Structured Abstract: Rhythmic lower-limb movements require precise coordination across multiple joints, a process in which the cerebellum is thought to play a critical role. This study investigated whether cerebellar neuromodulation synchronized with mechanical ankle assistance modulates use-dependent motor adaptation during cyclic movement in healthy young adults. A portable ankle-assist ergometer delivered phase-specific dorsiflexion torque during cycling, and participants completed three within-subject conditions: Sham stimulation, synchronized transcranial alternating current stimulation (tACS), and unsynchronized tACS. Ankle dorsiflexion angle and tibialis anterior muscle activity were assessed before, during, and after a 6-min assistance period. Baseline-normalized data were analyzed using linear mixed-effects models across assist and post-assist phases. Synchronized cerebellar stimulation significantly modulated the overall magnitude of the dorsiflexion aftereffect, whereas unsynchronized stimulation did not. In contrast, tibialis anterior muscle activity exhibited robust phase-dependent changes but did not differ across stimulation conditions, indicating that the kinematic modulation was not driven by sustained changes in agonist muscle activation. These findings demonstrate that phase-aligned cerebellar neuromodulation biases adaptive motor output during cyclic lower-limb movement, likely by influencing multijoint coordination and predictive control rather than peripheral muscle recruitment. The combination of a compact ankle-assist ergometer with precisely timed, non-invasive cerebellar stimulation provides an accessible platform for probing and biasing motor adaptation, with potential implications for future lower-limb rehabilitation strategies.
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Pavlovian biases reflect how evolutionarily hard-wired tendencies-automatic approach toward reward cues and withdrawal from threat cues-can interfere with flexible, goal-directed action. Such biases arise through three mechanisms: (a) anticipated rewards energize action while anticipated punishments suppress it (response bias), (b) agents learn differently from actions than from inactions (learning bias), and (c) reward/punishment cues themselves drive repetitive behavior, independent of outcomes (perseveration bias). The neural origin of these biases is unclear. Past evidence suggests dorsal anterior cingulate cortex (dACC) and anterior insula (aIns) as part of a "reset network" that rapidly responds to salient information and might contribute to these biases. We used transcranial ultrasonic stimulation (TUS) in 29 healthy participants to interfere with neural activity in these regions and test their causal role in a within-subject, counter-balanced design across three sessions (sham, TUS-dACC, TUS-aIns). Computational modeling revealed a functional differentiation of both regions in Pavlovian biases: while TUS to either region did not affect the response bias, TUS to the aIns decreased people's learning bias, while TUS to dACC increased participants' perseveration bias. Although the dACC and aIns are part of the same network and often co-activate during decision-making tasks, TUS interference reveals their distinct roles: the dACC mediates cue-dependent persistence while the aIns is critical for inferring whether outcomes are self-caused.
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Miniature implantable neural interface devices are increasingly critical for both neuroscience research and clinical neuromodulation applications. However, device miniaturization imposes stringent constraints on power, area, and performance, creating challenges for implementing energy-efficient neuromodulation, high-fidelity neural recording, and wireless data telemetry. This review provides a comprehensive overview of low-power circuit designs enabling next-generation neural interfaces. We discuss energy-efficient stimulation drivers for optogenetic neuromodulation, highlighting advanced switched-capacitor-based techniques that reduce supply voltage requirements while maintaining high-current LED pulses. Low-noise neural recording frontends, including preamplifier-fronted structures, as well as ΔΣ ADC-based and NS-SAR-based direct-digitizing architectures, are reviewed with emphasis on techniques for dynamic range extension, linearity improvement, and artifact tolerance. Finally, state-of-the-art backscatter-based wireless telemetry methods are presented, covering load-shift keying (LSK), frequency-splitting, and push-pull quadrature modulation approaches that decouple power and data transfer to achieve high data rates with minimal energy consumption. This review highlights the critical role of circuit-level innovations in overcoming the power and performance limitations of miniature implants and provides insights for the design of next-generation neural interface systems.
