Systematic review-based guideline "Parkinson's disease" of the German Society of Neurology: diagnostic use of transcranial sonography.

BACKGROUND AND OBJECTIVE: Transcranial brain parenchyma sonography (TCS) has been recommended as a tool for the early and differential diagnosis of Parkinson's disease (PD) in German and European clinical guidelines. Still, the brain structures to be examined for the diagnostic questions and the requirements for being a qualified investigator were not specified in detail. These issues have now been addressed in the 2023 update of the clinical guideline on PD by the German Society of Neurology (DGN). METHODS: The recommendations were based on a systematic literature review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three diagnostic questions were defined: (1) What is the accuracy of TCS in the differential diagnosis of PD versus atypical and secondary Parkinsonian syndromes? (2) What is the accuracy of TCS in the differential diagnosis of PD versus essential tremor? (3) What is the accuracy of TCS in the diagnosis of PD in persons with typical early symptoms, compared with the diagnosis established by clinical follow-up? The brain structures to be assessed and the level of recommendation were formulated for these questions. The training requirements for being regarded as qualified TCS investigator were stipulated by the responsible medical societies (German Society of Ultrasound in Medicine, DEGUM; German Society for Clinical Neurophysiology and Functional Imaging, DGKN). Finally, the recommendations for these diagnostic questions reached strong consensus (each ≥ 97%) of the guideline committee. Here, the details of review and recommendations are presented. CONCLUSION: The updated guideline clarifies the diagnostic uses and limitations of TCS in PD.

Current state of clinical ultrasound neuromodulation.

Unmatched by other non-invasive brain stimulation techniques, transcranial ultrasound (TUS) offers highly focal stimulation not only on the cortical surface but also in deep brain structures. These unique attributes are invaluable in both basic and clinical research and might open new avenues for treating neurological and psychiatric diseases. Here, we provide a concise overview of the expanding volume of clinical investigations in recent years and upcoming research initiatives concerning focused ultrasound neuromodulation. Currently, clinical TUS research addresses a variety of neuropsychiatric conditions, such as pain, dementia, movement disorders, psychiatric conditions, epilepsy, disorders of consciousness, and developmental disorders. As demonstrated in sham-controlled randomized studies, TUS neuromodulation improved cognitive functions and mood, and alleviated symptoms in schizophrenia and autism. Further, preliminary uncontrolled evidence suggests relieved anxiety, enhanced motor functions in movement disorders, reduced epileptic seizure frequency, improved responsiveness in patients with minimally conscious state, as well as pain reduction after neuromodulatory TUS. While constrained by the relatively modest number of investigations, primarily consisting of uncontrolled feasibility trials with small sample sizes, TUS holds encouraging prospects for treating neuropsychiatric disorders. Larger sham-controlled randomized trials, alongside further basic research into the mechanisms of action and optimal sonication parameters, are inevitably needed to unfold the full potential of TUS neuromodulation.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

Sustained reduction of essential tremor with low-power non-thermal transcranial focused ultrasound stimulations in humans.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. OBJECTIVE: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. METHODS: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. RESULTS: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. CONCLUSIONS: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions.

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.

ITRUSST consensus on standardised reporting for transcranial ultrasound stimulation.

As transcranial ultrasound stimulation (TUS) advances as a precise, non-invasive neuromodulatory method, there is a need for consistent reporting standards to enable comparison and reproducibility across studies. To this end, the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) formed a subcommittee of experts across several domains to review and suggest standardised reporting parameters for low intensity TUS, resulting in the guide presented here. The scope of the guide is limited to reporting the ultrasound aspects of a study. The guide and supplementary material provide a simple checklist covering the reporting of: (1) the transducer and drive system, (2) the drive system settings, (3) the free field acoustic parameters, (4) the pulse timing parameters, (5) in situ estimates of exposure parameters in the brain, and (6) intensity parameters. Detailed explanations for each of the parameters, including discussions on assumptions, measurements, and calculations, are also provided.

A review of functional neuromodulation in humans using low-intensity transcranial focused ultrasound.

