Sleep is essentially contributing to human health and well-being through multiple biological functions, including restoration and biosynthesis, brain clearance, energy metabolism, immunological and endocrine processing, synaptic plasticity, memory consolidation, and regulation of cognitive and emotional processes. Sleep disturbances are highly prevalent and are both a symptom and a contributing risk factor for psychiatric, neurological, and somatic disorders. Given the limitations of pharmacological interventions, noninvasive neuromodulation techniques ranging from noninvasive transcranial [transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), temporal interference stimulation (tTIS), and transcranial ultrasound stimulation (TUS)] to peripheral sensory (auditory, olfactory, visual, tactile, vestibular) and electrical nerve (galvanic vestibular, transcutaneous vagus nerve, and median nerve) stimulation have gained increasing attention as potential tools to modulate sleep physiology. These techniques offer promising avenues for both therapeutic applications and fundamental research into sleep-dependent neuroplasticity, interregional communication, and oscillatory activity. However, sleep is not a uniform state but a highly complex and dynamic phenomenon, with intricate macrostructural [e.g., non-rapid eye movement (NREM)-rapid eye movement (REM) sleep balance, sleep efficiency] and microstructural (e.g., hierarchically nested slow waves and spindles) characteristics that contribute to a variety of functions. This complexity necessitates precise targeting strategies, often employing real-time brain state-dependent stimulation, to modulate specific sleep-related processes effectively. In this review, we summarize the functions of sleep and the available noninvasive tools for its modulation, addressing key methodological challenges and providing recommendations for best practices in sleep neuromodulation.

Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.

Transcranial ultrasound stimulation (TUS) shows great promise for inducing neuroplastic changes that persist long after stimulation. Evidence of stimulation-locked (online) neural changes would enable the development of closed-loop application of TUS. However, such responses have been difficult to distinguish from coincident neural activity caused by auditory and somatosensory effects of TUS. To dissociate genuine online neuromodulatory effects from peripheral confounds, we leveraged the contralateral retinotopic organization of the early visual cortex in nineteen subjects. Using a hemifield visual stimulation paradigm combined with high-precision, functional MRI-guided TUS, we applied TUS to the left early visual cortex while participants viewed checkerboards presented in the left or right visual hemifield. Randomized delivery of TUS on half of the trials enabled within-subject comparisons of hemisphere-specific, pattern-locked visual evoked potentials (VEPs) across stimulated and unstimulated hemispheres, as well as across visual-stimulus and no-stimulus conditions. TUS to the left visual cortex reduced mean VEP amplitude over the stimulated (left) hemisphere for right-hemifield (contralateral) stimuli. No such reduction appeared at the symmetric right-hemisphere sites for left-hemifield stimuli. The degree of online suppression correlated positively with target engagement, estimated by modelling the TUS field that accounted for inter-individual heterogeneity in skull transmission and its overlap with the fMRI-defined target. This relationship suggests that greater target engagement is reliably associated with stronger TUS-induced neural modulation. These findings provide clear evidence of online, spatially specific TUS-induced neural modulation, dissociated from peripheral confounds. This approach establishes a robust framework for future studies aiming to map the TUS parameter space in real time by leveraging topographic organization to control for peripheral confounds, and supports the development of closed-loop neuromodulation protocols.

The ventromedial anterior temporal lobe (ATL) is a core transmodal hub for semantic memory, yet non-invasive modulation of this region has remained challenging. Transcranial ultrasound stimulation (TUS) offers high spatial precision suitable for deep brain targets. In this study, we investigated whether theta-burst TUS (tbTUS) to the ventromedial ATL enhances semantic memory, using a multimodal neuroimaging approach-magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and voxel-based morphometry (VBM). Compared to control stimulation, tbTUS improved semantic task performance. MRS showed decreased GABA and increased Glx, reflecting shifts in excitation-inhibition balance, alongside increases in NAA, creatine and choline, suggesting enhanced neuronal metabolism. fMRI demonstrated reduced ATL activity during semantic processing and strengthened effective connectivity across the semantic network. VBM revealed increased ATL grey matter volume. These findings provide convergent evidence that tbTUS modulates neurochemistry, functional dynamics, and brain morphology to enhance semantic memory, highlighting its neurorehabilitation potential.

