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Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety

Open AccessPublished:May 06, 2022DOI:https://doi.org/10.1016/j.brs.2022.05.002

      Highlights

      • TUS was investigated in patients with depression, epilepsy, dementia, pain and TBI.
      • Both unfocused diagnostic and focused devices was safely used for neuromodulation.
      • The effects appear to be dose-dependent and varying with distinct parameters.
      • No severe adverse events (AEs) has been reported.
      • Mild/moderate AEs were reported in 3% of individuals.

      Abstract

      Background

      Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers.

      Objective

      The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation.

      Methods

      A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included.

      Results

      A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis.

      Conclusions

      Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

      Keywords

      1. Introduction

      Since its first medical application in 1950s, ultrasound has evolved from a sensing and diagnostic tool to a treatment modality with extensive applications such as modulation of electrically-active tissues, opening the blood-brain barrier, drug delivery, and tissue ablation [
      • Meng Y.
      • Hynynen K.
      • Lipsman N.
      Applications of focused ultrasound in the brain: from thermoablation to drug delivery.
      ]. Transcranial ultrasound stimulation (TUS) is an increasingly popular, non-invasive form of neuromodulation, which is being rapidly and broadly investigated in novel therapeutic roles [
      • Darmani G.
      • Bergmann T.O.
      • Butts Pauly K.
      • Caskey C.F.
      • de Lecea L.
      • Fomenko A.
      • et al.
      Non-invasive transcranial ultrasound stimulation for neuromodulation.
      ]. Alongside other forms of non-invasive brain stimulation (NIBS) such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), TUS has been demonstrated to be safe and promising in initial human studies [
      • Hameroff S.
      • Trakas M.
      • Duffield C.
      • Annabi E.
      • Gerace M.B.
      • Boyle P.
      • et al.
      Transcranial ultrasound (TUS) effects on mental states: a pilot study.
      ,
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ,
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Monti M.M.
      • Schnakers C.
      • Korb A.S.
      • Bystritsky A.
      • Vespa P.M.
      Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report.
      ,
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ,
      • Legon W.
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      Neuromodulation with single-element transcranial focused ultrasound in human thalamus.
      ,
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ,
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ,
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ,
      • Badran B.W.
      • Caulfield K.A.
      • Stomberg-Firestein S.
      • Summers P.M.
      • Dowdle L.T.
      • Savoca M.
      • et al.
      Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
      ,
      • Brinker S.T.
      • Preiswerk F.
      • White P.J.
      • Mariano T.Y.
      • McDannold N.J.
      • Bubrick E.J.
      Focused ultrasound platform for investigating therapeutic neuromodulation across the human Hippocampus.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Sanguinetti J.L.
      • Hameroff S.
      • Smith E.E.
      • Sato T.
      • Daft C.M.W.
      • Tyler W.J.
      • et al.
      Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans.
      ,
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ,
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ,
      • Jeong H.
      • Im J.J.
      • Park J.S.
      • Na S.H.
      • Lee W.
      • Yoo S.S.
      • et al.
      A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.
      ,
      • Johnstone A.
      • Nandi T.
      • Martin E.
      • Bestmann S.
      • Stagg C.
      • Treeby B.
      A range of pulses commonly used for human transcranial ultrasound stimulation are clearly audible.
      ,
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ,
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ,
      • Stern J.M.
      • Spivak N.M.
      • Becerra S.A.
      • Kuhn T.P.
      • Korb A.S.
      • Kronemyer D.
      • et al.
      Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.
      ,
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ,
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ,
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ,
      • Guerra A.
      • Vicenzini E.
      • Cioffi E.
      • Colella D.
      • Cannavacciuolo A.
      • Pozzi S.
      • et al.
      Effects of transcranial ultrasound stimulation on trigeminal blink reflex excitability.
      ,
      • Cain J.A.
      • Spivak N.M.
      • Coetzee J.P.
      • Crone J.S.
      • Johnson M.A.
      • Lutkenhoff E.S.
      • et al.
      Ultrasonic thalamic stimulation in chronic disorders of consciousness.
      ,
      • Braun V.
      • Blackmore J.
      • Cleveland R.O.
      • Butler C.R.
      Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked.
      ,
      • Reznik S.J.
      • Sanguinetti J.L.
      • Tyler W.J.
      • Daft C.
      • Allen J.J.B.
      A double-blind pilot study of transcranial ultrasound (TUS) as a five-day intervention: TUS mitigates worry among depressed participants.
      ,
      • Heimbuch I.S.
      • Fan T.
      • Wu A.
      • Faas G.C.
      • Charles A.C.
      • Iacoboni M.
      Ultrasound stimulation of the motor cortex during tonic muscle contraction.
      ,
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ,
      • Schimek N.
      • Burke-Conte Z.
      • Abernethy J.
      • Schimek M.
      • Burke-Conte C.
      • Bobola M.
      • et al.
      Repeated application of transcranial diagnostic ultrasound towards the visual cortex induced illusory visual percepts in healthy participants.
      ,
      • Lambert J.
      • Mouraux A.
      Transcranial focused ultrasonic stimulation to modulate the human primary somatosensory cortex.
      ].
      The current surge of popularity in TUS research is motivated by ultrasound's ability to be focused to a high spatial resolution, its efficacy in targeting deep brain structures, and its relatively low cost, and favorable safety profile [
      • Fomenko A.
      • Neudorfer C.
      • Dallapiazza R.F.
      • Kalia S.K.
      • Lozano A.M.
      Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications.
      ]. The associated rapid growth in the relevant body of literature, combined with the accelerating breadth of novel applications of TUS can be challenging for physicians and researchers to assimilate and translate, as well as to integrate into new clinical studies. This is especially salient considering that long-term utility and optimal protocols to maximize effect are continually being elucidated. Thus, the goal of the present work is to systematically review the human clinical studies of TUS neuromodulation with an emphasis on historical progress, TUS devices used, sonication parameters, outcome measures, results, and adverse effects (AEs), as well as to highlight future directions of investigation. The list of all included articles and search methods were given in Table 1 and Supplementary Material, respectively.
      Table 1Characteristics of human TUS studies and Adverse Effect Profile.
      Author, Year# of SubjectsCohortTUS targetTUS deviceTotal # of Subjects with AEs
      Mild/moderate (transient)Severe (persistent)
      Hameroff, 201331Chr. Painpos FLdUS10
      Legon, 201430HealthyS1fTUSNRNR
      Muller, 201425HealthyS1fTUSNRNR
      Lee, 201512HealthyS1fTUS00
      Monti, 20161TBI/DOCThalamusfTUS00
      Ai, 20167HealthyM1, CdfTUSNRNR
      Lee, 2016(2)29HealthyV1fTUS00
      Lee, 201610HealthyS1/2fTUS00
      Legon, 2018(2)
      The subjects of these three trials together with 27 individuals of an unpublished trial from University of Minnesota were screened by email for adverse effects. The results were published as a separate article [44]. 7/64 of the individuals reported mild or moderate symptoms including neck pain, difficulty paying attention, muscle twitches and anxiety.
      40HealthyThalamusfTUSNRNR
      Legon, 2018
      The subjects of these three trials together with 27 individuals of an unpublished trial from University of Minnesota were screened by email for adverse effects. The results were published as a separate article [44]. 7/64 of the individuals reported mild or moderate symptoms including neck pain, difficulty paying attention, muscle twitches and anxiety.
      50HealthyM1fTUS+
      exact number not given in the original article.
      0
      Ai, 2018
      The subjects of these three trials together with 27 individuals of an unpublished trial from University of Minnesota were screened by email for adverse effects. The results were published as a separate article [44]. 7/64 of the individuals reported mild or moderate symptoms including neck pain, difficulty paying attention, muscle twitches and anxiety.
      5HealthyM1fTUSNRNR
      Gibson, 201840HealthyM1dUS00
      Nicodemus, 201922DementiaMTL, SNdUS00
      Beisteiner, 202035/10Dementia/HealthyPL-FL-PCUN/S1fTUS-TPS2
      Among the two study centers, only Center 1 (n = 19) performed a detailed quantification that revealed a patient with mood deterioration and another with a headache (positive headache history).
      0
      Badran, 202019HealthythalamusfTUS00
      Brinker, 20201DREHCPfTUS00
      Fomenko, 202018HealthyM1fTUS20
      Reznik, 202024DepressionFTLfTUSNRNR
      Sanguinetti, 202048HealthyPFCfTUSNRNR
      Yu, 202115HealthyM1fTUS0
      7/15 subjects experienced a tingling sensation on scalp while pulse repetition frequency is 3000 Hz.
      0
      Braun, 202018HealthyV1fTUSNRNR
      Schimek, 202021HealthyV1dUS00
      Lambert, 20207HealthyS1fTUS00
      Cain, 202116HealthyGPfTUSNRNR
      Heimbuch, 202110HealthyM1fTUSNRNR
      Jeong, 20214DementiaHCPfTUS00
      Lee, 20226DRESOZfTUS20
      Liu, 20219HealthyS1fTUS00
      Stern, 20218DREMTLfTUS00
      Xia, 202127HealthyM1fTUSNRNR
      Zeng, 202220HealthyM1/V1fTUS00
      Zhang, 202124HealthyM1fTUS00
      Guerra, 202116HealthySN, NRM, SCdUS00
      Jonstone, 202116HealthyInionfTUSNRNR
      Cain, 20213TBI/DOCThalamusfTUS00
      TOTAL6777+0
      “Hameroff, 2013” reported one patient with a transient headache. “Fomenko, 2020” noted 2 subjects, who reported a transient warm sensation at the sonication site. “Lee, 2021” included one subject with scalp heating and one subject with an impairment in naming and memory lasting a week (link to fTUS is weak).
      a exact number not given in the original article.
      b Among the two study centers, only Center 1 (n = 19) performed a detailed quantification that revealed a patient with mood deterioration and another with a headache (positive headache history).
      c 7/15 subjects experienced a tingling sensation on scalp while pulse repetition frequency is 3000 Hz.
      d The subjects of these three trials together with 27 individuals of an unpublished trial from University of Minnesota were screened by email for adverse effects. The results were published as a separate article [
      • Popescu T.
      • Pernet C.
      • Beisteiner R.
      Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: a follow-up study.
      ]. 7/64 of the individuals reported mild or moderate symptoms including neck pain, difficulty paying attention, muscle twitches and anxiety.