Transcranial ultrasonic neuromodulation is a rapidly burgeoning field where low-intensity transcranial focused ultrasound (tFUS), with exquisite spatial resolution and deep tissue penetration, is used to non-invasively activate or suppress neural activity in specific brain regions. Over the past decade, there has been a rapid increase of tFUS neuromodulation studies in healthy humans and subjects with central nervous system (CNS) disease conditions, including a recent surge of clinical investigations in patients. This narrative review summarized the findings of human neuromodulation studies using either tFUS or unfocused transcranial ultrasound (TUS) reported from 2013 to 2023. The studies were categorized into two separate sections: healthy human research and clinical studies. A total of 42 healthy human investigations were reviewed as grouped by targeted brain regions, including various cortical, subcortical, and deep brain areas including the thalamus. For clinical research, a total of 22 articles were reviewed for each studied CNS disease condition, including chronic pain, disorder of consciousness, Alzheimer's disease, Parkinson's disease, depression, schizophrenia, anxiety disorders, substance use disorder, drug-resistant epilepsy, and stroke. Detailed information on subjects/cohorts, target brain regions, sonication parameters, outcome readouts, and stimulatory efficacies were tabulated for each study. In later sections, considerations for planning tFUS neuromodulation in humans were also concisely discussed. With an excellent safety profile to date, the rapid growth of human tFUS research underscores the increasing interest and recognition of its significant potential in the field of non-invasive brain stimulation (NIBS), offering theranostic potential for neurological and psychiatric disease conditions and neuroscientific tools for functional brain mapping.

Effects of Transcranial Ultrasound Stimulation on Blood Oxygen Metabolism and Brain Rhythms in Nitroglycerin-Induced Migraine Mice.

OBJECTIVES: In this study, we aimed to investigate the regulatory mechanism of transcranial ultrasound stimulation (TUS) on nitroglycerin-induced migraine in mice. MATERIALS AND METHODS: The experiment was divided into four groups, namely, the normal saline control group (n = 9), ultrasound stimulation control group (n = 6), nitroglycerin-induced migraine group (n = 9), and ultrasound stimulation group (n = 9). The behavior, blood oxygen metabolism, and brain rhythm distribution of the four groups were analyzed. RESULTS: We found that after TUS, the movement time and speed of mice with migraine are modulated to those of the control groups, and the number of head scratching and grooming events is significantly reduced. TUS increased the deoxygenated hemoglobin, and the power of the 4-to-40 Hz frequency band of local field potentials in the cortex of migraine mice. TUS also decreased the expression of plasma calcitonin gene-related peptide and cortical c-Fos protein. CONCLUSIONS: Ultrasound stimulation can regulate brain rhythm and blood oxygen metabolism and reduce migraine symptoms in mice. The regulatory mechanism may be related to reducing calcitonin gene-related peptide in blood vessels.

New semi-analytical method for fast transcranial ultrasonic field simulation.

Objective.To optimize and ensure the safety of ultrasound brain therapy, personalized transcranial ultrasound simulations are very useful. They allow to predict the pressure field, depending on the patient skull and probe position. Most transcranial ultrasound simulations are based on numerical methods which have a long computation time and a high memory usage. The goal of this study is to develop a new semi-analytical field computation method that combines realism and computation speed.Approach.Instead of the classic ray tracing, the ultrasonic paths are computed by time of flight minimization. Then the pressure field is computed using the pencil method. This method requires a smooth and homogeneous skull model. The simulation algorithm, so-called SplineBeam, was numerically validated, by comparison with existing solvers, and experimentally validated by comparison with hydrophone measured pressure fields through anex vivohuman skull.Main results.SplineBeam simulated pressure fields were close to the experimentally measured ones, with a focus position difference of the order of the positioning error and a maximum pressure difference lower than 6.02%. In addition, for those configurations, SplineBeam computation time was lower than another simulation software, k-Wave's, by two orders of magnitude, thanks to its capacity to compute the field only at the focal spot.Significance.These results show the potential of this new method to compute fast and realistic transcranial pressure fields. The combination of this two assets makes it a promising tool for real time transcranial pressure field prediction during ultrasound brain therapy interventions.

Low-intensity transcranial ultrasound stimulation improves memory in vascular dementia by enhancing neuronal activity and promoting spine formation.