Substance use disorders (SUDs) remain a severe global public health challenge. Non-pharmacological interventions are widely used to improve mental health and quality of life (QoL) in people with SUDs, but their comparative effectiveness for these outcomes remains uncertain. To compare the relative efficacy of non-pharmacological interventions for anxiety, depression, and QoL in individuals with SUDs. Two reviewers independently screened studies and extracted data. We conducted a random-effects frequentist network meta-analysis and prioritized the earliest post-intervention assessment to improve comparability across trials. We included 117 RCTs from 25 countries (11,177 participants). Compared with a pooled control condition, several interventions showed reductions in anxiety symptoms, including neuromodulation, combined intervention, mind-body therapy, relapse prevention, and acupuncture. For depression, favorable estimates were observed for neuromodulation, conventional exercise, cognitive behavioral therapy, mind-body therapy, and acupuncture. For QoL, evidence did not show a reliable benefit at the earliest post-intervention time point; estimates were imprecise (e.g., mind-body therapy vs control). SUCRA rankings identified neuromodulation as the top-ranked option for both anxiety and QoL, with mind-body therapy ranking highest for depression. Subgroup analyses indicated that the relative effects of interventions may vary according to country development level and intervention duration. Several non-pharmacological interventions were associated with short-term improvements in anxiety and depressive symptoms in people with SUDs, while short-term QoL effects were uncertain. Comparative rankings should be interpreted cautiously given imprecision, heterogeneity, and sparse head-to-head evidence and should be integrated with feasibility, patient preferences, and local service capacity. https://www.crd.york.ac.uk/PROSPERO, identifier CRD420251265848.
Supraspinal somatosensory pathways neuroplasticity critically influences sensory recovery after spinal cord injury (SCI) and offers promising neuromodulation targets. However, distinctions between complete SCI (CSCI) and incomplete SCI (ISCI) patients remain unclear. We aimed to delineate injury severity-dependent neuroplasticity patterns in somatosensory pathways, and provide mechanistic insights for developing targeted rehabilitation strategies. Resting-state effective connectivity (EC) within supraspinal somatosensory pathways was analyzed using spectral dynamic causal modelling in 17 CSCI patients, 17 ISCI patients, and 37 healthy controls. The primary somatosensory cortex (S1), second somatosensory cortex (S2), thalamus (THA), insula (INS), cerebellar lobule VI (CB6) and primary motor cortex were employed as the regions of interest. A fully connected model was specified for each participant, and group-level differences in EC were assessed using parametric empirical Bayes. Connections with a posterior probability > 0.95 were considered significant. Additionally, correlation analyses were performed between significant EC and sensory scores. Both CSCI and ISCI groups exhibited impaired basic somatosensory conduction, including dysfunction from the THA to the S1 and dysregulation along the S1-S2-INS pathway. However, their specific connectivity patterns diverged. The CSCI group showed weakened self-inhibition within the THA and S1. The ISCI group exhibited stronger inhibitory EC from S2 to INS and from CB6 to S1. CSCI and ISCI patients predominantly exhibit decreased and increased EC within the supraspinal somatosensory pathways, respectively. The CSCI patients showed reduced THA/S1 self-inhibition, whereas ISCI patients exhibited strengthened S2-INS/CB6-S1 connectivity, possibly compensating for sensory deficits and suggesting neuromodulation targets for somatosensory recovery.
Quantum technologies-quantum computing, quantum sensing, and quantum-enabled materials-are increasingly proposed as tools to accelerate drug discovery. Yet "quantum advantage" is frequently asserted without standardized benchmarks, clinically meaningful endpoints, or controlled comparisons against modern classical workflows. This review separates (i) quantum computing for molecular simulation and optimization, (ii) quantum sensing for structural/biophysical characterization and diagnostics, and (iii) quantum nanotechnologies for imaging and sensing, and then extends the framework to include device-led and physical therapies that increasingly co-evolve with drug development: photobiomodulation (red/NIR), focused ultrasound for blood-brain barrier opening and delivery enhancement, noninvasive neuromodulation devices (tDCS/TMS), and optogenetic therapies. We summarize demonstrated capabilities and constraints of NISQ-era computing, outline algorithmic classes for quantum chemistry and hybrid variational methods, evaluate quantum error-mitigation strategies and their limits, and contrast claimed performance with classical baselines in computational chemistry and machine learning. We conclude that near-term translational value is most substantial for quantum sensing and for device/physical platforms with established clinical evidence. In contrast, quantum computing remains principally hypothesis-generating until fault tolerance and reproducible advantage are established. Device-based modalities-including transcranial photobiomodulation for neuropsychiatric indications, focused ultrasound enabling CNS drug delivery, and home-supervised neuromodulation-are already reshaping therapeutic landscapes and clinical trial design. For drug discovery, the central requirement is not quantum novelty but validated decision impact, demonstrated under controlled benchmarks aligned with reproducibility expectations comparable to those evolving for AI/ML-driven methods in regulated contexts.
