A Comprehensive Review of Low-Intensity Focused Ultrasound Parameters and Applications in Neurologic and Psychiatric Disorders

Treatments for neuropsychiatric disorders (depression, anxiety, chronic pain) have historically relied on pharmacologic and behavioral interventions, but there is growing interest in circuit-based neuromodulatory approaches. Implanted modalities like DBS and VNS can reach deep structures but require surgery and have risks; noninvasive options such as TMS and tDCS improve outcomes in some disorders but are limited to cortical targets and have relatively coarse spatial fidelity. In contrast, transcranial low-intensity focused ultrasound (LIFU) can noninvasively stimulate both deep and focal brain regions, opening access to therapeutic interventions previously infeasible. Early evidence for ultrasound neuromodulation dates to the 20th century, but interest surged in the 21st century with preclinical studies showing modulation of ion channels and induction of motor responses in animals. The review frames LIFU’s potential in the context of neuromodulation’s evolution, emphasizing its unique combination of focality, depth, and compatibility with neuroimaging.

The review synthesizes recent LIFU literature across three domains. First, it traces the history of ultrasound as a neuromodulatory tool, noting early demonstrations of reversible suppression of neuronal firing and vision-related potentials, and the subsequent resurgence driven by modern preclinical findings of mechanosensitive ion channel modulation and behavioral effects in animals. Second, it details LIFU stimulus parameter space—fundamental frequency, intensity metrics (ISPTA, ISPPA), mechanical index, pulse repetition frequency, duty cycle, pulse width, sonication duration—and their relationships to focality, skull attenuation, and biological outcomes. The literature suggests intensity and pulsing schemes influence excitatory versus inhibitory effects, with evidence for short/low-DC pulses tending toward inhibition and longer/higher-DC toward excitation, alongside mixed findings challenging simple polarity rules. Third, it consolidates clinical applications across neurologic and psychiatric conditions: motor cortex studies showing improved reaction times and motor evoked potentials; somatosensory cortex and thalamus studies demonstrating modulation of sensory evoked potentials, tactile percepts, and increased thermal pain thresholds; insula-targeted studies affecting pain ratings and autonomic measures; mood and anxiety research indicating changes in approach/withdrawal behaviors, mood, and functional connectivity, including RCTs in MDD; AD and neurodegenerative studies indicating metabolic and cognitive changes; DOC trials reporting transient improvements without durable gains; and SUD-focused NAc studies demonstrating safety, feasibility, and reduced cue-induced craving.

This is a comprehensive narrative review of recent LIFU neuromodulation literature. The authors organize the synthesis into: 1) historical context and comparison to other neuromodulation modalities; 2) technical parameters and proposed mechanisms of LIFU (including stimulus frequencies, intensities, pulsing protocols, duty cycle, sonication duration, and mechanical index); and 3) consolidation of clinical research across multiple neuropsychiatric domains and targets. Target engagement modalities discussed include magnetic resonance spectroscopy (demonstrating local neurochemical changes, e.g., GABA), BOLD fMRI and arterial spin labeling for perfusion/activity changes, and EEG for cortical evoked potentials, as well as computational modeling of acoustic propagation. The review does not describe a formal systematic search strategy (databases, inclusion/exclusion criteria), but emphasizes current peer-reviewed human studies, pilot trials, and preclinical research to describe safety, efficacy, and mechanistic insights.