Memory is closely associated with neuronal activity and dendritic spine formation. Low-intensity transcranial ultrasound stimulation (TUS) improves the memory of individuals with vascular dementia (VD). However, it is unclear whether neuronal activity and dendritic spine formation under ultrasound stimulation are involved in memory improvement in VD. In this study, we found that seven days of TUS improved memory in VD model while simultaneously increasing pyramidal neuron activity, promoting dendritic spine formation, and reducing dendritic spine elimination. These effects lasted for 7 days but disappeared on 14 d after TUS. Neuronal activity and dendritic spine formation strongly corresponded to improvements in memory behavior over time. In addition, we also found that the memory, neuronal activity and dendritic spine of VD mice cannot be restored again by TUS of 7 days after 28 d. Collectively, these findings suggest that TUS increases neuronal activity and promotes dendritic spine formation and is thus important for improving memory in patients with VD.

Correlation between Transcranial Ultrasound and CT Head to Detect Clinically Significant Conditions in Post-craniectomy Patients Performed by Emergency Physician: A Pilot Study.

Background: The main objective is to detect clinically significant conditions by transcranial ultrasound (TCS) in post-decompressive craniectomy (DC) patients who come to the emergency department. Materials and methods: This was a cross-sectional observational study. We studied 40 post-DC patients. After primary stabilization, TCS was done. Computer tomography of head was done within 2 hours of performing TCS. The correlation between both modalities were assessed by the measurement of lateral ventricle (LV) (Bland-Altman plot), Midline shift and mass lesion. Additionally, normal cerebral anatomy, 3rd and 4th ventricles and external ventricular drainage (EVD) catheter visualization were also done. Results: About 14/40 patients came with non-neurosurgical complaints and 26/40 patients came with neurosurgical complaints. Patients with non-neurosurgical complaints (4/14) had mass lesions and 1/14 had MLS. Patients with neurosurgical complaints (11/26) had mass lesions and about 5 patients had MLS. A good correlation was found between TCS and CT of head in measuring LV right (CT head = 17.4 ± 13.8 mm and TCS = 17.1 ± 14.8 mm. The mean difference (95% CI) = [0.28 (-1.9 to 1.33), ICC 0.93 (0.88-0.96)], Left [CT head = 17.8 ± 14.4 mm and TCS = 17.1 ± 14.2 mm, the mean difference (95% CI) 0.63 (-1.8 to 0.61), ICC 0.96 (0.93-0.98)], MLS [CT head = 6.16 ± 3.59 (n = 7) and TCS = 7.883 ± 4.17 (n = 6)] and mass lesions (kappa 0.84 [0.72-0.89] [95% CI] p-value < 0.001). The agreement between both modalities for detecting mass lesions is 93.75%. Conclusion: Point of care ultrasound (POCUS) is a bedside, easily operable, non-radiation hazard and dynamic imaging tool that can be used for TCS as a supplement to CT head in post-DC patients in emergency as well as in ICU. However, assessment of the ventricular system (pre/post-EVD insertion), monitoring of regression/progression of mass lesion, etc. can be done with TCS. Repeated scans are possible in less time which can decrease the frequency of CT head. How to cite this article: Chouhan R, Sinha TP, Bhoi S, Kumar A, Agrawal D, Nayer J, et al. Correlation between Transcranial Ultrasound and CT Head to Detect Clinically Significant Conditions in Post-craniectomy Patients Performed by Emergency Physician: A Pilot Study. Indian J Crit Care Med 2024;28(3):299-306.

Noninvasive intervention by transcranial ultrasound stimulation: Modulation of neural circuits and its clinical perspectives.

Low-intensity focused transcranial ultrasound stimulation (TUS) is an emerging noninvasive technique capable of stimulating both the cerebral cortex and deep brain structures with high spatial precision. This method is recognized for its potential to comprehensively perturb various brain regions, enabling the modulation of neural circuits, in a manner not achievable through conventional magnetic or electrical brain stimulation techniques. The underlying mechanisms of neuromodulation are based on a phenomenon where mechanical waves of ultrasound kinetically interact with neurons, specifically affecting neuronal membranes and mechanosensitive channels. This interaction induces alterations in the excitability of neurons within the stimulated region. In this review, we briefly present the fundamental principles of ultrasound physics and the physiological mechanisms of TUS neuromodulation. We explain the experimental apparatus and procedures for TUS in humans. Due to the focality, the integration of various methods, including magnetic resonance imaging and magnetic resonance-guided neuronavigation systems, is important to perform TUS experiments for precise targeting. We then review the current state of the literature on TUS neuromodulation, with a particular focus on human subjects, targeting both the cerebral cortex and deep subcortical structures. Finally, we outline future perspectives of TUS in clinical applications in psychiatric and neurological fields.