Safety and efficacy of low intensity transcranial ultrasound stimulation for depression: A single-blind randomized controlled clinical study.

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is increasingly recognized for its systemic effects, including neuroinflammation and cognitive deficits mediated through the gut-brain axis. This study investigates the potential mechanisms for treating UC with low-intensity pulsed ultrasound (LIPUS). A murine model of UC was established using 3% dextran sulfate sodium (DSS) in C57BL/6J mice. Disease progression was monitored via the Disease Activity Index (DAI). Histopathological evaluations were conducted using Hematoxylin and Eosin (H&E) staining. To elucidate molecular alterations, hippocampal tissues underwent quantitative proteomic analysis employing high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were identified and analyzed to understand the impact of both abdominal and transcranial LIPUS treatments. Both abdominal and transcranial LIPUS treatments were found to alleviate symptoms of colitis. Proteomic analysis of hippocampal tissues identified five DEPs—REPS1, MYG1, KRT13, SRSF10, and CDC42BPG—whose expression levels were modulated by LIPUS interventions. Notably, REPS1 and MYG1, which were downregulated in UC conditions, showed increased expression following LIPUS treatment. KEGG pathway enrichment analysis revealed that these DEPs are primarily involved in the Ras/MAPK signaling pathways. The modulation of these pathways by LIPUS suggests a mechanism by which it exerts anti-inflammatory effects, potentially restoring metabolic balance and reducing inflammation in both the gut and brain. These findings highlight the role of the gut-brain axis in mediating the beneficial effects of LIPUS and suggest its potential as a non-invasive therapeutic strategy for UC and associated neuroinflammatory conditions.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13036-025-00619-4.

Despite the high potential of transcranial ultrasound stimulation (TUS) for non-invasive brain therapy and interrogation, real-time monitoring of brain responses to TUS remains a challenge. Traditional methods to monitor direct neural responses are invasive and mostly incompatible with precise TUS delivery while other non-invasive approaches to visualize the induced responses suffer from poor penetration depth, lack of sensitivity, or low temporal resolution. We present an integrated approach for high precision delivery of ultrasound into the mouse brain and simultaneous whole-brain oximetry with functional optoacoustic tomography to characterize the hemodynamic response elicited by TUS. A spherically focused ultrasound array was employed to non-invasively deliver holographic TUS and simultaneously detect multispectral optoacoustic signals from the brains of anesthetized mice. Ultrasound pressure and pulse duration were varied, while the number of stimuli (5), stimulation duration (15s), and ultrasound frequency (3MHz) were kept constant. The acquired optoacoustic data were tomographically reconstructed and spectrally unmixed to render three-dimensional maps of oxygenated and deoxygenated hemoglobin in real time. TUS-evoked brain-wide hemodynamics were efficiently monitored via spectroscopic optoacoustic imaging with high spatial and temporal resolution. Holographic TUS targeted to the somatosensory cortex elicited distinct hemodynamic responses, which extended beyond the stimulated region, involving subcortical arteries and pial veins. Our method provides new transformative non-invasive capabilities to study the effects of ultrasound on a living brain thus help unleash the strong potential of TUS in neuroscience and medicine.

Exploration of the epilepsy cortical network is helpful for understanding the pathophysiological mechanisms of epilepsy and optimizing the treatment direction of epilepsy. Low-intensity transcranial ultrasound stimulation (TUS), characterized by non-invasiveness, high penetration depth, and high spatial resolution, has the potential to modulate brain functional networks. Nevertheless, the specific mechanisms by which TUS influences the cortical network in awake epilepsy model mice remain inadequately understood. Here, we observed that TUS significantly decreased the power of the whole cerebral cortex, diminished the phase lag index functional connectivity strength of the whole cerebral cortex, reduced the strength of cortical network connections, and accelerated the transition process from the epileptic seizure state to the normal state. Taken together, these findings indicated that epileptic seizures were suppressed after TUS modulated cortical functional network connections in mice.

