pain that is linked to brain‐based processes.

Background: Parkinson's disease (PD) often involves motor fluctuations and dyskinesia, which are difficult to manage with medication alone. Conventional deep brain stimulation (cDBS) effectively alleviates symptoms but has limitations, including the challenge of balancing therapeutic effects against potential side effects, as well as limited battery life. To address these issues, adaptive DBS (aDBS) systems, which dynamically adjust stimulation parameters based on real‐time physiological feedback, have attracted growing interest. Objectives: The aim of this study was to assess the efficacy, tolerability, and safety of aDBS in patients with advanced PD over a 1‐year period, using the Movement Disorder Society‐Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) and Parkinson's Disease Questionnaire‐39 (PDQ‐39). Methods: This prospective, single‐arm study involved 19 patients who transitioned from cDBS to aDBS. Baseline assessments were conducted under cDBS, and patients were re‐evaluated 1 year after switching to aDBS. Results: Sixteen patients completed 1 year of aDBS. Significant improvements in motor function, as measured by MDS‐UPDRS Part III scores in the medication‐off/stimulation‐on condition, were observed. Patients with severe baseline wearing‐off showed greater reductions in motor fluctuation (MDS‐UPDRS Part IV) scores. Younger patients showed better quality of life (PDQ‐39) and activity of daily living (MDS‐UPDRS Part II) scores, though overall changes were not statistically significant. Conclusions: aDBS shows promise in managing motor symptoms in PD, particularly in patients with pronounced wearing‐off and younger patients, by dynamically adjusting stimulation parameters. Although further optimization and long‐term studies are necessary, these findings underscore the potential of aDBS to offer personalized treatment options for advanced PD.

In this study, the authors aimed to investigate the efficacy of intrathecal baclofen (ITB) therapy in alleviating intractable spasticity in patients with infantile-onset dentatorubral-pallidoluysian atrophy (DRPLA). Given the lack of effective treatments for the severe spasticity observed in infantile-onset DRPLA patients, this study explored ITB therapy as a potential therapeutic strategy. The authors included 3 patients (2 males and 1 female, aged 9-24 years) diagnosed with infantile-onset DRPLA who underwent ITB pump implantation. All patients exhibited severe spasticity unresponsive to conventional treatments. Patient demographics, clinical history, cytosine-adenine-guanine repeat number, radiological findings, and symptomatic improvements after ITB therapy were recorded and analyzed. The 3 patients demonstrated marked improvement in spasticity following ITB therapy, with significant reductions in modified Ashworth scale score and alleviation of pain, facilitating easier care and improving quality of life. Improvements were also noted in paroxysmal hypertonia frequency, sleep disturbances, and emaciation. ITB therapy significantly reduced intractable spasticity and associated symptoms in patients with infantile-onset DRPLA, offering a promising therapeutic option for this patient population. Further studies are warranted to explore the long-term efficacy and safety of ITB therapy in a larger cohort of DRPLA patients. https://thejns.org/doi/10.3171/CASE24784.

Objective: Discriminating between epileptogenic and physiological ripples in the hippocampus is important for identifying epileptogenic (EP) zones; however, distinguishing these ripples on the basis of their waveforms is difficult. We hypothesized that the nocturnal synchronization of hippocampal ripples and cortical delta power could be used to classify epileptogenic and physiological ripples in the hippocampus.Methods: We enrolled 38 patients with electrodes implanted in the hippocampus or parahippocampal gyrus between April 2014 and March 2023 at our institution. We divided 11 patients (11 hippocampi) who were pathologically diagnosed with hippocampal sclerosis into the EP group and five patients (six hippocampi) with no epileptogenicity in the hippocampus into the nonepileptogenic (NE) group. Hippocampal ripples were detected using intracranial electroencephalography with hippocampal or parahippocampal electrodes. Cortical delta power (0.5–4 Hz) was assessed using cortical electrodes. The Pearson correlation coefficient between the ripple rates and cortical delta power (Corr‐RD) was calculated on the basis of the intracranial electroencephalographic signals recorded each night.Results: Although hippocampal ripples were similar among the EP and NE groups based on their waveforms and frequency properties, the Corr‐RDs in the EP group (mean [standard deviation]: 0.20 [0.049]) were significantly lower than those in the NE group (0.67 [0.070]). On the basis of the minimum Corr‐RDs, the two groups were classified with 94.1% accuracy.Interpretation: Our results demonstrate that the Corr‐RD is a biomarker of hippocampal epileptogenicity.

While electroencephalography (EEG) and magnetoencephalography (MEG) are well-established noninvasive methods in neuroscience and clinical medicine, they suffer from low spatial resolution. Electrophysiological source imaging (ESI) addresses this by noninvasively exploring the neuronal origins of M/EEG signals. Although subcortical structures are crucial to many brain functions and neuronal diseases, accurately localizing subcortical sources of M/EEG remains particularly challenging, and the feasibility is still a subject of debate. Traditional ESIs, which depend on explicitly defined regularization priors, have struggled to set optimal priors and accurately localize brain sources. To overcome this, we introduced a data-driven, deep learning-based ESI approach without the need for these priors. We proposed a four-layered convolutional neural network (4LCNN) designed to locate both subcortical and cortical sources underlying M/EEG signals. We also employed a sophisticated realistic head conductivity model using the state-of-the-art segmentation method of ten different head tissues from individual MRI data to generate realistic training data. This is the first attempt at deep learning-based ESI targeting subcortical regions. Our method showed excellent accuracy in source localization, particularly in subcortical areas compared to other methods. This was validated through M/EEG simulations, evoked responses, and invasive recordings. The potential for accurate source localization of the 4LCNNs demonstrated in this study suggests future contributions to various research endeavors such as the clinical diagnosis, understanding of the pathophysiology of various neuronal diseases, and basic brain functions.