      2. Milestones of human TUS studies

      The utilization of TUS in humans is in its infancy as the first human study dates back to 2013 (Fig. 1). This seminal publication was a double-blind crossover study that showed improvement of pain and mood scores after sonication of the frontal cortex in patients with chronic pain [
      • Hameroff S.
      • Trakas M.
      • Duffield C.
      • Annabi E.
      • Gerace M.B.
      • Boyle P.
      • et al.
      Transcranial ultrasound (TUS) effects on mental states: a pilot study.
      ]. One year later, it was shown that TUS modulated the activity of the primary somatosensory cortex (S1) [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ], as well as intrinsic and evoked electroencephalography (EEG) dynamics [
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ]. Later, direct effects of TUS were demonstrated as sonication of S1 produced phantom sensations in the hand and elicited sonication-specific evoked potentials [
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ]. The same group showed similarities between visual-evoked potentials (VEP) from photic stimulation and primary visual cortex (V1) TUS-evoked potentials [
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ], induced phosphenes by V1 sonication [
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ] and used multiple transducers to stimulate different regions simultaneously [
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ].
      Fig. 1
      Fig. 1Milestones in the application of low-intensity transcranial ultrasound to human subjects. Highlighted studies report the first instance of modulation of a particular neurophysiological outcome, first application in a specific brain target/patient population, or a particularly important insight in the technical application of transcranial ultrasound. AD: Alzheimer's Disease; BOLD: blood oxygen level dependent; EEG: electroencephalography; ESI: electrophysiological source imaging; fMRI: functional magnetic resonance imaging; MEP: motor evoked potential; MRCP: movement related cortical potential; PET: positron emission tomography; S1: primary somatosensory cortex; SEEG: stereoelectroencephalography; SEP: Somatosensory-evoked potential; TBI: traumatic brain injury; TMS: transcranial magnetic stimulation; TUS: transcranial ultrasound.
      In 2016, Ai et al. published the first functional magnetic resonance imaging (fMRI)-TUS study and revealed the potential of TUS to induce changes in blood oxygen-level dependent (BOLD) signals [
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ]. The same year, Monti et al. presented a case report of patient with traumatic brain injury who received thalamic TUS and later showed clinical improvement [
      • Monti M.M.
      • Schnakers C.
      • Korb A.S.
      • Bystritsky A.
      • Vespa P.M.
      Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report.
      ]. The first TMS – motor-evoked potential (MEP) studies were published in 2018 [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ]. While focused transcranial ultrasound stimulation (fTUS) attenuated TMS-evoked MEP amplitudes during stimulation (online effect) in one study [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ], another showed the opposite effect with diagnostic ultrasound (dUS) after stimulation (offline effect) [
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ]. In the following year, trials in patients with dementia were reported [
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ,
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ].
      The growth of TUS human studies has recently increased as more than half of the studies to date were published in 2020 or later. The safety of TUS has been shown in two new patient cohorts: drug-resistant epilepsy [
      • Brinker S.T.
      • Preiswerk F.
      • White P.J.
      • Mariano T.Y.
      • McDannold N.J.
      • Bubrick E.J.
      Focused ultrasound platform for investigating therapeutic neuromodulation across the human Hippocampus.
      ] and depression [
      • Reznik S.J.
      • Sanguinetti J.L.
      • Tyler W.J.
      • Daft C.
      • Allen J.J.B.
      A double-blind pilot study of transcranial ultrasound (TUS) as a five-day intervention: TUS mitigates worry among depressed participants.
      ]. fTUS studies in healthy subjects showed that MEP suppression during sonication and its effects depend on the sonication parameters [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ], pain thresholds can be altered [
      • Badran B.W.
      • Caulfield K.A.
      • Stomberg-Firestein S.
      • Summers P.M.
      • Dowdle L.T.
      • Savoca M.
      • et al.
      Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
      ], and auditory confounding associated with TUS can be masked by delivering an audio waveform through earphones [
      • Braun V.
      • Blackmore J.
      • Cleveland R.O.
      • Butler C.R.
      Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked.
      ]. Neurophysiological demonstration of motor cortical plasticity induction by repetitive fTUS [
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ] and theta-burst fTUS protocols [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] was among the biggest achievements of the year 2021. Other achievements of that year include the utilization of positron emission tomography to assess cerebral glucose metabolism in dementia patients [
      • Jeong H.
      • Im J.J.
      • Park J.S.
      • Na S.H.
      • Lee W.
      • Yoo S.S.
      • et al.
      A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.
      ], modulation of brainstem excitability tested by blink reflex [
      • Guerra A.
      • Vicenzini E.
      • Cioffi E.
      • Colella D.
      • Cannavacciuolo A.
      • Pozzi S.
      • et al.
      Effects of transcranial ultrasound stimulation on trigeminal blink reflex excitability.
      ], and assessment of stereoelectroencephalography (SEEG) recordings and histology of tissues in patients with epilepsy [
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ,
      • Stern J.M.
      • Spivak N.M.
      • Becerra S.A.
      • Kuhn T.P.
      • Korb A.S.
      • Kronemyer D.
      • et al.
      Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.
      ].