Although transcranial ultrasound stimulation (TUS) can noninvasively target the hippocampal oscillatory network, which serves as a critical interface between cellular functions and cognition, its modulatory efficiency is constrained by the low-pass filtering properties of neuronal membranes. To overcome this limitation, we developed a low-frequency amplitude-modulated (AM) TUS paradigm to enhance neuromodulatory efficiency by improving resonance within the hippocampal oscillatory network. We applied 5, 40, and 80 Hz sinusoidal AM-TUS and 5 Hz pulsed AM-TUS to the mouse hippocampus, and analyzed local field potentials before and after stimulation. Results showed that 5 Hz sinusoidal AM-TUS significantly enhanced the phase locked value (PLV) (increment: $0.054\pm 0.017$ ) and coherence (increment: $0.040\pm 0.016$ ) in the theta band, and the phase-amplitude coupling (PAC) in theta-low gamma (increment, $1.521\pm 0.249$ ) and theta-high gamma (increment, $0.821\pm 0.299$ ) bands. In contrast, the 5 Hz pulsed AM-TUS showed negligible effects. While the 40 Hz sinusoidal AM-TUS enhanced PLV and coherence in the theta band and PAC in theta-low gamma bands, the 80 Hz sinusoidal AM-TUS only enhanced PLV in the theta band. Thus, the 5 Hz sinusoidal AM-TUS demonstrated superior neuromodulatory efficiency over all other paradigms. The outstanding modulatory efficiency of 5 Hz sinusoidal AM-TUS on the oscillatory network was further confirmed in the 14-day TUS, demonstrating enhancements in spatial learning and memory. The 5 Hz sinusoidal AM-TUS presents a novel and efficient approach to precisely modulating hippocampal oscillatory network through entrainment.

ABSTRACTObjectivePoststroke cognitive impairment (PSCI) is a common neurological consequence of stroke that significantly impacts patients' quality of life and functional recovery. This meta‐analysis aimed to evaluate and compare the efficacy of various treatment modalities for PSCI.MethodWe conducted a systematic search of multiple databases and identified eligible randomized controlled trials (RCTs) investigating treatments for PSCI. Eleven RCTs with 904 participants evaluating seven different interventions were included in the network meta‐analysis. The treatments included transcranial direct current stimulation (tDCS), acupuncture, Baduanjin exercise, transcranial ultrasound stimulation (TUS), moderate‐intensity aerobic exercise, modified Suanzaoren decoction, and cognitive training alone (control).ResultsNetwork meta‐analysis showed that all interventions demonstrated some degree of efficacy compared to cognitive training alone, with Baduanjin exercise and tDCS ranking highest for improving cognitive function. Publication bias assessment showed no significant bias.ConclusionThis comprehensive analysis suggests that non‐pharmacological interventions, particularly neuromodulation techniques and traditional Chinese exercise, may offer promising approaches for PSCI treatment. These findings provide evidence‐based guidance for clinical decision‐making, though more large‐scale, high‐quality RCTs are needed to strengthen these conclusions.

