TANM
Full-Spectrum Review
From Ultrasound Stimulation to Full-Spectrum Acoustic Neuromodulation: A Paradigm Reconstruction — International Evidence Map · Four-Evidence × Spectrum Matrix · 2021–2025
Abstract
Core Argument
Transcranial Acoustic Neuromodulation (TANM) is proposed as a unified overarching framework that repositions acoustic neuromodulation from an "ultrasound medicine" technology to an active dialogue paradigm with neural oscillation dynamics. The determinants of neuromodulatory effect directionality are not the ultrasound carrier frequency (MHz range), but rather the timing parameters operating within the neural oscillation frequency band (1 Hz–1 kHz): pulse repetition frequency (PRF), duty cycle (DC), and phase-locking patterns.
This review integrates two new analytical dimensions — the Full-Spectrum Evidence Map and the Four-Evidence × Spectrum Matrix — systematically evaluating 2021–2025 international literature across four evidence tiers: molecular mechanisms, behavioral validation, clinical translation, and engineering breakthroughs.
Section I Conceptual Reconstruction: From TUS to TANM
1.1 The Nomenclature Crisis and Hidden Conceptual Bias
The history of non-invasive brain stimulation nomenclature reveals a consistent pattern: terminology choices lock in a field's theoretical framework, shaping researchers' problem-consciousness and experimental design for years. Transcranial Magnetic Stimulation (TMS) emphasizes the physical mechanism; transcranial Direct Current Stimulation (tDCS) emphasizes the stimulation waveform; and Transcranial Ultrasound Stimulation (TUS/tFUS) embeds the frequency range into the very definition of the technology.
As research deepened, an increasingly clear fact emerged: in low-intensity neuromodulation applications, the parameters determining the directionality and magnitude of neural effects are not the carrier frequency, but rather the timing parameters operating in the audible and infrasound bands — pulse repetition frequency (PRF) and slow-wave modulation patterns.
A bibliometric analysis covering 2004–2024 literature shows annual TUS publications have grown exponentially since 2013 (Wang et al., 2025), yet 37.8% of experiments failed to report estimated intracranial acoustic intensity (inTUS DATABASE, 2025) — a problem rooted precisely in the absence of a conceptual framework.
1.2 The Four Core Claims of the TANM Framework
- Claim 1 · Frequency Neutrality: TANM does not presuppose a frequency range, encompassing the complete acoustic spectrum from infrasound (<20 Hz) through audible sound to ultrasound (>20 kHz). The ultrasound carrier is the most commonly used intracranial transmission medium but is neither the only one nor the primary determinant of effects.
- Claim 2 · Mechanistic Hierarchy Distinction: TANM explicitly distinguishes the "delivery layer" (ultrasound physics) from the "modulation layer" (neural oscillations), preventing conflation of transducer parameters with neural effect mechanisms.
- Claim 3 · Natural Interface with Neurodynamics: Core parameters (PRF, DC, phase-locking) map directly onto the neural oscillation spectrum (δ/θ/α/β/γ), enabling acoustic neuromodulation to embed naturally within neurodynamics theory.
- Claim 4 · Compatibility and Operability: TANM retains TUS/tFUS as engineering sub-categories, requires no renaming of existing literature, and ensures the framework's practical operability.
Section II Full-Spectrum Acoustic Neuromodulation: International Evidence Map
The following matrix maps TANM international evidence along two dimensions: frequency band (rows) and spectral position (columns). Color depth encodes evidence quality. Darker shading indicates stronger, higher-grade evidence.