      3. TUS devices used in human studies

      The device models utilized in human studies were summarized in Table 2. Devices can be broadly divided into two categories; 1) focused transcranial ultrasound stimulation (fTUS), and 2) unfocused diagnostic ultrasound (dUS) devices. In order to better describe the operation of these systems, it is first necessary to review the relevant acoustic principles. For instance, increasing the fundamental frequency (f0) decreases the focal spot size, but leads to higher attenuation of sound waves by the skull. Several studies demonstrated that the optimum acoustic f0 for skull penetration is below 700 kHz [
      • Darmani G.
      • Bergmann T.O.
      • Butts Pauly K.
      • Caskey C.F.
      • de Lecea L.
      • Fomenko A.
      • et al.
      Non-invasive transcranial ultrasound stimulation for neuromodulation.
      ,
      • White P.J.
      • Clement G.T.
      • Hynynen K.
      Local frequency dependence in transcranial ultrasound transmission.
      ]. In addition, the focal spot size also decreases with increasing the aperture size of the transducer [
      • Kim S.
      • Jo Y.
      • Kook G.
      • Pasquinelli C.
      • Kim H.
      • Kim K.
      • et al.
      Transcranial focused ultrasound stimulation with high spatial resolution.
      ].
      Table 2TUS devices used in human trials.
      1) Focused Transcranial Ultrasound Stimulation DevicesPublication
      Custom-made[
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ,
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ,
      • Legon W.
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      Neuromodulation with single-element transcranial focused ultrasound in human thalamus.
      ,
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ,
      • Brinker S.T.
      • Preiswerk F.
      • White P.J.
      • Mariano T.Y.
      • McDannold N.J.
      • Bubrick E.J.
      Focused ultrasound platform for investigating therapeutic neuromodulation across the human Hippocampus.
      ,
      • Sanguinetti J.L.
      • Hameroff S.
      • Smith E.E.
      • Sato T.
      • Daft C.M.W.
      • Tyler W.J.
      • et al.
      Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans.
      ,
      • Heimbuch I.S.
      • Fan T.
      • Wu A.
      • Faas G.C.
      • Charles A.C.
      • Iacoboni M.
      Ultrasound stimulation of the motor cortex during tonic muscle contraction.
      ]
      Commercialized
      AT31529 (Blatek Industries, Inc., Boalsburg, PA, USA)[
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ,
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ]
      BXPulsar (BrainSonix Inc., Sherman Oaks, CA, USA)[
      • Monti M.M.
      • Schnakers C.
      • Korb A.S.
      • Bystritsky A.
      • Vespa P.M.
      Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report.
      ,
      • Badran B.W.
      • Caulfield K.A.
      • Stomberg-Firestein S.
      • Summers P.M.
      • Dowdle L.T.
      • Savoca M.
      • et al.
      Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
      ,
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ,
      • Stern J.M.
      • Spivak N.M.
      • Becerra S.A.
      • Kuhn T.P.
      • Korb A.S.
      • Kronemyer D.
      • et al.
      Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.
      ,
      • Cain J.A.
      • Spivak N.M.
      • Coetzee J.P.
      • Crone J.S.
      • Johnson M.A.
      • Lutkenhoff E.S.
      • et al.
      Ultrasonic thalamic stimulation in chronic disorders of consciousness.
      ]
      DWL Doppler-BoxX (Compumedics Germany GmbH, Singen, Germany)[
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ]
      H-series (Sonic Concepts Inc., Bothell, WA, USA)[
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Johnstone A.
      • Nandi T.
      • Martin E.
      • Bestmann S.
      • Stagg C.
      • Treeby B.
      A range of pulses commonly used for human transcranial ultrasound stimulation are clearly audible.
      ,
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ,
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ,
      • Braun V.
      • Blackmore J.
      • Cleveland R.O.
      • Butler C.R.
      Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked.
      ]
      NaviFUS (NaviFUS Corp., Taipei City, Taiwan)[
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ]
      NS-US100 (Neurosona Co., Ltd., Seoul, Korea)[
      • Jeong H.
      • Im J.J.
      • Park J.S.
      • Na S.H.
      • Lee W.
      • Yoo S.S.
      • et al.
      A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.
      ]
      U+ (Neurotrek Inc., Los Gatos, CA, USA)[
      • Reznik S.J.
      • Sanguinetti J.L.
      • Tyler W.J.
      • Daft C.
      • Allen J.J.B.
      A double-blind pilot study of transcranial ultrasound (TUS) as a five-day intervention: TUS mitigates worry among depressed participants.
      ]
      V391-SU (Olympus NDT, Inc., Waltham, MA, USA)[
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ]
      GPS-350-D25-P50 (Ultran, USA)[
      • Lambert J.
      • Mouraux A.
      Transcranial focused ultrasonic stimulation to modulate the human primary somatosensory cortex.
      ]
      Transcranial Pulse System
      NEUROLITH (Storz Medical AG, Tägerwilen, Switzerland)[
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ]
      2) Diagnostic Unfocused Ultrasound Devices
      Acuson 4P1 Phased Array Probe with Siemens S2000 (Siemens Healthcare GmbH, Erlangen, Germany)[
      • Guerra A.
      • Vicenzini E.
      • Cioffi E.
      • Colella D.
      • Cannavacciuolo A.
      • Pozzi S.
      • et al.
      Effects of transcranial ultrasound stimulation on trigeminal blink reflex excitability.
      ]
      CX50 Diagnostic Imaging Ultrasound System (Philips, Amsterdam, Netherlands)[
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ]
      L25x transducer attached to a Sonosite M-Turbo Ultrasound system (FUJI Sonosite, Bothell, WA, USA)[
      • Schimek N.
      • Burke-Conte Z.
      • Abernethy J.
      • Schimek M.
      • Burke-Conte C.
      • Bobola M.
      • et al.
      Repeated application of transcranial diagnostic ultrasound towards the visual cortex induced illusory visual percepts in healthy participants.
      ]
      LOGIQ e Ultrasound System with a 12L-RS probe (GE Healthcare, North Richland Hills, TX, USA)[
      • Hameroff S.
      • Trakas M.
      • Duffield C.
      • Annabi E.
      • Gerace M.B.
      • Boyle P.
      • et al.
      Transcranial ultrasound (TUS) effects on mental states: a pilot study.
      ]
      In light of these principles, the differences between fTUS and dUS systems can be summarized as;
      • a)
        fTUS can focus the beam unto a relatively small area compared to divergent beams of dUS affecting larger areas [
        • di Biase L.
        • Falato E.
        • Di Lazzaro V.
        Transcranial focused ultrasound (tFUS) and transcranial unfocused ultrasound (tUS) neuromodulation: from theoretical principles to stimulation practices.
        ].
      • b)
        fTUS devices allow pulsed-wave protocols, whereas dUS devices usually use continuous-wave patterns [
        • di Biase L.
        • Falato E.
        • Di Lazzaro V.
        Transcranial focused ultrasound (tFUS) and transcranial unfocused ultrasound (tUS) neuromodulation: from theoretical principles to stimulation practices.
        ].
      • c)
        dUS devices operate at high f0 (1–15 MHz) for high-quality image resolution, whereas the f0 in fTUS devices is usually set <700 kHz [
        • Darmani G.
        • Bergmann T.O.
        • Butts Pauly K.
        • Caskey C.F.
        • de Lecea L.
        • Fomenko A.
        • et al.
        Non-invasive transcranial ultrasound stimulation for neuromodulation.
        ].
      • d)
        Transducer shapes (acoustic lens focusing concave or multi-channel phase focusing flat for fTUS, convex for dUS) and aperture size differ between systems.
      Transcranial pulse stimulation (TPS) with ultrasound (NEUROLITH, Storz Medical, Switzerland) is a new CE-approved technique that differs from conventional fTUS. The TPS system generates single ultrashort (3μs) ultrasound pulses with energy levels of 0.2–0.3 mj mm−2 and pulse frequencies of 1–5 Hz. These shockwave-like, single pulses have a large positive peak amplitude which is followed by a smaller, negative-amplitude pulse; in contrast, fTUS applies high frequency periodic waves (i.e. sinusoids) and long sonication trains in the range of several hundred milliseconds. The mechanism of action of TPS is not clear and may differ from that of fTUS. It has been suggested that the TPS system may better avoid hazardous brain heating and secondary stimulation maxima, in addition to having better skull penetrance due to lower frequency of pulses compared to conventional fTUS [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ].