Tremor in Parkinson's disease (PD) is a disabling symptom that often persists despite pharmacological treatment. High-intensity focused ultrasound (HIFU) targeting the ventral intermediate nucleus (VIM) alleviates Essential Tremor, but recent evidence suggests the zona incerta (ZI) may be a superior target for Parkinsonian tremor. This study compared the effects of transcranial ultrasound stimulation (TUS) to the VIM and ZI on postural and rest tremor, and examined related neural correlates using resting-state fMRI (rs-fMRI). In this within-subject, crossover study, 19 participants with PD and right-hand tremor received both left VIM- and ZI-TUS on the same day in randomized order, separated by a 4-h washout period. Tremor severity and rs-fMRI data were collected before and after each session. Normalized changes in tremor intensity, resting-state functional connectivity (Δrs-FC), and fractional amplitude of low-frequency fluctuations (ΔfALFF) within the cerebello-thalamo-cortical network were analysed. TUS effects differed by target and tremor type. VIM-TUS significantly reduced postural tremor (p<0.001) but not rest tremor, whereas ZI-TUS improved both postural (p=0.005) and rest (p=0.005) tremor. Although no overall group-level rs-FC changes were observed, individual Δrs-FC of the ZI following ZI-TUS correlated with tremor improvement (postural: r=0.762, p<0.001; rest: r=0.586, p=0.008), with similar findings for ΔfALFF. ZI-TUS modulates tremor more robustly than VIM-TUS, suggesting that ZI may be a promising target for treatment of Parkinsonian tremor.

There is substantial scientific interest in improving approaches that can enhance cognition through brain stimulation. We implemented a non-invasive focal Transcranial Ultrasound Stimulation (TUS) approach with known longer-lasting post-stimulation effects in two rhesus macaques performing a context-dependent memory-sequencing task implemented on multiple touchscreens within their home units. Consistently in both monkeys, TUS to the anterior – but not posterior – medial temporal lobe enhanced performance under stable memory-sequencing contexts. TUS to the medial prefrontal cortex, on the other hand, selectively improved performance when contexts were unstable and the monkey needed to adapt to both a change in context and temporal sequence. These findings shed new light on fronto-temporal nodes that, when perturbed, can selectively enhance cognitive performance, paving the way for further developing non-invasive approaches to improve cognitive function in humans and to study neural circuits under focal perturbation across species.

Transcranial ultrasound stimulation (TUS) has emerged as a clinically validated neuromodulation technique. Particularly, phased array ultrasound can be applied in TUS to focus on the cortex or deep brain non-invasively, such as the ventral intermediate thalamic nucleus (VIM) and Precuneus (PCu) region for the treatment of essential tremor (ET) and Alzheimer Disease (AD). Current TUS treatment planning relies on computed tomography (CT)-derived skull porosity measurements, which involve patient radiation exposure and potential registration errors. This study proposes a Porosity Index (PI)-based method, derived from Ultrashort Echo Time (UTE) Magnetic Resonance (MR) images, for establishing skull acoustic models as a viable alternative, aiming to eliminate these limitations. Acoustic simulations using the K-Wave open-source platform were performed to validate the PI method’s accuracy in predicting skull porosity and simulating focal distributions compared to CT. Focal spot characteristics were quantified using five metrics: peak intensity, target intensity, focal positioning error, Dice similarity coefficient, and Pearson correlation coefficient between CT- and PI-based simulation results. Statistical differences between these metrics were assessed using Tukey’s multiple comparisons test. Quantitative comparisons against the gold-standard CT approach demonstrated comparable performance in peak focal intensity (deviation < 5%) and spatial pressure distribution patterns (Dice coefficient > 0.82). No significant differences (p > 0.05) were observed for any of the evaluated metrics. Our findings demonstrate that both the sound pressure distribution and prediction of the porosity are comparable with those from the reference CT. Using the PI to replace the traditional CT porosity has high feasibility and can achieve the purpose of reducing unnecessary radiation exposure and registration error for patients.