LIFU parameters and mechanisms: - Frequency in the 250–650 kHz range balances skull attenuation and focal resolution for human applications. Intensity metrics (ISPTA, ISPPA) and MI relate to biological and adverse effect risks; effects are intensity- and pulse-parameter dependent. Evidence suggests low-intensity effects are primarily mechanical via acoustic radiation force on mechanosensitive ion channels; thermal contributions are negligible and cavitation unlikely at clinical intensities. - Pulsing protocols influence polarity: shorter pulses/low duty cycles more often inhibitory; longer pulses/higher duty cycles more often excitatory, though findings are mixed and challenge the modified NICE model. Target engagement and neuroplasticity: - MRS shows sustained GABA changes up to 50 minutes post-sonication (posterior cingulate). BOLD and ASL confirm target activity changes (ASL shows inhibition lasting minutes vs seconds for BOLD). EEG demonstrates sonication-specific evoked potentials in somatosensory targets. Motor function: - M1 LIFU in healthy adults reduced reaction times in simple and visuomotor tasks, potentiated movement-related cortical potentials, decreased movement time, increased motor evoked potentials during sonication, and improved motor inhibitory control (decreased stop-signal time) compared to sham. Somatosensation and pain: - S1 LIFU significantly attenuated SEP amplitudes and modulated spectral content; improved two-point and vibration frequency discrimination versus sham. Sonication elicited transient, anatomically specific tactile sensations contralaterally; simultaneous SI/SII stimulation produced tactile percepts. - Thalamic sonication altered SEP amplitude and task performance; MRI-guided anterior thalamus LIFU (two 10-min sessions) increased thermal pain thresholds and blunted sensitization in healthy subjects. - In chronic pain patients, unfocused dUS to posterior frontal cortex improved mood at 10 and 40 minutes versus sham; pain ratings trended lower but were not significant (p = 0.07). Insula and autonomic effects: - AI and PI LIFU reduced perceived pain to noxious stimuli; AI sonication affected heart rate variability, indicating autonomic modulation alongside pain modulation. Mood and anxiety disorders: - Right PFC LIFU (>150 volunteers) shifted behavior toward approach and reduced withdrawal in a virtual T-maze without subjective mood change. - rIFG LIFU increased self-reported mood (20–30 minutes post), increased FC between rIFG and right middle frontal gyrus, and decreased FC with other prefrontal/limbic areas; DMN regions showed general FC decreases. - In mildly depressed participants (n=24), 5-day right frontotemporal sonication did not change mood but reduced trait worry compared with placebo. - RCT in MDD: left dorsolateral PFC LIFU (6 sessions over 6 weeks) significantly improved MADRS during treatment and 2 weeks post; increased rsFC between subgenual ACC and medial PFC/MFG/OFC (no correlation between rsFC change and symptom change reported). - Treatment-refractory GAD (n=25): weekly right amygdala LIFU (10 minutes for 8 weeks) led to 60% achieving >30% reduction in HAM-A, 32% remission (HAM-A <14), and 64% reporting PGI-I >2. Substance use disorders: - NAc sonication was safe and well tolerated; increased FC between NAc and medial PFC; enhanced-dose LIFU attenuated cue-induced craving, with reductions persisting up to 90 days post-treatment. Neurologic disorders (dementia/AD, PD): - AD pilot (hippocampal LIFU): increased resting cerebral glucose metabolism (superior frontal gyrus, middle cingulate, fusiform), mild improvements in memory/executive/global cognition, no BBB opening. - TPS (frontoparietal lobe, AD): improved language and memory lasting 3 months; neuropsychologic improvements correlated with increased cortical thickness and FC between frontal cortex and hippocampus. - Neurodegenerative dementia (AD/PD) with dUS: mixed outcomes; most patients’ cognition remained stable; 62.5% improved cognitive scores; 87–87.5% stable or improved fine/gross motor scores. Disorders of consciousness: - Preliminary thalamic LIFU studies (chronic DOC): some initial CRS-R improvements, one decrease; no maintained functional gains at 3–6 months. Safety/tolerability: - Across trials, no serious adverse events reported; multiple studies explicitly report none, and imaging showed no edema or hemorrhage.

The compiled evidence supports LIFU as a noninvasive modality capable of modulating both cortical and deep brain structures with high spatial precision. Mechanistically, the literature converges on mechanical interactions—acoustic radiation force affecting mechanosensitive ion channels in neurons and glia—producing online effects and potentially offline neuroplastic changes via NMDA receptor-dependent LTP/LTD. Imaging and electrophysiology confirm target engagement and parameter-dependent modulation. Clinically, LIFU demonstrates promise in improving motor behavior, sensory discrimination and pain thresholds, modulating mood-related behaviors and functional connectivity, reducing anxiety symptoms, and attenuating substance craving, with early signals in dementia and DOC. The findings address the central hypothesis that LIFU can safely and effectively influence deep neurocircuitry relevant to neuropsychiatric disorders. However, heterogeneity in outcomes, mixed results regarding excitatory vs inhibitory polarity, and limited durability in some populations underscore the need to refine parameter regimes, personalize targets based on tissue/cell-type composition, and expand rigorous trials to establish efficacy and mechanisms.

LIFU combines noninvasiveness with focal, deep-brain targetability, positioning it as a potentially transformative neuromodulation tool for neuropsychiatric conditions. The review synthesizes current knowledge of parameters, mechanisms, target engagement, and clinical applications across motor function, pain, mood and anxiety disorders, dementia, DOC, and substance use, highlighting a favorable safety profile. Future work should prioritize: 1) definitive mechanistic studies clarifying ion-channel and cell-type contributions (neuronal vs glial, white vs gray matter), 2) systematic optimization of sonication parameters to achieve desired polarity and durable effects, 3) standardized protocols and intracranial dose estimation, 4) larger randomized controlled trials with long-term follow-up in targeted clinical populations, and 5) integration with neuroimaging/EEG for precise targeting and biomarker development.

As a narrative review, formal systematic search methods and inclusion/exclusion criteria are not specified. Many cited studies are small, pilot, or single-site with limited sample sizes and sham controls; durability of effects is often short-term and variable (e.g., DOC improvements not maintained at 3–6 months). Reported intensities frequently reference free-water measurements rather than intracranial estimates, complicating dose comparisons. Parameter-outcome relationships (e.g., duty cycle predicting polarity) show inconsistencies across studies. Mechanistic understanding remains incomplete (thermal negligible; cavitation unlikely; acoustic radiation force/mechanosensitive channels implicated but not definitively established for all targets). Generalizability across populations and optimal targeting strategies require further investigation.