      4. Stimulation effects

      We categorized the studies into two major groups; a) healthy subjects and b) patient populations. Later, they were subcategorized according to their; (1) stimulation target, (2) disease type, (3) type of outcome (neurophysiology, neuroimaging, clinical-behavioral) and/or (4) TUS protocol (online, offline). We referred to TUS outcomes that are measured during or immediately after sonication as “online effects”, whereas they are termed “offline effects” if measured after a certain timeframe after sonication. A summary of the outcome measures and targets is depicted in Fig. 2. The effects of TUS on M1 and S1 in healthy subjects are summarized in Table 3.
      Fig. 2
      Fig. 2Sunburst chart for outcome measures and targets. Outcome measures used in human transcranial ultrasound studies were categorized under 4 headings; 1) Clinical (blue), 2) Neurophysiological (orange), 3) Neuroimaging (red), and 4) Histological (purple). While the darker tones are depicting the categories and sub-categories, lighter tone portrays the specific test/scale/technique. The outer rim was colored according to the cohort and legend shows cohorts and their corresponding colors. The targets were noted inside the color-coded outer rim boxes. Each study was given a number and these numbers were linked to the outer rim, which means that this study utilized the linked outcome measure in the given target and cohort. If there are more than one target given, this means that some studies linked to that box sonicated this region, while the other linked studies sonicated the others. As an example of reading the chart, the study number 1 (Hameroff 2013) used the NRS/VAS pain scales in chronic pain patients and sonicated posterior frontal lobe. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Table 3Summary of TUS effects on M1 and S1 in healthy subjects.
      M1S1
      Online Effects
      NeurophysiologySingle pulse TMS-induced MEP amplitude was suppressed with fTUS. The effect was dose dependent [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ].
      fTUS attenuated MN stimulation-elicited SEP [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ,
      • Lambert J.
      • Mouraux A.
      Transcranial focused ultrasonic stimulation to modulate the human primary somatosensory cortex.
      ] and enhanced vibrotactile stimulation-elicited SEP with distinctive parameters [
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ].
      Paired-pulse TMS protocols: 1) fTUS attenuated ICF but had no effect on SICI [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ]; 2) fTUS increased SICI and did not affect ICF or LICI [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ].
      fTUS attenuated the power of alpha- and beta-band baseline activity and short-latency evoked gamma activity [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ].
      The excitability of contralateral M1 was not affected by sonication of the ipsilateral M1 [
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ].
      Applying fTUS to the S1/S2 hand area resulted in sonication evoked potentials similar to MN stimulation-elicited SEP [
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ].
      fTUS increased the amplitude of MRCP at the EEG sensor level and at the source domain [
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ].
      No concurrent change in finger EMG activity from M1-fTUS during voluntary muscle contraction [
      • Heimbuch I.S.
      • Fan T.
      • Wu A.
      • Faas G.C.
      • Charles A.C.
      • Iacoboni M.
      Ultrasound stimulation of the motor cortex during tonic muscle contraction.
      ].
      NeuroimagingESI showed an increase in MRCP source profile amplitude [
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ].
      ESI showed significant brain activation at the targeted cortex [
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ].
      fTUS increased BOLD signal in the sonicated region and augmented the movement-related signals [
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ].
      Clinical-BehavioralfTUS decreased reaction time [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ].
      fTUS enhanced 2-point and frequency discrimination abilities [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ].
      fTUS elicited phantom tactile sensations corresponding to the somatotopy of the stimulated region [
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ].
      Offline Effects
      NeurophysiologyLong-lasting (>30 min) MEP amplitude increase with a repetitive [
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ] and a theta burst [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] fTUS protocol.
      Theta burst fTUS reduced SICI and increased ICF [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ].
      A short-lasting M1 excitability increase was demonstrated with dUS [
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ].
      Clinical-BehavioralfTUS decreased movement time but not reaction time [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ].
      A) Healthy Subjects.
      A1) Primary motor cortex (M1)
      A1.1) Online Effects/Neurophysiology.
      M1 is the most commonly targeted region in human studies (10/35 studies). In contrast to rodent studies [
      • Lee W.
      • Croce P.
      • Margolin R.W.
      • Cammalleri A.
      • Yoon K.
      • Yoo S.S.
      Transcranial focused ultrasound stimulation of motor cortical areas in freely-moving awake rats.
      ], no studies in humans have reported direct physical motor response to sonication alone. The ultrasound transducer can be attached to a TMS coil for concurrent use to assess online effects, specifically, on TMS-induced MEPs [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ]. M1 sonication studies mostly use a f0 of approximately 500 kHz (Fig. 3). Single-pulse TMS-induced MEP amplitude change with TUS is dose-dependent (varying sonication parameters affects outcome) [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ]. While other parameters were held constant, 10% and 30% duty cycle (DC) in a blocked fashion suppressed MEPs, but not 50% DC. A similar phenomenon was also true for sonication duration (SD), as 400ms and 500ms SD significantly suppressed MEPs while 100–300ms did not. MEP suppression was evident in all pulse repetition frequencies (PRF) tested (200, 500, 1000Hz). Therefore, to induce inhibition of M1 with fTUS, the optimal parameters appear to be a lower DC (<50%) and a SD of at least 400ms. These parameters are consistent with other studies (f0 = 500 kHz, PRF = 1000 Hz, SD = 500ms, DC = 36% [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ] and 30% [
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ]) that demonstrated a decrement in TMS-evoked M1 excitability with fTUS [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ].
      Fig. 3
      Fig. 3Sonication parameters (f0: fundamental frequency (kHz); PRF: pulse repetition frequency (Hz); DC: duty cycle (%); SD: sonication duration (ms); Isppa: spatial peak pulse average intensity (W/cm2)) of transcranial focused ultrasound studies that targeted primary motor cortex (M1) and primary somatosensory cortex (S1) with a neurophysiological outcome. NO EFF: No effect; MEP: Motor-evoked potential, EMG: Electromyography; ↑ and ↓ indicates excitatory and inhibitory, respectively. ∗: only parameters marked with an ∗ have a significant effect.
      Paired-pulse protocols showed attenuation of intracortical facilitation (ICF) but no effect on short-interval intracortical inhibition (SICI) [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ]. With several methodological differences, our group revealed fTUS increased SICI and did not affect ICF or long-interval intracortical inhibition (LICI) [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ]. We assessed the contralateral excitability and time course of the effects in a different study [
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ] and found out that excitability of the contralateral M1 was not affected by sonication of the ipsilateral M1, and ipsilateral M1 cortical excitability slightly outlasted the sonication but did not produce long-lasting effects. In another study, fTUS (f0 = 500 kHz, PRF = 300 Hz and 3000 Hz, SD = 500ms, DC: 6% and 60%, respectively) was found to increase the amplitude of movement-related cortical potential (MRCP) at the EEG sensor level and at the source domain. The excitatory effect was more prominent at a higher PRF (3000 Hz) compared to low PRF (300 Hz) [
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ]. High ultrasound energy in a high PRF (3000 Hz) and DC (60%) condition may lead to an excitatory effect at M1 that differs from the other studies, which demonstrated an inhibitory effect [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Xia X.
      • Fomenko A.
      • Nankoo J.F.
      • Zeng K.
      • Wang Y.
      • Zhang J.
      • et al.
      Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.
      ]. Moreover, the state of the subject (foot movement vs. rest) and outcome measures (EEG potentials vs. TMS induced MEP) were also different in these studies. fTUS effects in M1 were also evaluated during muscle contraction to evaluate effects on the cortical silent period, in which TMS of M1 involuntarily suppresses voluntary motor activity. No overt silent periods were visible during TUS [
      • Heimbuch I.S.
      • Fan T.
      • Wu A.
      • Faas G.C.
      • Charles A.C.
      • Iacoboni M.
      Ultrasound stimulation of the motor cortex during tonic muscle contraction.
      ].
      A1.2) Offline Effects/Neurophysiology.
      A long-lasting offline MEP amplitude increment with a f0 of 500 kHz, a low PRF (100 and 5 Hz, respectively) and low DC (5% and 10%, respectively) was shown with a repetitive TUS (rTUS) protocol by Zhang et al. [
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ] and a theta burst TUS (tbTUS) protocol by Zeng et al. [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] The latter study demonstrated reduction of SICI and increase in ICF by tbTUS, and also assessed parameters (f0 = 500 kHz, PRF = 1000 Hz, SD = 500ms, DC = 32%, 80 s) that produced no significant change in MEP amplitudes. A noteworthy difference between the sonication protocols of these two studies [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ,
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ] is that while the total sonication duration was 80s in tbTUS protocol, it was 15min in the rTUS protocol. In both studies, the increased MEP amplitude lasted for at least 30min post-sonication. A short-lasting increase in M1 excitability was also reported using a dUS device (f0 = 2.32 MHz, SD = 2 mins) by showing increased MEP amplitudes at 1- and 6-min post-sonication [
      • Gibson B.C.
      • Sanguinetti J.L.
      • Badran B.W.
      • Yu A.B.
      • Klein E.P.
      • Abbott C.C.
      • et al.
      Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation.
      ].
      A1.3) Online Effects/Neuroimaging.
      Ai et al. tested M1-TUS both in 3 and 7 T MRI [
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ,
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ] and with no safety concerns. fTUS alone increased BOLD signals in the sonicated region, as well as augmented movement-related signals [
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ]. The parameters may need to be individualized to elicit the BOLD response because while focal response was evident in some subjects, no response was detected in others even with identical parameters, target location, and MRI conditions [
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ]. Electrophysiological source imaging (ESI) is a functional imaging technique that estimates neural electrical activity underlying non-invasive electromagnetic measurements such as EEG [
      • He B.
      • Sohrabpour A.
      • Brown E.
      • Liu Z.
      Electrophysiological source imaging: a noninvasive window to brain dynamics.
      ]. By using this technique, it was demonstrated that M1-TUS significantly increases the MRCP source profile amplitude [
      • Yu K.
      • Liu C.
      • Niu X.
      • He B.
      Transcranial focused ultrasound neuromodulation of voluntary movement-related cortical activity in humans.
      ].
      A1.4) Online-Offline Effects/Clinical-Behavioral.
      Behavioral results of fTUS delivery including the effects of TUS on reaction time (sensorimotor tasks: simple stimulus-response task [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ], visuomotor task [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] and stop-signal task [
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ]) and movement time [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] were examined in some studies. Online TUS significantly decreased reaction time in three studies [