Precisely neuromodulating deep brain regions could bring transformative advancements in both neuroscience and treatment. We demonstrate that non-invasive transcranial ultrasound stimulation (TUS) can selectively modulate deep brain activity and affect learning and decision making, comparable to deep brain stimulation (DBS). We tested whether TUS could causally influence neural and behavioural responses by targeting the nucleus accumbens (NAcc) using a reinforcement learning task. Twenty-six healthy adults completed a within-subject TUS–fMRI experiment with three conditions: TUS to the NAcc, dorsal anterior cingulate cortex (dACC), or Sham. After TUS, participants performed a probabilistic learning task during fMRI. TUS-NAcc altered BOLD responses to reward expectation in the NAcc and surrounding areas. It also affected reward-related behaviours, including win–stay strategy use, learning rate following rewards, learning curves, and repetition rates of rewarded choices. DBS-NAcc perturbed the same features, confirming target engagement. These findings establish TUS as a viable approach for non-invasive deep-brain neuromodulation.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent challenges in social interaction and behavior, and is frequently accompanied by comorbidities such as epilepsy, anxiety, and sleep disturbances. Conventional therapies including applied behavior analysis delivered via early intensive behavioral Intervention, speech-language therapy and symptom-focused pharmacological agents offer symptomatic relief, but require extensive resources and do not directly target underlying neurobiological mechanisms. Emerging interventions, including SHANK3 gene replacement and Excitation/Inhibition (E/I) modulators, remain in preclinical or early clinical stages but show strong potential to target core ASD symptoms at their biological source. Additionally, neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS), may help reshape aberrant neural activity, with early evidence indicating improvements in language, cognition, and emotional regulation. Furthermore, biomarker-driven approaches using tools like EEG can support the development of personalized treatment plans tailored to individual neurobiological profiles. This review aims to evaluate the effectiveness of both conventional and novel treatment strategies and to propose an integrative framework that supports individualized, biologically informed care for individuals with ASD.

Transcranial ultrasound stimulation (TUS) is a promising new form of non-invasive neuromodulation. As a nascent technique, replication of its effects on brain function is important. Of particular interest is offline 5 Hz repetitive TUS (5 Hz-rTUS), originally reported by Zeng et al. (2022) to elicit lasting corticospinal excitability increases, with large effect sizes. Here, we conducted a pre-registered (https://osf.io/p5n4q) replication of this protocol that benefited from three additional features: double-blind application of TUS, neuronavigation for consistent TMS positioning, and individualised 3D acoustic simulations to assess M1 target exposure to TUS. Changes in resting motor thresholds (rMT), motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) in response to TUS (5 Hz-rTUS vs. sham) were measured in the right first dorsal interosseous (FDI), abductor digiti minimi (ADM), and abductor pollicis brevis (APB) muscles. Transducer location was determined by the TMS-hotspot for motor representations of the right FDI, as in the original work. No significant effects of 5 Hz-TUS (vs. sham) were observed. Post-hoc simulations showed considerable variability of the acoustic focus, which was outside the anatomical M1-hand area in 67% of participants—in line with the known poor correspondence of TMS-hotspot location and M1-hand area. Our results indicate that the effect sizes of the neuromodulatory effects of 5 Hz-rTUS on M1 may be more variable than previously appreciated. We suggest that double-blinding, neuronavigated TMS, individualised acoustic simulations for TUS targeting and pre-registration will aid reproducibility across studies.

BackgroundRecent randomized controlled trials (RCTs) in patients with prolonged disorders of consciousness (pDoC) have yielded limited success. Among them, only studies involving amantadine have provided Class II evidence. The effects of other non-invasive brain stimulation techniques remain inconclusive, largely due to patient heterogeneity and the clinical complexities of implementing such interventions. Low-intensity focused ultrasound pulses (LIFUP), as a novel, non-invasive, and safe neuromodulation technique, have the potential to both stimulate and inhibit deep subcortical structures. This makes LIFUP a promising approach for modulating consciousness and promoting recovery in patients with pDoC. This study aims to evaluate the therapeutic efficacy and safety of LIFUP through a randomized controlled design.Methods and analysisOur primary research focus involves conducting multimodal neurofunctional assessments throughout the intervention period. Specifically, we intend to investigate the relationship between Blood Oxygen Level-Dependent (BOLD) signals, electroencephalography (EEG) patterns, thalamic concentrations of glutamate and glutamine (Glx) and gamma-aminobutyric acid (GABA) and behavioral outcomes under two different LIFUP parameter settings (100 Hz transcranial ultrasound stimulation [TUS] and theta-burst TUS [tbTUS]).DiscussionThrough a comprehensive exploration of parameter setting combined with multimodal neurofunctional assessments, this study evaluates both therapeutic potential and safety considerations of ultrasound-based interventions for pDoC. We hypothesize that the two stimulation protocols (100 Hz TUS and tb TUS) will differentially modulate neural connectivity, thalamus activity, and the Glx/GABA balance. The findings may advance evidence-based interventions for pDoC and identify potential neuroplasticity biomarkers to guide future therapeutic strategies.Clinical trial registrationChinese Clinical Trial Registry, ChiCTR2400092904. Registered on 26 November 2024.