Detection of moderate to severe middle cerebral artery atherosclerotic stenosis in stroke patients: Transcranial color-coded duplex sonography versus computed tomography angiography.

Background: Intracranial atherosclerotic stenosis is a common cause of ischemic cerebrovascular events and is associated with a high risk of stroke recurrence. This study aimed to assess the diagnostic accuracy of transcranial color-coded duplex sonography for moderate-to-severe middle cerebral artery stenosis in stroke patients. Methods: A retrospective analysis was carried out, including 31 patients aged ⩾18 years hospitalized for ischemic cerebrovascular event in whom middle cerebral artery stenosis ⩾30% was identified on computed tomography angiography. Transcranial color-coded duplex sonography findings were compared to the degree of stenosis blindly identified on the computed tomography angiography used as the reference method. Results: Overall, 27 patients had M1 stenosis and the other 4 had M2 stenosis. To detect M2 stenosis ⩾ 50% and ⩾ 70%, stenotic to pre-stenotic ratio ⩾ 2 and ⩾ 3 had a sensitivity of 100%, respectively. To detect M1 stenosis ⩾ 70%, peak systolic velocity ⩾ 300 cm/s had a sensitivity of 53.8% and specificity of 85.7% with area under the receiver-operating characteristic curve of 0.753 (95% confidence interval: 0.568-0.938; p = 0.026), and stenotic to pre-stenotic ratio ⩾ 3 had a sensitivity of 84.6% and a specificity of 78.6% (area under the curve = 0.854; 95% confidence interval: 0.707-1; p = 0.002). Middle cerebral artery/anterior cerebral artery velocity ratio < 0.7 had a sensitivity of 57.1% and specificity of 90% to detect dampened pre-stenotic flow in middle cerebral artery secondary to downstream M1 stenosis ⩾ 70% (area under the curve = 0.800; 95% confidence interval: 0.584-1; p = 0.040). Conclusion: This study showed that stenotic to pre-stenotic ratio ⩾ 3 was more sensitive than peak systolic velocity ⩾ 300 cm/s to screen M1 stenosis ⩾ 70%. Middle cerebral artery/anterior cerebral artery ratio < 0.7 was a good indirect sign to detect dampened pre-stenotic flow due to M1 stenosis ⩾ 70%.

Transcranial ultrasound estimation of viscoelasticity and fluidity in brain tumors aided by transcranial shear waves.

Cerebral diseases, such as brain tumors, are intricately linked to the mechanical properties of brain tissues. Estimating the mechanical properties of brain tumors using transcranial ultrasound is a promising approach. However, the complexity of cranial features introduces challenges, such as ultrasound attenuation and interference from multidirectional transcranial shear waves induced by impact vibrations. To address these issues, this study proposes a transcranial ultrasound estimation method assisted by transcranial shear vibrations. Transcranial vibrations apply shear forces on the parietal bone, inducing unidirectional transcranial shear waves within brain tissue, as validated through simulations. Shear waves at different frequencies were captured via transcranial ultrasound, which were used to assess the viscoelasticity and fluidity of brain tumors. Transcranial experimental validations were conducted in 3D-printed models with tumor phantoms and ex vivo animal tumors. Vibration safety assessments were also performed. The results demonstrate that transcranial ultrasound can detect micron displacements induced by transcranial shear waves. In phantom and ex vivo animal experiments, speed distribution maps were employed to determine the size and location of one or two tumors enclosed in the skull model. The results revealed that the proposed approach could detect tumors with a minimum diameter of 0.8 cm and an inter-tumor distance of 0.8 cm. Notably, significant differences in viscoelasticity and fluidity between normal brain tissue and brain tumors were found (p<0.001). The maximum assessment errors for the elasticity, viscosity, and fluidity using transcranial ultrasound were 11.90%, 4.82%, and 0.73%, respectively, indicating that fluidity was more robust than viscoelasticity. The maximum accelerations of the skull were only 3.21 ms-2.

Noninvasive assessment of pressure distribution and fractional flow in middle cerebral artery using microbubbles and plane wave in vitro.