      • Legon W.
      • Bansal P.
      • Tyshynsky R.
      • Ai L.
      • Mueller J.K.
      Transcranial focused ultrasound neuromodulation of the human primary motor cortex.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ]. An offline study demonstrated a decrease in movement time but not in reaction time [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ].
      A2) Primary somatosensory cortex (S1)
      A2.1) Online Effects/Neurophysiology.
      S1 is another common target for TUS. Using f0 = 500 kHz (or 350kHz [
      • Lambert J.
      • Mouraux A.
      Transcranial focused ultrasonic stimulation to modulate the human primary somatosensory cortex.
      ]), PRF = 1000 Hz, SD = 500 ms, DC = 36%, studies have found that fTUS attenuated the short-latency N20–P27 and P27–N33 components of somatosensory evoked potentials (SEPs) elicited by median nerve (MN) stimulation [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ,
      • Lambert J.
      • Mouraux A.
      Transcranial focused ultrasonic stimulation to modulate the human primary somatosensory cortex.
      ]. S1-fTUS also attenuated the power of alpha- and beta-band baseline activity and short-latency evoked gamma activity [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ]. More recently, by increasing pulse repetition period and decreasing tone-burst duration (f0 = 500 kHz, PRF = 300 Hz, SD = 500ms, DC = 6%), a study reported enhancement of vibrotactile stimulation-elicited SEP [
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ]. Applying fTUS [f0 = 250 kHz, PRF = 500 Hz, SD = 300ms, DC = 50% (f0 = 210 kHZ, SD = 500 ms in the follow-up study)] to the S1/S2 hand area resulted in tactile sensation in the targeted hand area and sonication evoked potentials similar to MN stimulation-elicited SEP [
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ]. The excitatory effects of TUS on S1 may be inversely related with PRF (i.e. ≤ 500 Hz); however, this should be tested with a systematic study in the future. The TPS system was also tested in SEP experiments, resulting in an increase in neuromodulatory effects with increasing pulse numbers; namely, 1000 pulses decreased P27/N140 and increased N70 [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ].
      A2.2) Online Effects/Neuroimaging.
      ESI showed significant brain activation at the targeted cortex with S1-fTUS [
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ].
      A2.3) Online Effects/Clinical-Behavioral.
      S1 or thalamus fTUS enhanced 2-point (pin test) and frequency (air puff test or vibration test) discrimination abilities [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Legon W.
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      Neuromodulation with single-element transcranial focused ultrasound in human thalamus.
      ,
      • Liu C.
      • Yu K.
      • Niu X.
      • He B.
      Transcranial focused ultrasound enhances sensory discrimination capability through somatosensory cortical excitation.
      ]. Another study elicited phantom tactile sensations corresponding to the somatotopy of the stimulated region [
      • Lee W.
      • Kim H.
      • Jung Y.
      • Song I.U.
      • Chung Y.A.
      • Yoo S.S.
      Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex.
      ,
      • Lee W.
      • Chung Y.A.
      • Jung Y.
      • Song I.U.
      • Yoo S.S.
      Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.
      ].
      A3) Other brain regions.
      A3.1) Online-Offline Effects/Neurophysiology.
      Other sonicated brain regions include V1, prefrontal cortex, thalamus and basal ganglia. Online fTUS on V1 (f0 = 270 kHz, PRF = 500 Hz, SD = 300 ms, DC = 50%) evoked potentials comparable to photic stimulation elicited visual evoked potentials (VEP) [
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ]. With thalamic sonication, Legon et al. demonstrated that online fTUS (f0 = 500 kHz, PRF = 1000 Hz, SD = 500ms, DC = 36%) attenuated SEP [
      • Legon W.
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      Neuromodulation with single-element transcranial focused ultrasound in human thalamus.
      ]. An offline study demonstrated that dUS of superior colliculus, but not nucleus raphe magnus and substantia nigra (SN), increased the conditioned R2 component of the trigeminal blink reflex at 3-min but not at 30-min post-stimulation [
      • Guerra A.
      • Vicenzini E.
      • Cioffi E.
      • Colella D.
      • Cannavacciuolo A.
      • Pozzi S.
      • et al.
      Effects of transcranial ultrasound stimulation on trigeminal blink reflex excitability.
      ]. This study demonstrated that superior colliculus dUS can transiently increase the excitability of brainstem circuits.
      A3.2) Online-Offline Effects/Neuroimaging.
      Online V1 [
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ] and subcortical (caudate [
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ] and globus pallidus (GP) [
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ]) fTUS induced BOLD signal changes both in sonicated regions and in distant hubs to the sonicated target. The signal change may be in either direction (increase [
      • Leo A.
      • Mueller J.K.
      • Grant A.
      • Eryaman Y.
      • Wynn L.
      Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ,
      • Ai L.
      • Bansal P.
      • Mueller J.K.
      • Legon W.
      Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.
      ] or decrease [
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ]) depending on the target and parameters. An offline fMRI study targeting the inferior frontal gyrus (IFG) revealed decreased connectivity between IFG and subgenual cingulate cortex, orbitofrontal cortex, inferior prefrontal gyrus, dorsal anterior cingulate cortex, and entorhinal cortex. Increased connectivity was present only for premotor cortex [
      • Sanguinetti J.L.
      • Hameroff S.
      • Smith E.E.
      • Sato T.
      • Daft C.M.W.
      • Tyler W.J.
      • et al.
      Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans.
      ]. The effects of GP sonication were also assessed offline by an MR perfusion weighted imaging technique known as Arterial Spin Labeling (ASL). Following sonication, a generalized decrease in relative perfusion throughout the cerebrum was observed [
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ].
      A3.3) Online-Offline Effects/Clinical-Behavioral.
      Both online V1-fTUS [
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ] and V1-dUS [
      • Schimek N.
      • Burke-Conte Z.
      • Abernethy J.
      • Schimek M.
      • Burke-Conte C.
      • Bobola M.
      • et al.
      Repeated application of transcranial diagnostic ultrasound towards the visual cortex induced illusory visual percepts in healthy participants.
      ] protocols were found to elicit subjective phosphene perception. Audibility of sonications and the effects of sound on EEG recordings were assessed by two studies which targeted V1/inion [
      • Johnstone A.
      • Nandi T.
      • Martin E.
      • Bestmann S.
      • Stagg C.
      • Treeby B.
      A range of pulses commonly used for human transcranial ultrasound stimulation are clearly audible.
      ,
      • Braun V.
      • Blackmore J.
      • Cleveland R.O.
      • Butler C.R.
      Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked.
      ]. By utilizing the quantitative sensory thresholding (QST) test, which assesses sensory, pain, and tolerance thresholds to thermal stimuli, thalamic-fTUS (f0 = 650 kHz, PRF = 10 Hz, SD = 30 s, DC = 5%) was shown to produce offline antinociceptive effects, possibly by inhibitory mechanisms [
      • Badran B.W.
      • Caulfield K.A.
      • Stomberg-Firestein S.
      • Summers P.M.
      • Dowdle L.T.
      • Savoca M.
      • et al.
      Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
      ].
      B) Patient Populations.
      B1) Alzheimer's-Parkinson's Disease (PD) dementia/Offline effects.
      Cognitive tests improved with fronto-parietal-TPS [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ], mesial temporal lobe(MTL) and SN-dUS [
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ], and hippocampal-fTUS [
      • Jeong H.
      • Im J.J.
      • Park J.S.
      • Na S.H.
      • Lee W.
      • Yoo S.S.
      • et al.
      A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.
      ] stimulation. This improvement persisted up to three months for TPS [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ]. MRI in TPS-sonicated patients showed increased functional connectivity for the hippocampus, parahippocampal/parietal cortices, and precuneus [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ], as well as increased cortical thickness [
      • Popescu T.
      • Pernet C.
      • Beisteiner R.
      Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: a follow-up study.
      ] which correlated positively with clinical outcome. Among the 22 dUS-sonicated patients, 14 (64%) patients had at least one improved cognitive score and 7 (32%) patients had at least one declined cognitive score without an opposing score. No patients exhibited a decline or improvement on both motor functioning and dexterity scores [
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ]. Two dUS-sonicated patients underwent ASL that showed markedly increased perfusion at the hippocampus [
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ]. Regional cerebral metabolic rate of glucose increased in the superior frontal, middle cingulate, and fusiform gyri after hippocampal-fTUS [
      • Jeong H.
      • Im J.J.
      • Park J.S.
      • Na S.H.
      • Lee W.
      • Yoo S.S.
      • et al.
      A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.
      ].
      B2) Drug-resistant Epilepsy/Online-Offline effects.
      Seizure-onset zone (frontal, temporal, insular or cingulate cortices) fTUS (PRF = 100 Hz, SD = 10m, DC = 30%, Ispta = 2.8 W/cm2) decreased or increased the seizure frequency and interictal epileptiform discharges in different patients. The spectral power of SEEG from target electrodes increased in one of the four frequency bands during 10min sonication for 5/6 patients, followed by a decrease at the 10-min period after sonication for 3/6 patients [
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ]. Offline MTL-fTUS (f0 = 650 kHz, PRF = 100/250 Hz, SD = 0.5/30s, DC = 5/50%, Ispta = 720/5760 mW/cm2) did not produce any change in neuropsychological tests [
      • Stern J.M.
      • Spivak N.M.
      • Becerra S.A.
      • Kuhn T.P.
      • Korb A.S.
      • Kronemyer D.
      • et al.
      Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.
      ]. Surgical resection of the sonicated brain tissue did not reveal any damage except acidophilic neurons and extravasation in one patient. However, since the control sample also showed these changes, the results may not be related to sonication itself [
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ,
      • Stern J.M.
      • Spivak N.M.
      • Becerra S.A.
      • Kuhn T.P.
      • Korb A.S.
      • Kronemyer D.
      • et al.
      Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.
      ].
      B3) Disorders of Consciousness/Offline effects.
      Three patients received two thalamic-fTUS sessions one week apart. The Coma Recovery Scale-Revised scores at 6-months initially improved then declined for the first patient, improved for the second and declined for the third [
      • Monti M.M.
      • Schnakers C.
      • Korb A.S.
      • Bystritsky A.
      • Vespa P.M.
      Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report.
      ,
      • Cain J.A.
      • Spivak N.M.
      • Coetzee J.P.
      • Crone J.S.
      • Johnson M.A.
      • Lutkenhoff E.S.
      • et al.
      Ultrasonic thalamic stimulation in chronic disorders of consciousness.
      ].
      B4) Chronic Pain/Offline effects.
      Subjective mood scores at 10 and 40min significantly improved with frontal-dUS compared to placebo; however, pain scores did not change [
      • Hameroff S.
      • Trakas M.
      • Duffield C.
      • Annabi E.
      • Gerace M.B.
      • Boyle P.
      • et al.
      Transcranial ultrasound (TUS) effects on mental states: a pilot study.
      ].
      B5) Depression/Offline effects.
      Depression scores did not change 10–30 mins after fronto-temporal-fTUS, but trait worry decreased with fTUS and increased in the placebo group [
      • Reznik S.J.
      • Sanguinetti J.L.
      • Tyler W.J.
      • Daft C.
      • Allen J.J.B.
      A double-blind pilot study of transcranial ultrasound (TUS) as a five-day intervention: TUS mitigates worry among depressed participants.
      ].