Abstract Background: Transcranial ultrasound stimulation (TUS) is a new technique used for non-invasive brain stimulation. Theta burst TUS (tbTUS) as a repetitive TUS protocol can increase human motor cortical excitability, but its neuromodulatory effects on the other cortex are still unclear. Objective: This study aims to explore the effect of tbTUS on the human auditory cortex. Methods: To evaluate the modulation effect on auditory function, we recorded the auditory evoked potentials (AEP) and the auditory steady-state response (ASSR) before and after delivering real/sham tbTUS to auditory cortex. Results: The results showed that the P300 components in AEP significantly decreased at parietal after real but not sham tbTUS. However, there was no significant change in ASSR after tbTUS. Conclusion: AEP and ASSR are intrinsically different in response to tbTUS, which suggest that tbTUS can specifically modulate the auditory function. Significance: These findings offer valuable insights in designing TUS for the treatment of psychiatric and neurological disorders.

Focused transcranial ultrasound stimulation (TUS) can affect neural activity with high spatial precision, advancing noninvasive neuromodulation toward targeted treatment of brain disorders. Direct monitoring of TUS responses is crucial for ensuring optimal outcomes. Blood-oxygenation-level–dependent (BOLD) functional magnetic resonance imaging has primarily been used for studying TUS effects in both human and nonhuman primate brains. However, the physiology and mechanisms underlying BOLD remain largely unknown due to its highly convoluted nature. To address these limitations, we developed a hybrid system for concurrent optoacoustic and magnetic resonance imaging of TUS (OMRITUS) to comprehensively characterize the hemodynamic changes in murine brains. Our findings reveal paradoxical negative BOLD signals in the activated cortical regions, coupled with increased total hemoglobin levels simultaneously monitored with optoacoustic tomography. Multispectral optoacoustic readings further demonstrated a stronger increase in deoxygenated versus oxygenated hemoglobin, suggesting a potential molecular basis for the negative BOLD responses. OMRITUS enables the study of complex TUS-hemodynamic interactions, paving the way for precise neuromodulatory interventions.

Transcranial focused ultrasound is a promising noninvasive technique for neuromodulation in neurological and psychiatric disorders, but accurate prediction of acoustic transmission through the skull remains a major challenge. In this study, we present a five-layer numerical human head model that integrates frequency-dependent acoustic parameters with nonlinear time-explicit dynamics to realistically capture ultrasound propagation. The model explicitly represents skin, trabecular bone, cortical bone, and brain, each assigned experimentally derived acoustic properties across a clinically relevant frequency range (0.5–5 MHz). Numerical simulations were performed in the frequency domain and time-explicit to quantify sound transmission loss and focal depth under high-intensity and high-frequency stimulation. The results show the effect of frequency, radius of curvature, and skull thickness on maximum pressure ratio, focal depth, and focus zone inside the brain tissue. Findings indicate that skull geometry, particularly radius of curvature and thickness, strongly influences the focal zone, with thinner skull regions allowing deeper penetration and reduced transmission loss. Comparison of the frequency-domain model with the time-explicit model demonstrated broadly similar trends; however, the frequency-domain approach consistently underestimated transmission loss and was unable to capture nonlinear effects such as frequency harmonics. These findings highlight the importance of nonlinear, time-explicit modeling for accurate transcranial ultrasound planning and suggest that the proposed framework provides a robust tool for optimizing stimulation parameters and identifying ideal target zones, supporting the development of safer and more effective neuromodulation strategies.