Neuromuscular fatigability impairs motor performance in both healthy and neurological populations. Corticomuscular coherence (CMC), derived from EEG and EMG recordings, reflects the brain-muscle interaction during movement. However, the impact of neuromuscular fatigability on CMC in healthy and neurological populations remains unclear. A systematic search of PubMed, Web of Science, and Embase was conducted up to 02/02/2026. Eligible studies investigated CMC changes related to fatiguing tasks in healthy or neurological participants. Two reviewers independently screened, extracted data, and assessed the risk of bias. Fifteen non-randomized experimental studies were included, comprising predominantly neurologically healthy adults (n= 174) and a limited number of individuals with neurological conditions (n= 14). Fatiguing tasks varied widely in muscle group, contraction type, mode, and intensity. Across studies, neuromuscular fatigability was associated with heterogeneous changes in CMC, most commonly involving reductions in beta band coherence as fatigue progressed. However, preserved or increased beta band CMC was also reported in both upper- and lower-limb tasks, particularly during sustained or low- to moderate-intensity contractions. Alpha and gamma band CMC were less reported across the included studies. No consistent or limb-specific pattern of CMC modulation emerged, with observed responses depending on task demands, contraction intensity, muscle group, and stage of fatigue. Evidence from neurological populations was sparse but suggested generally lower CMC magnitude and greater disruption during fatiguing tasks compared with healthy controls. These findings indicate that fatigue-related changes in CMC do not reflect a uniform loss of corticomuscular coupling but rather task- and context-dependent adaptations in brain-muscle communication. Reductions in CMC may reflect diminished efficacy of corticospinal synchronization, whereas preserved or increased coherence may represent stabilization to maintain motor output with fatigue. By synthesizing how neuromuscular fatigability reshapes CMC across different experimental contexts and highlighting key methodological limitations, this review provides a framework to inform the design of future rehabilitation or neuromodulation trials targeting fatigability in both healthy and neurological populations.
Persistent genital arousal disorder (PGAD) is a distressing, often debilitating condition of unwanted genital arousal occurring independent of desire and difficult to relieve, with substantial psychosocial burden. We systematically reviewed peer-reviewed studies (2015-2025) to synthesize the evidence for diagnosis, etiology, and treatment. PubMed, Ovid (MEDLINE/Embase), and CINAHL (English-language, human studies; last searched on August 31, 2025) were searched. Two reviewers independently screened the records and extracted data, with disagreements resolved by the consensus and third-reviewer adjudication. Risk of bias was assessed using ROBINS-I for comparative observational studies and Joanna Briggs Institute tools for case series. The findings were synthesized narratively in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020. The review protocol was registered prospectively in PROSPERO (CRD420251108714). Of 799 records identified, 56 duplicates were removed; 743 titles/abstracts were screened, 197 full texts were assessed, and 14 studies were included. Eligible designs comprised cross-sectional surveys, case-control/cohort studies, case series ≥3 patients, and one clinical review with embedded cases; no randomized controlled trials (RCTs) were identified. Owing to clinical and methodological heterogeneity, meta-analysis was not performed. Participants were predominantly women. Diagnostic practice was inconsistent: Most used symptom-based criteria aligned to International Society for the Study of Women's Sexual Health or Leiblum-Nathan frameworks, variably combined with targeted imaging, neurophysiology, or small-fiber testing. Etiologic signals most often implicated neuropathic/structural mechanisms - sacral radiculopathy, Tarlov cysts, and pudendal or small-fiber neuropathy - alongside central neurobiological and psychosocial contributors. Interventions included pelvic-floor physiotherapy, cognitive-behavioral approaches, pharmacologic agents (e.g., gabapentinoids and benzodiazepines), neuromodulation, and selected surgical decompressions for defined lesions; outcomes were mixed and follow-up/safety reporting limited. Overall, PGAD appears multifactorial and under-standardized in assessment. It should be prioritized to include a consensus, multimodal diagnostic pathway and prospective, comparative studies using validated patient-reported outcomes to inform individualized, evidence-based care.