| Band / Range | Infrasound <20 Hz |
Audible 20Hz–20kHz |
Low US 20–250 kHz |
Mid US 250–500 kHz |
High US >500 kHz |
Evidence Grade |
|---|---|---|---|---|---|---|
| δ / SWO 0.5–4 Hz |
Sleep Memory consol. |
CLAS system RCT validated |
Low-US PRF modulation |
tFUS phase- locking core |
High-res 1–5mm focus |
I-A RCT proven |
| θ / tb-TUS 4–8 Hz |
— | Binaural / isochronic beats |
tb-TUS LTP induction |
Cortical excitability + |
Deep targets hippocampus |
I-B Multi-site |
| α / CLAS 8–13 Hz |
— | CLAS sleep SOL −10 min |
PRF=10Hz MEP inhibition |
Primary PRF mod. band |
Fine focus 1–5mm |
I-A RCT n=21 |
| β/γ High 13–100 Hz |
— | Isochronic rhythm entrn. |
PRF=100Hz gamma gating |
Gamma inhib. prolonged |
Cortical circ. precision |
II-A Double-blind |
| US Carrier MHz level |
— | — | Cavitation / thermal |
Standard tFUS carrier |
HIFU ablation FDA cleared |
I-A FDA RCT |
- The delta/slow-wave band (0.5–4 Hz) has the most robust evidence of any TANM modulation target. Whether auditory CLAS (Ngo 2013 Neuron, RCT-validated) or ultrasonic PRF modulation, effects have achieved Grade I-A evidence in humans.
- The alpha band (8–13 Hz) CLAS sleep-onset intervention is backed by the highest-quality RCT evidence to date (Bressler 2024, Sci Rep, n=21, p=0.0019): SOL reduction of 9.62 minutes, efficacy equivalent to benzodiazepines without side effects.
- Theta/tb-TUS (4–8 Hz) demonstrates LTP-like synaptic plasticity induction effects, but Fong 2024's independent replication raises questions about reproducibility requiring multi-site validation.
- The ultrasound carrier (MHz level) makes limited direct contribution to neural effect directionality — its primary function is skull penetration and focal shaping. This is the central thesis of the TANM framework.
Section III TANM Four-Evidence × Full-Spectrum Matrix
Five major TANM modulation categories (rows) are evaluated against four independent evidence dimensions (columns), yielding an overall evidence grade for each domain. This multi-dimensional assessment reveals evidence completeness and identifies critical gaps.
| Evidence Dimension | Mechanistic (Molecular/Cell) |
Behavioral (Animal/Human) |
Clinical (RCT/Cohort) |
Engineering (Device/Precision) |
Overall Grade |
|---|---|---|---|---|---|
| δ / SWO modulation |
Piezo1/TRPV1 NMDA-LTP |
Ngo 2013 CLAS-RCT |
MADRS −61% n=5 TRD |
NEUSLeeP wearable CL |
★★★★★ |
| θ / tb-TUS | Synaptic plast. NMDA activ. |
Samuel 2022 MEP +30min |
Fong 2024 indep. replic.? |
80s protocol 5Hz envelope |
★★★☆☆ |
| α / CLAS sleep onset |
Phase reset coherence ↓ |
Bressler 2024 SOL −9.6min |
RCT n=21 p=0.0019 |
ENMod wearable PLV=0.92 |
★★★★☆ |
| Acoustic metamaterials |
Wavefront phase correction |
Skull aberr. ±0.09mm |
StimulUS 80% response |
Metalens/hTUS 3D-print $50–200 |
★★★★☆ |
| Closed-loop AI adaptive ctrl. |
Neural state real-time classif. |
NEUSLeeP REM extended |
Epilepsy resp. prototype |
EEG→AI→transducer <10ms latency |
★★★☆☆ |
- Delta/SWO modulation is the only TANM domain achieving high-quality levels across all four evidence dimensions (★★★★★) — the most mature pathway to clinical translation.
- Alpha/CLAS sleep onset has the highest-quality RCT evidence (p=0.0019), but requires paired BCI for commercialization.
- Acoustic metamaterials have definitively overcome the precision engineering bottleneck, extending deep-target millimeter-level accuracy to portable single-element devices.
- Theta/tb-TUS and Closed-loop AI have insufficient evidence but extremely high strategic value — the most critical gaps for the field's next phase.