      4.1 Adverse effects

      Headache, neck pain, seizure, tinnitus, cognitive impairment, and mood changes have been reported with NIBS modalities such as TMS [
      • Machii K.
      • Cohen D.
      • Ramos-Estebanez C.
      • Pascual-Leone A.
      Safety of rTMS to non-motor cortical areas in healthy participants and patients.
      ]. Among 704 subjects who underwent TUS (27 subjects from a not-yet-published trial [
      • Legon W.
      • Adams S.
      • Bansal P.
      • Patel P.D.
      • Hobbs L.
      • Ai L.
      • et al.
      A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.
      ]), no severe AEs related to sonication were documented; however, 10 studies did not report presence or absence of AEs (Table 1). Mild/moderate (mostly transient) symptoms including headache [
      • Hameroff S.
      • Trakas M.
      • Duffield C.
      • Annabi E.
      • Gerace M.B.
      • Boyle P.
      • et al.
      Transcranial ultrasound (TUS) effects on mental states: a pilot study.
      ,
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ,
      • Legon W.
      • Adams S.
      • Bansal P.
      • Patel P.D.
      • Hobbs L.
      • Ai L.
      • et al.
      A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.
      ], mood deterioration [
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in alzheimer's disease-A new navigated focal brain therapy.
      ], scalp heating [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ], cognitive problems [
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ,
      • Legon W.
      • Adams S.
      • Bansal P.
      • Patel P.D.
      • Hobbs L.
      • Ai L.
      • et al.
      A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.
      ], neck pain, muscle twitches, anxiety, sleepiness and itchiness [
      • Legon W.
      • Adams S.
      • Bansal P.
      • Patel P.D.
      • Hobbs L.
      • Ai L.
      • et al.
      A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.
      ] were reported in 14 individuals (14/425, 3.3%).

      5. Future directions

      5.1 Potential novel outcome measures

      5.1.1 Local field potential (LFP)

      Investigation of network activity by measuring extracellular field potential has long been practiced and the biophysics related to these measurements are well understood [
      • Buzsaki G.
      • Anastassiou C.A.
      • Koch C.
      The origin of extracellular fields and currents--EEG, ECoG, LFP and spikes.
      ]. LFP recording, specifically beta oscillations in PD patients, have served as an outcome measure in non-invasive neuromodulation studies [
      • Gaynor L.M.
      • Kuhn A.A.
      • Dileone M.
      • Litvak V.
      • Eusebio A.
      • Pogosyan A.
      • et al.
      Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans.
      ]. Beta band power in the subthalamic nucleus (STN) correlates with severity of PD motor signs [
      • Neumann W.J.
      • Degen K.
      • Schneider G.H.
      • Brucke C.
      • Huebl J.
      • Brown P.
      • et al.
      Subthalamic synchronized oscillatory activity correlates with motor impairment in patients with Parkinson's disease.
      ] and M1-TMS significantly suppressed beta activity in human STNs recorded with externalized deep brain stimulation (DBS) leads [
      • Gaynor L.M.
      • Kuhn A.A.
      • Dileone M.
      • Litvak V.
      • Eusebio A.
      • Pogosyan A.
      • et al.
      Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans.
      ]. Although the effect of TUS on human LFPs is not known, a preclinical TUS study demonstrated that STN sonication decreased M1 beta band activity in parkinsonian mice [
      • Wang Z.
      • Yan J.
      • Wang X.
      • Yuan Y.
      • Li X.
      Transcranial ultrasound stimulation directly influences the cortical excitability of the motor cortex in parkinsonian mice.
      ]. DBS has also been shown to reduce beta activity [
      • Feldmann L.K.
      • Neumann W.J.
      • Krause P.
      • Lofredi R.
      • Schneider G.H.
      • Kuhn A.A.
      Subthalamic beta band suppression reflects effective neuromodulation in chronic recordings.
      ], thus beta power has been used as a biomarker to modulate the stimulation amplitude for adaptive DBS [
      • Feldmann L.K.
      • Neumann W.J.
      • Krause P.
      • Lofredi R.
      • Schneider G.H.
      • Kuhn A.A.
      Subthalamic beta band suppression reflects effective neuromodulation in chronic recordings.
      ]. New DBS systems such as Medtronic Percept PC can record LFP through implanted DBS electrodes [
      • Sarica C.
      • Iorio-Morin C.
      • Aguirre-Padilla D.H.
      • Najjar A.
      • Paff M.
      • Fomenko A.
      • et al.
      Implantable pulse generators for deep brain stimulation: challenges, complications, and strategies for practicality and longevity.
      ]. Studying the effects of TUS on LFP in Percept PC implanted subjects may provide a novel objective outcome measure to TUS investigations. The safety of direct TUS of an implanted electrode in humans was shown in a TUS-SEEG study [
      • Lee C.C.
      • Chou C.C.
      • Hsiao F.J.
      • Chen Y.H.
      • Lin C.F.
      • Chen C.J.
      • et al.
      Pilot study of focused ultrasound for drug-resistant epilepsy.
      ]. Our group also tested the ex-vivo kinetic and thermal effects of acoustic waves on DBS electrodes and did not observe any safety concerns, paving the way for future trials in humans [
      • Sarica C.
      • Fomenko A.
      • Nankoo J.F.
      • Darmani G.
      • Vetkas A.
      • Yamamoto K.
      • et al.
      Toward focused ultrasound neuromodulation in deep brain stimulator implanted patients: ex-vivo thermal, kinetic and targeting feasibility assessment.
      ].

      5.1.2 Proton magnetic resonance spectroscopy (1H-MRS)

      1H-MRS is a non-invasive neuroimaging method for the detection and quantification of metabolites in the brain [
      • Castillo M.
      • Kwock L.
      • Mukherji S.K.
      Clinical applications of proton MR spectroscopy.
      ]. In humans, 1H-MRS has been successfully combined with TMS neuromodulation to measure alterations in the molecular concentrations of metabolites [
      • Cuypers K.
      • Marsman A.
      Transcranial magnetic stimulation and magnetic resonance spectroscopy: opportunities for a bimodal approach in human neuroscience.
      ]. In the future, MRS can be used to interrogate the neural network and measure global and local metabolic responses in combination with TUS.