Recent developments in intracranial EEG (iEEG) allow direct recordings from the human thalamus, offering new insight into thalamocortical relationships in the human brain. In this study, we applied direct intracranial electrical stimulation (iES) to the mid-thalamus, within or close to the mediodorsal nucleus, to examine its impact on conscious experience and causal brain connectivity in 30 patients with focal epilepsy (10 females, 128 sites; 4±1 sites per patient). Applying 50Hz stimulations (iESHF) in the mid-thalamus region elicited changes in conscious experience in 11 of 12 patients (39 sites; 83 stimulations across 27 unique pairs), predominantly in the visceral, emotional, or somatosensory domains and often described as unpleasant without any seemingly obvious lateralization effect. Our connectivity analyses based on single pulse 0.5Hz stimulations (iESLF), at the individual brain level, revealed strong electrophysiological connectivity between the mid-thalamus and the insula, anterior- and mid-cingulate, as well as the other prefrontal cortices (PFC) and medial temporal lobe structures. Notably, inflow signals from some of the sites to the mid-thalamus were significantly stronger than those in the reverse direction, indicating clear asymmetry in connectivity. These findings demonstrate that stimulation of the human thalamus modulates conscious experience and reveal an asymmetric electrophysiological relationship between the thalamus and human cerebral cortex.Significance statement Our findings provide a functional and causal map of the mid-thalamus in the human brain. We provide direct evidence that stimulation of the human thalamus can modulate conscious experience. This study also holds clinical and translational value for identifying thalamic pathways involved in the propagation and generalization of seizures, especially seizures involving the medial temporal lobe, as well as for neuromodulation in epilepsy and other neuropsychiatric disorders.
Visceral pain is a common and debilitating symptom of bowel disorders, such as irritable bowel syndrome and inflammatory bowel disease (IBD). Sacral nerve stimulation (SNS), widely used for fecal incontinence, has shown promise in treating inflammation and visceral hypersensitivity in rodent models, although its efficacy in IBD-associated visceral pain remains unclear. This study evaluated the effectiveness and underlying mechanisms of SNS on visceral hypersensitivity in a rodent IBD model. Visceral hypersensitivity was induced through intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rats received SNS or sham treatment (one h/d for ten days) beginning five days post-TNBS. SNS was applied using a set of parameters previously shown effective in treating visceral pain in other methods of neuromodulation. Daily disease activity index scores increased significantly after TNBS but improved with SNS (p < 0.05). Tumor necrosis factor α levels in the distal colon rose in TNBS rats (55.2 pg/mg vs 37.5 pg/mg in saline, p = 0.004) and decreased with SNS (43.2 pg/mg, p = 0.025 vs sham). Visceral motor reflex (VMR) responses to colorectal distension (40-80 mm Hg) were elevated three- to fourfold in TNBS rats, which was reduced by 34%-73% with SNS (p < 0.001). Colitis reduced transepithelial electrical resistance (TEER, reflecting colonic epithelial permeability) by 48% (18.3 Ω·cm2), which improved by SNS (26.0 Ω·cm2, p = 0.035). Plasma lipopolysaccharide levels were elevated in TNBS-sham rats (0.72 EU/mL vs 0.20 EU/mL saline, p < 0.001) and reduced with SNS (0.45 EU/mL, p = 0.042). TEER negatively correlated with VMR responses. SNS attenuates TNBS-induced visceral hypersensitivity by reducing inflammation and enhancing epithelial barrier integrity.