Section IV Dual-Layer Frequency Parameter System and Neural Effect Directionality
4.1 Ultrasound Carrier Layer: Physical Constraints of Skull Penetration
The human skull causes 65–90% acoustic intensity attenuation in the 0.25–0.65 MHz typical neuromodulation band. Acoustic metamaterials (metalens, holographic lenses) now enable single-element transducers to achieve millimeter-level deep-target precision (Attali et al., 2025; Estrada & Razansky, 2025), fundamentally restructuring this constraint boundary.
4.2 Pulse Repetition Frequency (PRF): The Frequency-Selective Window for Neural Effects
PRF is the most critical neuromodulatory parameter in the TANM framework. A 2024 double-blind randomized sham-controlled study at the University of Calgary (n=30, target: M1) provided the most systematic PRF effect profile to date:
| PRF Condition | Neural Effect | Duration | Mechanism |
|---|---|---|---|
| 10 Hz (alpha band) | MEP significant inhibition (LTD-like) | ≥30 minutes | Alpha oscillation resonance gating |
| 100 Hz (gamma band) | MEP inhibition, stronger and more sustained | ≥60 minutes | Gamma-band hypersynchronization |
| 1000 Hz (supra-gamma) | No significant change in corticospinal excitability | Null | Exceeds oscillation frequency ceiling |
| Sham | Baseline | — | Control |
This result directly demonstrates that the key modulatory variable for neural effects is the temporal pattern of the pulse envelope (PRF), not the ultrasound carrier itself (Zadeh et al., 2024, Brain Stimulation).
4.3 Duty Cycle and the Online/Offline Dual-Track Model
Duty cycle (DC = pulse duration/pulse period × 100%) regulates effect directionality through control of time-averaged acoustic intensity (ISPTA): low DC (<10%) tends toward inhibition, while high DC shifts toward excitation (Fomenko et al., 2020; inTUS database, 2025). TANM neural effects exhibit a dual-track temporal architecture: online effects (sub-millisecond mechanical activation of ion channels) and offline effects (NMDA receptor-dependent synaptic plasticity changes persisting for tens of minutes to hours).
Section V Cross-Band Coupling: A Unified Four-Layer Temporal Model
5.1 Acoustic Theta-Burst Stimulation (tb-TUS)
Typical tb-TUS protocol: 80 seconds of training, each theta cycle (200 ms, 5 Hz) containing a 20 ms acoustic pulse, driving the ultrasound carrier (~500 kHz) through neural circuits at 5 Hz macroscopically. Preliminary evidence shows M1 cortical excitability enhancement lasting ~30 minutes (Samuel et al., 2022, 2023; Bao et al., 2024), but Fong 2024's independent replication raises questions about reproducibility.
5.2 Slow-Wave Phase-Locking
Slow-wave phase-locking represents the most precise dialogue between TANM and the delta rhythm (0.5–2 Hz). Dong et al. (2023, Cerebral Cortex) demonstrated that phase-locked tFUS during NREM sleep can increase hippocampal sharp-wave ripple rates and alter REM theta-gamma coupling via NMDA receptor modulation — with significant phase-dependence (non-phase-locked stimulation showed greatly attenuated effects). The NEUSLeeP system (bioRxiv 2025) achieved the world's first wearable closed-loop TANM for human sleep, significantly extending REM sleep duration.
5.3 Unified Four-Layer Temporal Coupling Model
- Layer 1 (millisecond scale): Ultrasound mechanical forces directly activate mechanosensitive ion channels (Piezo1, TRPV1, K2P), altering membrane permeability — the molecular gateway of neuromodulation.
- Layer 2 (10–100 ms scale): PRF-modulated pulse envelopes drive neurons at rhythms matching neural oscillation frequencies, analogous to resonance amplification — explaining why 10/100 Hz PRF is effective while 1000 Hz is not.
- Layer 3 (second scale): Theta-burst patterns form high/low-frequency nested structures over tens of seconds, inducing lasting synaptic weight changes through frequency-dependent NMDA receptor activation.
- Layer 4 (minutes–hours scale): Slow-wave phase-locking exploits the NREM cortical slow oscillation up-state as a natural time window for synaptic plasticity, amplifying the hippocampal-cortical memory consolidation chain.
