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Krembil Research Institute, University Health Network, Toronto, ON, CanadaDivision of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, CanadaDepartment of Neurosurgery, Tartu University Hospital, University of Tartu, Tartu, Estonia
Krembil Research Institute, University Health Network, Toronto, ON, CanadaDivision of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
Krembil Research Institute, University Health Network, Toronto, ON, CanadaEdmond J. Safra Program in Parkinson's Disease, University Health Network, Toronto, ON, CanadaDivision of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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.
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 [
]. Transcranial ultrasound stimulation (TUS) is an increasingly popular, non-invasive form of neuromodulation, which is being rapidly and broadly investigated in novel therapeutic roles [
]. 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 [
Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
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 [
]. 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.
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.
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.
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.
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).
7/15 subjects experienced a tingling sensation on scalp while pulse repetition frequency is 3000 Hz.
0
Braun, 2020
18
Healthy
V1
fTUS
NR
NR
Schimek, 2020
21
Healthy
V1
dUS
0
0
Lambert, 2020
7
Healthy
S1
fTUS
0
0
Cain, 2021
16
Healthy
GP
fTUS
NR
NR
Heimbuch, 2021
10
Healthy
M1
fTUS
NR
NR
Jeong, 2021
4
Dementia
HCP
fTUS
0
0
Lee, 2022
6
DRE
SOZ
fTUS
2
0
Liu, 2021
9
Healthy
S1
fTUS
0
0
Stern, 2021
8
DRE
MTL
fTUS
0
0
Xia, 2021
27
Healthy
M1
fTUS
NR
NR
Zeng, 2022
20
Healthy
M1/V1
fTUS
0
0
Zhang, 2021
24
Healthy
M1
fTUS
0
0
Guerra, 2021
16
Healthy
SN, NRM, SC
dUS
0
0
Jonstone, 2021
16
Healthy
Inion
fTUS
NR
NR
Cain, 2021
3
TBI/DOC
Thalamus
fTUS
0
0
TOTAL
677
–
–
–
7+
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 [
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 [
]. Later, direct effects of TUS were demonstrated as sonication of S1 produced phantom sensations in the hand and elicited sonication-specific evoked potentials [
]. The same group showed similarities between visual-evoked potentials (VEP) from photic stimulation and primary visual cortex (V1) TUS-evoked potentials [
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 [
]. 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 [
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 [
Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
] 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 [
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 [
Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
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 [
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. 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.)
], 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 [
]. 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) [
]. 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% [
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.
]. With several methodological differences, our group revealed fTUS increased SICI and did not affect ICF or long-interval intracortical inhibition (LICI) [
] 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) [
]. 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 [
]. 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 [
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. [
] 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 [
] 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 [
]. 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 [
]. Electrophysiological source imaging (ESI) is a functional imaging technique that estimates neural electrical activity underlying non-invasive electromagnetic measurements such as EEG [
]), 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]) 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 [
]) 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 [
]. 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 [
] 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 [
]. 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 [
Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled 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 [
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 [
]. 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 [
]. 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 [
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 [
]), 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 [
Investigation of network activity by measuring extracellular field potential has long been practiced and the biophysics related to these measurements are well understood [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
Chapter 7 - tools to explore neuroplasticity in humans: combining interventional neurophysiology with functional and structural magnetic resonance imaging and spectroscopy.
in: Handbook of clinical neurology. Angelo quartarone, maria felice ghilardi. 184. François Boller,
2022: 105-119
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 [
Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
] 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]; 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.
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:
Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: a double-blind, sham-controlled study.
Chapter 7 - tools to explore neuroplasticity in humans: combining interventional neurophysiology with functional and structural magnetic resonance imaging and spectroscopy.
in: Handbook of clinical neurology. Angelo quartarone, maria felice ghilardi. 184. François Boller,
2022: 105-119
Diffusion tensor imaging evaluation of neural network development in patients undergoing therapeutic repetitive transcranial magnetic stimulation following stroke.
Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.
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