Cortical traveling waves (TWs) are brain oscillation patterns that support the transfer of neural information across distinct brain regions, with their direction shaping cognitive function. However, direct evidence for their causal influence on brain dynamics and behavior remains lacking. Here, we establish such a causal link by externally applying TW-like electric field patterns. To achieve this, we develop a noninvasive brain stimulation protocol, traveling-wave transcranial alternating current stimulation (twtACS). twtACS can generate a precise directional electric field that propagates across the cortical surface, which we validate using human intracranial recordings. In monkey recordings, we show that neural spiking was directionally modulated, shifting systematically across space in line with the direction of twtACS. In humans, twtACS led to direction-dependent improvements in cognitive performance. Together, these findings demonstrate that externally imposed TWs can causally shape neural activity and cognition, highlighting the potential of twtACS as a neuromodulation technique for cognitive enhancement.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking reliable noninvasive indicators for early diagnosis. Transcorneal electrical stimulation (TES) has emerged as a noninvasive neuromodulation approach, yet its effects on AD-related pathology and eye-brain interactions remain unclear. In this study, TES was applied to wild-type (WT) and AD mice, followed by longitudinal optical coherence tomography (OCT) and OCT angiography (OCTA) imaging of the retina and cerebral cortex over a 30-day period. Quantitative imaging metrics, together with histologically assessed amyloid-β (Aβ) plaque deposition, were used to assess TES-associated structural and neurovascular changes. In addition to retinal thickness, retinal vascular density (VD) was evaluated as an objective, noninvasive imaging metric associated with AD-related neurovascular alterations. These findings demonstrate the utility of longitudinal OCT/OCTA imaging for investigating intervention-associated retinal and cerebral neurovascular changes along the eye-brain axis.
This literature review critically examines the design, validation, and application of non-invasive in-ear electroencephalography (ear-EEG) systems as emerging wearable platforms for long-term neurophysiological monitoring and intervention. Following PRISMA guidelines, studies published between 2010 and 2025 were systematically selected from four major databases and organized into four thematic domains: in-ear wearable system design and validation, multimodal sensing and stimulation, embedded intelligence, and brain-state monitoring and rehabilitation. The review focuses exclusively on wearable, ear-centered EEG technologies, explicitly excluding cochlear implants and other invasive or behind-the-ear systems. We analyze key engineering challenges unique to ear-EEG, including electrode placement constraints, mechanical-electrical coupling, motion robustness, power efficiency, and long-term wearability. The review highlights a growing transition toward compact, wireless ear-EEG systems with on-device signal processing and embedded machine learning, enabling real-time brain-state estimation under ambulatory conditions. Multimodal integration, combining ear-EEG with complementary sensors such as EOG, inertial units, and cardiovascular signals is shown to improve artifact awareness, contextual interpretation, and closed-loop capability. Beyond summarizing existing technologies, this review identifies critical gaps limiting clinical translation, including the lack of standardized validation protocols, limited embedded autonomy, and underexplored closed-loop neurofeedback and neuromodulation architectures. By synthesizing advances across hardware design, signal processing, and intelligent system integration, this work provides a systems-level roadmap for the future development of wearable, intelligent, and clinically robust ear-EEG platforms for mental health, neurorehabilitation, and continuous brain monitoring.
Modulating brain oscillations has significant therapeutic promise. Traditional non-invasive neuromodulation techniques can alleviate clinical signs of Alzheimer's disease (AD) by restoring normal neural oscillatory activity in certain brain regions. As a novel non-invasive brain modulation technique, temporal interference (TI) has been demonstrated to precisely control hippocampus neural oscillations while minimizing its impact on cortical neural activity, but its exact mechanism of action is still unclear. We simulated and experimentally measured the intracranial electric field under TI to determine the precision of TI intervention. Subsequently, TI stimulation was applied to the APP/PS1 transgenic AD mouse model, and the impact of TI stimulation on the stimulated brain region was compared from the perspectives of behavior, electrophysiology, and cell biology. This work showed that in the APP/PS1 Alzheimer's disease mice model, TI stimulation significantly increased GABA levels and decreased NMDA receptor activation at the targeted region. Following neurotransmitter regulation, the rhythm of the gamma oscillations they associate also changed. This, in turn, influenced other memory-related neural oscillation frequencies and brain regions through cross-frequency coupling and brain connectivity, ultimately improving the behavioral performance of AD model mice. The results of our work demonstrated how TI stimulation alters brain oscillations to enhance memory in mice with Alzheimer's disease, offering a possible theoretical foundation for TI's clinical application.