Section VI The Acoustic Metamaterial Revolution
6.1 StimulUS Trial: Portable Millimeter-Level Deep Targeting
The StimulUS study (Attali et al., Brain Stimulation, April 2025) represents a landmark in TANM precision engineering. The individualized acoustic metalens system compensates skull phase delays through pre-distorted wavefronts:
| Parameter | Value | Clinical Significance |
|---|---|---|
| Target | Subcortical cingulate cortex (SCC) | Deep target unreachable by TMS |
| Targeting accuracy | 0.09 ± 0.07 mm | Neuronavigation-grade, single-element transducer |
| MADRS reduction | Mean 61% (range 30–84%) | 5 days, 25 stimulations — exceeds most pharmacotherapy |
| Response / Remission | 80% / 40% | Treatment-resistant depression (n=5) |
| Safety | No serious adverse events | Throughout all 25 stimulations |
6.2 Holographic TUS (hTUS) and 3D-Printed Lenses
The hTUS study from ETH Zurich's Razansky group (Nature BME, 2025) reports a dynamic multi-focal modulation pathway: three-dimensional acoustic field shaping through acoustic holograms reduces the activation excitability threshold by approximately one order of magnitude. 3D-printed acoustic holographic lenses (Applied Physics Letters, 2024) reduce skull aberration correction material costs to $50–200 per lens, providing a decisive cost-reduction pathway to clinical accessibility.
Section VII Molecular Basis: Mechanosensitive Channels and Cell-Type Selectivity
Piezo1: Zhu et al. (PNAS, 2023) demonstrated ultrasound-induced shear stress activates Piezo1, causing intracellular Ca²⁺ elevation and regulating neural excitability. TRPV1: Mechanically compatible sensing rather than thermal activation (requires >42°C). K2P two-pore potassium channels: Direct mechanical activation of TRAAK/TREK-1/2 constitutes an important molecular basis for TUS inhibitory effects.
A 2025 Journal of Neuroscience study revealed significant cell-type specificity: regular-spiking units (RSUs, excitatory pyramidal neurons) showed inhibitory responses to 30 Hz PRF, while fast-spiking units (FSUs, inhibitory interneurons) showed excitatory responses to 1500–3000 Hz PRF. Sonogenetics represents the theoretical limit of cell-type selectivity, with concept validation completed in C. elegans and mouse models.
Section VIII Clinical Translation: From Proof-of-Concept to Initial Efficacy Validation
8.1 Treatment-Resistant Depression (TRD)
TRD is the domain of fastest evidence accumulation in TANM clinical translation. TRD's deep neural circuit pathology (subcortical cingulate, ventral striatum) lies precisely in regions difficult to reach with TMS/tDCS. Beyond StimulUS (MADRS mean −61%, 5 days), Oh et al. 2024's double-blind Korean RCT validated safety and preliminary efficacy signals for low-intensity tFUS targeting prefrontal cortex.
8.2 Neurological and Psychiatric Applications
| Indication | Current Stage | Representative Evidence |
|---|---|---|
| Alzheimer's Disease | Early clinical validation | TPS targeting hippocampus; 63% cognitive improvement (Beisteiner 2020) |
| Parkinson's Disease | Dual-track strategy | UPDRS-III positive effects (Grippe 2024); HIFU ablation FDA-cleared |
| Disorders of Consciousness | Proof-of-concept | Accelerated behavioral responsiveness recovery (Cain 2022) |
| Schizophrenia | Preliminary RCT | DLPFC targeting, negative symptom improvement (Zhai 2023) |
| Chronic Pain | Multi-center reports | ACC/insular targeting, neuropathic pain relief (Legon 2024) |
| Sleep Disorders | Rapid progression | NEUSLeeP closed-loop system, REM extension (bioRxiv 2025) |
8.3 Safety Boundaries: ITRUSST 2023 Consensus
- Mechanical safety: Mechanical Index (MI) or transcranial MI (MItc) ≤ 1.9
- Thermal safety: Temperature rise <2°C, or thermal dose <0.25 CEM43, or exposure time controlled by Thermal Index (TI ≤ 2.0, max 80 minutes)
- Practical guidance: Low duty cycle (typically <10%) + appropriate pulse duration + adequate inter-stimulus intervals
- Adverse events: Headache (<5%), fatigue, occasional nausea; no serious neurological injury reported
- Auditory confound: Bone-conduction hearing activation from skull vibration requires acoustic shielding controls; standardized protocols established 2024–2025
Section IX TANM and AI Integration: Intelligent Closed-Loop Neuromodulation
Closed-loop TANM systems contain three real-time modules: (1) Sensing module — EEG/LFP real-time acquisition → neural state classification; (2) Decision module — AI model computes optimal stimulation parameters based on current neural state; (3) Execution module — transducer precision triggering, latency <10 ms. This architecture has been prototype-validated in the NEUSLeeP sleep modulation system and epilepsy-responsive neurostimulation systems.