      5.1.3 Diffusion-weighted MRI (dMRI)

      dMRI is a powerful technique for microstructural imaging based on mapping the diffusion of water molecules [
      • Alexander D.C.
      • Dyrby T.B.
      • Nilsson M.
      • Zhang H.
      Imaging brain microstructure with diffusion MRI: practicality and applications.
      ]. The water diffusion in a voxel can be modelled by the diffusion tensor imaging (DTI) method that generates a map that displays direction of diffusion (fractional anisotropy) and diffusion rate (mean diffusivity) for each voxel. Complex morphology in a voxel including axonal dispersion (i.e., crossing fibers) and micro-anatomic features (i.e., axon density) limits the specificity of classical DTI. However, recent technical advances such as constrained-spherical deconvolution models [
      • Sheng Z.
      • Yu J.
      • Chen Z.
      • Sun Y.
      • Bu X.
      • Wang M.
      • et al.
      Constrained-spherical deconvolution tractography in the evaluation of the corticospinal tract in glioma surgery.
      ] or diffusion basis spectrum imaging [
      • Isaacs A.M.
      • Neil J.J.
      • McAllister J.P.
      • Dahiya S.
      • Castaneyra-Ruiz L.
      • Merisaari H.
      • et al.
      Microstructural periventricular white matter injury in post-hemorrhagic ventricular dilatation.
      ] have solved these problems to some extent and made dMRI a powerful tool to study structural neuro-connectivity [
      • Christiansen L.
      • Siebner H.R.
      Chapter 7 - tools to explore neuroplasticity in humans: combining interventional neurophysiology with functional and structural magnetic resonance imaging and spectroscopy.
      ]. Structural plasticity was demonstrated using dMRI in post-stroke patients and healthy subjects after repetitive tDCS [
      • Hong X.
      • Lu Z.K.
      • Teh I.
      • Nasrallah F.A.
      • Teo W.P.
      • Ang K.K.
      • et al.
      Brain plasticity following MI-BCI training combined with tDCS in a randomized trial in chronic subcortical stroke subjects: a preliminary study.
      ,
      • Hirtz R.
      • Weiss T.
      • Huonker R.
      • Witte O.W.
      Impact of transcranial direct current stimulation on structural plasticity of the somatosensory system.
      ] and TMS [
      • Yamada N.
      • Ueda R.
      • Kakuda W.
      • Momosaki R.
      • Kondo T.
      • Hada T.
      • et al.
      Diffusion tensor imaging evaluation of neural network development in patients undergoing therapeutic repetitive transcranial magnetic stimulation following stroke.
      ] treatments. Additionally, dMRI also depicted clinically correlating structural changes after focused ultrasound ablation of the thalamus in essential tremor (ET) patients [
      • Wintermark M.
      • Huss D.S.
      • Shah B.B.
      • Tustison N.
      • Druzgal T.J.
      • Kassell N.
      • et al.
      Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.
      ]. Motor cortical plasticity induced by TUS is short-lived, not evident at 1 h after stimulation [
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ,
      • Zhang Y.
      • Ren L.
      • Liu K.
      • Tong S.
      • Yuan T.F.
      • Sun J.
      Transcranial ultrasound stimulation of the human motor cortex.
      ]. However, repeated TUS sessions may have longer-lasting effects and dMRI may reflect the potential alterations of structural connectivity.

      5.1.4 Magnetoencephalogram (MEG)

      EEG and electrocorticography (ECoG) can measure sub-second variations in neural activity; however, they are limited in their spatial resolution and invasiveness in the case of ECoG. MEG is a recording modality that ideally bridges the desired temporo-spatial continuum [
      • Boele F.W.
      • Rooney A.G.
      • Grant R.
      • Klein M.
      Psychiatric symptoms in glioma patients: from diagnosis to management.
      ]. It is similar to EEG and ECoG in that it localizes neural activity in the brain on the order of milliseconds; however, it is fundamentally different from these modalities in that it does not detect the voltages generated by neural currents, but rather from the resultant magnetic fields [
      • Chang E.F.
      • Nagarajan S.S.
      • Mantle M.
      • Barbaro N.M.
      • Kirsch H.E.
      Magnetic source imaging for the surgical evaluation of electroencephalography-confirmed secondary bilateral synchrony in intractable epilepsy.
      ]. Over the past decade, MEG has been increasingly utilized as a tool to inform the neural circuit dynamics associated with stimulation modalities such as DBS. There are over 30 publications on the combined use of DBS-MEG that have aided our understanding of the pathophysiology of PD by describing the STN-cortical network and providing insight into how the network correlates with clinical symptoms [
      • Harmsen I.E.
      • Rowland N.C.
      • Wennberg R.A.
      • Lozano A.M.
      Characterizing the effects of deep brain stimulation with magnetoencephalography: a review.
      ]. Moreover, these studies have shed light on how such networks can be modulated pharmacologically or with active neurostimulation. Similarly, MEG has uncovered the oscillatory networks in various cohorts including PD patients with pedunculopontine nucleus DBS, dystonia patients with pallidal DBS, and stimulation in patients in chronic pain [
      • Harmsen I.E.
      • Rowland N.C.
      • Wennberg R.A.
      • Lozano A.M.
      Characterizing the effects of deep brain stimulation with magnetoencephalography: a review.
      ]. Taken together, the use of MEG has provided direct insight into the neurophysiologic mechanisms of DBS in various pathologies. There is significant potential for MEG to uncover similar insights into the mechanistic basis of TUS-mediated neurologic effects.
      Potential Novel Study Populations.
      There is a vast number of conditions in which NIBS has been applied such as stroke, headache and tinnitus, and TUS may be used in these conditions in the future. But, herein, we highlighted two populations; movement disorders and pediatrics patients.

      5.1.5 Movement disorders (MD)

      The ability to induce brain plasticity, high spatial resolution, and deep targeting abilities of TUS exhibit great potential for a therapeutical role for MDs. Past experience from repetitive TMS studies in MD patients may direct future TUS trials [
      • Lefaucheur J.P.
      • Aleman A.
      • Baeken C.
      • Benninger D.H.
      • Brunelin J.
      • Di Lazzaro V.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).
      ]. Regarding the targets, the premotor and motor cortices may be potential targets to be investigated for PD [
      • Latorre A.
      • Rocchi L.
      • Berardelli A.
      • Bhatia K.P.
      • Rothwell J.C.
      The use of transcranial magnetic stimulation as a treatment for movement disorders: a critical review.
      ,
      • Yang C.
      • Guo Z.
      • Peng H.
      • Xing G.
      • Chen H.
      • McClure M.A.
      • et al.
      Repetitive transcranial magnetic stimulation therapy for motor recovery in Parkinson's disease: a Meta-analysis.
      ,
      • Lauro P.M.
      • Lee S.
      • Akbar U.
      • Asaad W.F.
      Subthalamic-cortical network reorganization during Parkinson's tremor.
      ], whereas the cerebellum may be studied for dystonia or ET [
      • Koch G.
      • Porcacchia P.
      • Ponzo V.
      • Carrillo F.
      • Caceres-Redondo M.T.
      • Brusa L.
      • et al.
      Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients.
      ]. Modulation of classical DBS targets (STN, GP, thalamus) by TUS displays potential, but specific targeting techniques for these small-sized nuclei may need to be validated. Other movement disorders such as tic disorder and restless leg syndrome may also be potentially modulated by targeting the basal ganglia and premotor area, respectively [
      • Lefaucheur J.P.
      • Aleman A.
      • Baeken C.
      • Benninger D.H.
      • Brunelin J.
      • Di Lazzaro V.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018).
      ]. Currently, MD-TUS studies are only limited to rodent studies [
      • Wang Z.
      • Yan J.
      • Wang X.
      • Yuan Y.
      • Li X.
      Transcranial ultrasound stimulation directly influences the cortical excitability of the motor cortex in parkinsonian mice.
      ,
      • Xu T.
      • Lu X.
      • Peng D.
      • Wang G.
      • Chen C.
      • Liu W.
      • et al.
      Ultrasonic stimulation of the brain to enhance the release of dopamine - a potential novel treatment for Parkinson's disease.
      ] and TUS is an unexplored territory in MD patients. In addition to stand-alone utilization of TUS, it may be used as an adjunct treatment in DBS implanted patients to further control the symptoms [
      • Sarica C.
      • Fomenko A.
      • Nankoo J.F.
      • Darmani G.
      • Vetkas A.
      • Yamamoto K.
      • et al.
      Toward focused ultrasound neuromodulation in deep brain stimulator implanted patients: ex-vivo thermal, kinetic and targeting feasibility assessment.
      ].