We propose the Optimal-Transport Gated Echo-State Network (OT-ESN), a two-timescale reservoir that replaces ad hoc inter-module couplings with a principled, mass-conserving transport mechanism on a cortical-sheet geometry. At each step, a slow, exogenous controller computes an entropically regularized optimal-transport plan Π between the previous distribution of column activity (source) and an input-derived "intent" over columns (target), using a geometric cost that encodes anatomical or functional proximity. The resulting plan-doubly stochastic up to prescribed marginals-acts as a bounded, geometry-aware mixer that gates inter-column blocks of the reservoir at the next fast update. This one-step delay ensures that Π is absent from the time-t Jacobian, so with a 1-Lipschitz nonlinearity and fixed leak, the echo-state property collapses to a single spectral-norm inequality on pre-scaled intra- and inter-column operators, yielding a uniform contraction certificate. OT-ESN, thus, achieves interpretable, neuromodulation-like routing of assembly activity while preserving the simplicity of readout-only training. Computationally, Sinkhorn iterations on a J×J kernel provide efficient, smooth control, with the regularization parameter spanning diffuse (diffusion-like) to sharp (path-like) transports without jeopardizing stability. Ergo, via optimal transport, OT-ESN enables long, structured memory and geometry-respecting information flow in a provably stable recurrent substrate.
Whereas the brain-heart axis is an emerging field in neuropsychocardiology, a central autonomic network including the insular cortex (Ic) regulates the cardiovascular system via the intrinsic cardiac nervous system. Cardiac interoception, represented in Ic, has been studied in cardiovascular diseases and inflammation. Therefore, it is important to investigate how interoception is related to cardiovascular disease in terms of its prevention and treatment. To examine the role of the Ic in cardiovascular and immune regulation, we focus on converging evidence from human stroke cohorts, lesion-symptom mapping studies, and experimental models that implicate the Ic as a causal hub within the brain-heart-immune axis. In particular, Ic plays a pivotal role in processing interoception as well as immunoception, and based on this information, Ic regulates cardiovascular and immune systems via efferent autonomic networks. Furthermore, vagally mediated neuromodulation is likely to influence interoception and immunoception and plays a pivotal role in improving cardiovascular dysregulation.
Aripiprazole (ARI), an atypical antipsychotic, has demonstrated anticancer activity in several malignancies and may be a candidate for drug repurposing as an intravesical therapy for bladder cancer, particularly non-muscle-invasive bladder cancer (NMIBC). This study evaluated whether brief, intravesical-like ARI exposure could induce cytotoxic effects in bladder cancer cells while preserving normal bladder structure and function. RT4 and T24 bladder cancer cells, together with non-malignant UROtsa urothelial cells, were exposed to ARI (1-300 μM) for 30 min or 2 h, and viability was assessed at 24, 48 and 72 h. Reactive oxygen species (ROS) generation was measured in RT4 and T24 cells after 2 h pretreatment, while caspase-3 activity and stress-associated protein expression were examined in T24 cells. In parallel, an ex vivo porcine bladder model was used to assess the effects of luminal ARI pretreatment (300 μM, 2 h) on urothelial thickness, ATP and acetylcholine release, detrusor contractility, β-adrenergic relaxation, and nerve-evoked responses. ARI reduced viability in a concentration-dependent manner in RT4, T24 and UROtsa cells, with greater cytotoxicity after 2 h pretreatment. In bladder cancer cells, ROS increased only at higher concentrations, whereas ARI increased caspase-3 activity at lower concentrations and altered multiple stress-related proteins in T24 cells. In porcine bladder, ARI preserved urothelial structure and mediator release, maintained detrusor and neurogenic function, and enhanced the inhibitory influence attributed to urothelium-derived inhibitory factor (UDIF). Collectively, these findings identify ARI as a mechanistically active yet bladder-sparing candidate for intravesical repurposing and support its further evaluation as a potential therapy for bladder cancer.