Development of MRI-compatible transducers (ceramic/PVDF-based, 2023–2025) enables real-time TUS modulation under resting-state and task-based fMRI monitoring. TANM-BCI integration represents a promising neural rehabilitation pathway: BCI detects motor intent; TANM activates spinal cord/muscle targets; together forming an intent-activation closed loop.
Section X Methodological Challenges and Standardization Pathways
10.1 Parameter Reporting Inconsistency
The inTUS database (2024–2025) reveals that over 37% of studies failed to report estimated intracranial acoustic intensity, rendering inter-study dose comparisons foundationally incomparable. Solutions: enforce ITRUSST parameter reporting standards; promote computational acoustic field simulation software (k-Plan, BabelBrain); establish a skull acoustics database to support parameter estimation for individuals without CT imaging.
10.2 Effect Directionality Control
TANM effect directionality is jointly determined by PRF, DC, acoustic pressure, stimulation duration, online/offline paradigm, and individual neural state, with complex interactions among factors. Current univariate exploratory analyses are insufficient to establish reliable predictive models — a situation analogous to the TMS field in the 1990s, requiring systematically designed factorial experiments and larger-sample RCTs.
10.3 Individualized Precision Treatment
Individual differences in skull morphology, cortical thickness, sulcal orientation, and resting neural oscillation frequency collectively drive significant inter-subject variability. Tractography-based targeting (as employed in StimulUS) is the most feasible current pathway. AI-assisted individualized planning — using multimodal imaging data to predict optimal target coordinates with real-time protocol adjustment via neurophysiological biomarkers — is emerging as a new growth area.
Section XI Future Research Priority Agenda
Near-Term (1–3 Years): Standardization and Reproducibility
- Mandate reporting of estimated intracranial acoustic intensity (ISSPA_brain) in all human TANM studies; promote k-Plan and BabelBrain computational tools
- Establish cross-laboratory PRF-DC-effect directionality standardization curves using M1-TMS-MEP as standardized readout
- Conduct multi-center independent replication studies validating tb-TUS and slow-wave phase-locking effect reliability
- Establish standardized auditory confound control protocols distinguishing genuine neuromodulation from auditory-evoked pseudo-effects
Mid-Term (3–7 Years): Precision and Clinical Validation
- Complete Phase II/III RCTs of TANM in TRD, AD, and PD
- Develop and validate individualized neuroimaging-based closed-loop TANM treatment planning systems
- Explore synergistic effects of TANM combined with neuromodulatory pharmacotherapy
- Establish a long-term TANM safety follow-up database (≥2 years)
Long-Term (7–15 Years): Paradigm Breakthroughs
- Sonogenetics combined with gene therapy for sub-neuron-type precision acoustic modulation (NHP → human translation)
- Fully implantable miniature focused ultrasound devices for long-term closed-loop neuromodulation of chronic disease
- Multi-target synchronous TANM (holographic TUS + AI) for dynamic reconstruction of large-scale brain networks
- Exploratory applications of TANM in cognitive enhancement, neuroprotection, and anti-aging
Section XII Conclusions
- Acoustic timing parameters, not the ultrasound carrier frequency, govern neural effects. PRF demonstrates significant frequency-selective effects in the neural oscillation band (10–1000 Hz) and is the most important controllable parameter for predicting effect directionality.