      5.1.6 Pediatric and neonatal patients

      Brain injury in the early phase of life adversely impacts both the neurodevelopment of the affected individual and parental mental health [
      • Novak I.
      • Morgan C.
      High-risk follow-up: early intervention and rehabilitation.
      ,
      • Bemister T.B.
      • Brooks B.L.
      • Dyck R.H.
      • Kirton A.
      Parent and family impact of raising a child with perinatal stroke.
      ]. Although early therapeutic intervention programs that focus on physical rehabilitation help optimize neural plasticity and reduce neurologic disease burden, these interventions are time-sensitive, time-intensive and costly [
      • Gordon A.M.
      To constrain or not to constrain, and other stories of intensive upper extremity training for children with unilateral cerebral palsy.
      ]. Non-invasive brain stimulation techniques, such as TMS, tDCS or transcranial static magnetic field stimulation (tSMFS), are potential complementary modalities to rehabilitation that have been investigated particularly in pediatric stroke models to optimize endogenous neural plasticity by inducing neuroplasticity [
      • Hilderley A.J.
      • Metzler M.J.
      • Kirton A.
      Noninvasive neuromodulation to promote motor skill gains after perinatal stroke.
      ]. The focus of pediatric non-invasive brain stimulation studies has been on school-aged children; however, animal studies suggest that the optimal window of neural plasticity is the first year of life [
      • Hilderley A.J.
      • Metzler M.J.
      • Kirton A.
      Noninvasive neuromodulation to promote motor skill gains after perinatal stroke.
      ]. Currently, there are no standard of care neuromodulation methods for neonates and treatment is limited to early rehabilitation after discharge from the neonatal intensive care unit (ICU). Thus, TUS may potentially create new opportunities for both treatment of the pathologic condition (i.e., clot lysis following intraventricular hemorrhage [IVH]) and neuromodulation to promote brain plasticity while the neonates are still in the ICU. Recently, clot lysis in an IVH porcine model was achieved [
      • Looi T.
      • Piorkowska K.
      • Mougenot C.
      • Waspe A.
      • Hynynen K.
      • Drake J.
      An MR-based quantitative intraventricular hemorrhage porcine model for MR-guided focused ultrasound thrombolysis.
      ]; however, to the best of our knowledge this technique has not been studied in human neonates. The neuromodulatory aspects of TUS can hypothetically be used to diminish permanent motor impairment after neonatal ischemic or hemorrhagic brain injury by targeting the periventricular white matter tracts. Targeting neural plasticity early in life may result in significant gains not only for motor development but also for cognitive and psychological development, leading to a higher quality of life in adulthood.

      6. Conclusion

      TUS is a promising non-invasive neuromodulation approach that has been investigated in healthy subjects, as well as in patients with neurologic and psychiatric conditions including depression, epilepsy, dementia, chronic pain and TBI. Direct physical responses to TUS were demonstrated in humans with tactile sensations and phosphene perception, whereas a similar response for motor function (e.g. muscle twitch) has not been reported. Neuromodulatory effects, which could be excitatory or inhibitory in nature depending on the sonication parameters, have been demonstrated through sonication of various targets such as the primary motor or somatosensory cortices. Moreover, novel protocols have been developed to induce motor cortex plasticity. While mild/moderate AEs were reported in 3% of individuals, no severe AEs have been reported after TUS.
      Future studies may utilize new outcome measures (e.g. LFP, MEG, dMRI or 1H-MRS) to better define the underlying neurophysiological mechanisms of TUS. In addition, novel patient cohorts such as those with movement disorders or pediatric patients can be tested for therapeutic efficiency. Advances in technology and growing experience in the field may overcome the current limitations of TUS by improving targeting of deeper and smaller structures, delineating safety limits, optimizing sonication protocols, and modelling ultrasound transmission.

      7. Contributors

      C.S. and J.F.N conceptualized and drafted the manuscript; C.S., K.Y. and A.F. prepared the figures and tables; T.C.G., M.N.C., A.V., N.S. and V.M. contributed drafting; R.C and A.M.L supervised the article; all authors reviewed the manuscript and provided critical revision.

      Funding

      The study was funded by the Natural Sciences and Engineering Research Council of Canada ( RGPIN-2020-04176 , RTI-2020-00249 ) and the Canadian Institutes of Health Research ( FDN-154292 , ENG 173,742 ).
      C.S. has been receiving fellowship grants from Michael and Amira Dan Foundation and the Turkish Neurosurgical Society.
      J.F.N. is funded by a Parkinson Canada Fellowship award.
      A.F. is funded by CIHR Banting and Best Doctoral Award and the University of Manitoba Clinician Investigator Program.
      Abbreviations:
      Outcome Measures: 2-p & freq dscrm: two point and frequency discrimination; ASL: arterial spin labeling; BDI: Beck depression inventory; BVMT: brief visuospatial memory test; CDR: clinical dementia rating; CERAD: consortium to establish a registry for Alzheimer's disease; conscious.: consciousness; CRS-R: coma recovery scale-revised; DTI: diffusion tensor imaging; ESI: electrophysiological source imaging; fMRI: functional magnetic resonance imaging; H-MRS: proton magnetic resonance spectroscopy; ICF: intra-cortical facilitation; IED: interictal epileptiform discharges; IHI: interhemispheric inhibition; MEP: motor evoked potential; MEP amp/lat: amplitude and latency; MoCA: Montreal cognitive assessment; Mov. Time: movement time; MRCP: movement related cortical potential; MR PWI: magnetic resonance perfusion weighted imaging; NRS: numeric rating scale; OASIS: overall anxiety severity and impairment scale; PET: positron emission tomography; Phosphene: phosphene perception; PSWQ: Penn State worry questionnaire; QST: quantitative sensory thresholding test; RAVLT: Rey auditory verbal learning Test; RBANS: repeatable battery for assessment of neuropsychological status; rCMRglu: regional cerebral metabolic rate of glucose; React Time: reaction time; RRS: ruminative responses scale; SEEG: stereoelectroencephalography; SEP: somatosensory-evoked potential; SICI: short interval intracortical inhibition; SON: supraorbital nerve; Tactile: location of tactile sensation; Thermal: sensory thresholds for thermal stimuli; TMS: transcranial magnetic stimulation; VAMS: visual analog mood scale; VAS: visual analog scale; VEP: visual-evoked potential.
      Cohorts: AD: Alzheimer's Disease; TBI: traumatic brain injury.
      Targets: Cd: caudate; FL: frontal lobe; FTL: fronto-temporal lobe; GP: globus pallidus; HPC: hippocampus; MTL: mesial temporal lobe; M1: primary motor cortex; NRM: nucleus raphe magnus; PCUN: precuneus; PFC: prefrontal cortex; PL: parietal lobe; pos: posterior; SC: superior colliculus; SN: substantia nigra; SOZ: seizure-onset zone; S1: primary somatosensory cortex; S2: secondary somatosensory cortex; V1: primary visual cortex.
      Abbreviations: AE: Adverse Effect; Chr. Pain: chronic pain; DOC: Disorders of Consciousness; DRE: drug resistant epilepsy; dUS: diagnostic ultrasound; NR: not reported; TBI: traumatic brain injury; fTUS: transcranial focused ultrasound; TUS: transcranial ultrasound.
      Targets: Cd: Caudate; FL: frontal lobe; FTL: fronto-temporal lobe; GP: Globus pallidus; HPC: hippocampus; M1: primary motor cortex; MTL: Mesial temporal lobe; NRM: nucleus raphe magnus; PCUN: precuneus; PFC: prefrontal cortex; PL: parietal lobe; S1: primary somatosensory cortex; S2: secondary somatosensory cortex; SC: superior Colliculus; SN: Substantia nigra; SOZ: seizure-onset zone; pos: posterior; V1: primary visual cortex.
      [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Mueller J.
      • Legon W.
      • Opitz A.
      • Sato T.F.
      • Tyler W.J.
      Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.
      ,
      • Sanguinetti J.L.
      • Hameroff S.
      • Smith E.E.
      • Sato T.
      • Daft C.M.W.
      • Tyler W.J.
      • et al.
      Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans.
      ,
      • Heimbuch I.S.
      • Fan T.
      • Wu A.
      • Faas G.C.
      • Charles A.C.
      • Iacoboni M.
      Ultrasound stimulation of the motor cortex during tonic muscle contraction.
      ]: Devices were produced by Blatek Industries, but the model was not specified.
      [
      • Cain J.A.
      • Spivak N.M.
      • Coetzee J.P.
      • Crone J.S.
      • Johnson M.A.
      • Lutkenhoff E.S.
      • et al.
      Ultrasonic thalamic stimulation in chronic disorders of consciousness.
      ]: The model was not specified.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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