- The full-spectrum evidence map reveals delta/SWO modulation as the most mature TANM domain. High-quality evidence across all four dimensions (★★★★★) represents the most certain current pathway to clinical translation.
- Acoustic metamaterials have fundamentally restructured TANM's precision boundaries. Portable individualized aberration correction extends deep-target millimeter-level precision from phased array systems to single-element portable devices — the decisive technical inflection point for TANM clinical accessibility.
- TANM clinical translation is advancing from proof-of-concept into initial efficacy validation. Early TRD data (MADRS mean −61%) are promising, but large-scale multi-center RCTs with rigorous design are urgently needed.
- Parameter standardization and effect reproducibility are the most urgent current methodological tasks. The TANM framework and the inTUS community database represent coordinated measures to systematically address the reproducibility crisis.
The field of non-invasive brain stimulation is undergoing a paradigm evolution driven by the fusion of acoustic physics, neural oscillation dynamics, and acoustic engineering. The defining characteristic of next-generation neuromodulation technologies will not be the physical distinction between "ultrasound" and "electromagnetic" modalities, but rather the depth of their dialogue with the brain's endogenous oscillatory dynamics.
References
- Attali D, et al. Deep transcranial ultrasound stimulation using personalized acoustic metamaterials improves treatment-resistant depression in humans. Brain Stimulation. 2025;18(3):1004-1014.
- Estrada H, Razansky D, et al. Holographic transcranial ultrasound neuromodulation enhances stimulation efficacy by cooperatively recruiting distributed brain circuits. Nature Biomedical Engineering. 2025 (July).
- Zadeh AK, et al. The effect of transcranial ultrasound pulse repetition frequency on sustained inhibition in the human primary motor cortex: A double-blind, sham-controlled study. Brain Stimulation. 2024.
- Bressler S, Neely R, Yost RM, Wang D. A randomized controlled trial of alpha phase-locked auditory stimulation to treat symptoms of sleep onset insomnia. Scientific Reports. 2024;14:13039.
- Ngo HV, Martinetz T, Born J, Molle M. Auditory closed-loop stimulation of the sleep slow oscillation enhances memory. Neuron. 2013;78:545-553.
- Dong S, Xie Z, Yuan Y. Transcranial ultrasound stimulation modulates neural activities during NREM and REM depending on the stimulation phase. Cerebral Cortex. 2023.
- Zhu J, et al. The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation. PNAS. 2023;120:e2300291120.
- Fomenko A, et al. Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior. eLife. 2020;9:e54497.
- Samuel A, et al. Theta-burst transcranial focused ultrasound stimulation. Series of studies 2022-2023.
- Bao SC, et al. Theta-burst focused ultrasound stimulation of primary motor cortex. Brain Stimulation. 2024.
- NEUSLeeP: Wearable Focused Ultrasound Neuromodulation and Electrophysiological Recording Platform. bioRxiv. 2025.
- inTUS Community Resource. Neuromodulation with Ultrasound: Hypotheses on the Directionality of Effects. eLife (reviewed preprint). 2024-2025.
- ITRUSST Consortium. Safety and Standards for Transcranial Ultrasonic Stimulation. 2023 Consensus Guidelines.
- Wang X, et al. Transcranial ultrasound stimulation in neuromodulation: a bibliometric analysis 2004-2024. Frontiers in Neuroscience. 2025.
- JNeurosci 2025. Transcranial focused ultrasound modulates feedforward and feedback cortico-thalamo-cortical pathways. Journal of Neuroscience. 2025.
- Acoustic holographic lenses for transcranial focusing in ex vivo human skull. Applied Physics Letters. 2024.
- Legon W, Strohman A. Low-intensity focused ultrasound for human neuromodulation. Nature Reviews Methods Primers. 2024.
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