Fractional flow has been proposed for quantifying the degree of functional stenosis in cerebral arteries. Herein, subharmonic aided pressure estimation (SHAPE) combined with plane wave (PW) transmission was employed to noninvasively estimate the pressure distribution and fractional flow in the middle cerebral artery (MCA) in vitro. Consequently, the effects of incident sound pressure (peak negative pressures of 86-653 kPa), pulse repetition frequency (PRF), number of pulses, and blood flow rate on the subharmonic pressure relationship were investigated. The radio frequency data were stored and beamformed offline, and the subharmonic amplitude over a 0.4 MHz bandwidth was extracted using a 12-cycle PW at 4 MHz. The optimal incident sound pressure was 217 kPa without skull (sensitivity = 0.09 dB/mmHg; r2 = 0.997) and 410 kPa with skull (median sensitivity = 0.06 dB/mmHg; median r2 = 0.981). The optimal PRF was 500 Hz, as this value affords the highest sensitivity (0.09 dB/mmHg; r2 = 0.976) and temporal resolution. In addition, the blood flow rate exhibited a lesser effect on the subharmonic pressure relationship in our experimental setup. Using the optimized parameters, the blood pressure distribution and fractional flow (FFs) were measured. As such, the FFs value was in high agreement with the value measured using the pressure sensor (FFm). The mean ± standard deviations of the FF difference (FFm - FFs) were 0.03 ± 0.06 without skull and 0.01 ± 0.05 with skull.

The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies.

Low-intensity transcranial ultrasound stimulation (LITUS) is a novel non-invasive neuromodulation technique. We conducted a systematic review to evaluate current evidence on the efficacy and safety of LITUS neuromodulation. Five databases were searched from inception to May 31, 2023. Randomized controlled human trials and controlled animal studies were included. The neuromodulation effects of LITUS on clinical or pre-clinical, neurophysiological, neuroimaging, histological and biochemical outcomes, and adverse events were summarized. In total, 11 human studies and 44 animal studies were identified. LITUS demonstrated therapeutic efficacy in neurological disorders, psychiatric disorders, pain, sleep disorders and hypertension. LITUS-related changes in neuronal structure and cortical activity were found. From histological and biochemical perspectives, prominent findings included suppressing the inflammatory response and facilitating neurogenesis. No adverse effects were reported in controlled animal studies included in our review, while reversible headache, nausea, and vomiting were reported in a few human subjects. Overall, LITUS alleviates various symptoms and modulates associated brain circuits without major side effects. Future research needs to establish a solid therapeutic framework for LITUS.

A frontopolar-temporal circuit determines the impact of social information in macaque decision making.

When choosing, primates are guided not only by personal experience of objects but also by social information such as others' attitudes toward the objects. Crucially, both sources of information-personal and socially derived-vary in reliability. To choose optimally, one must sometimes override choice guidance by personal experience and follow social cues instead, and sometimes one must do the opposite. The dorsomedial frontopolar cortex (dmFPC) tracks reliability of social information and determines whether it will be attended to guide behavior. To do this, dmFPC activity enters specific patterns of interaction with a region in the mid-superior temporal sulcus (mSTS). Reversible disruption of dmFPC activity with transcranial ultrasound stimulation (TUS) led macaques to fail to be guided by social information when it was reliable but to be more likely to use it when it was unreliable. By contrast, mSTS disruption uniformly downregulated the impact of social information on behavior.

Transcranial ultrasound stimulation selectively affects cortical neurovascular coupling across neuronal types and LFP frequency bands.

Previous studies have affirmed that transcranial ultrasound stimulation (TUS) can influence cortical neurovascular coupling across low-frequency (0-2 Hz)/high-frequency (160-200 Hz) neural oscillations and hemodynamics. Nevertheless, the selectivity of this coupling triggered by transcranial ultrasound stimulation for spike activity (> 300 Hz) and additional frequency bands (4-150 Hz) remains elusive. We applied transcranial ultrasound stimulation to mice visual cortex while simultaneously recording total hemoglobin concentration, spike activity, and local field potentials. Our findings include (1) a significant increase in coupling strength between spike firing rates of putative inhibitory neurons/putative excitatory neurons and total hemoglobin concentration post-transcranial ultrasound stimulation; (2) an ~ 2.1-fold higher Pearson correlation coefficient between putative inhibitory neurons and total hemoglobin concentration compared with putative excitatory neurons and total hemoglobin concentration (*P < 0.05); (3) a notably greater cross-correlation between putative inhibitory neurons and total hemoglobin concentration than that between putative excitatory neurons and total hemoglobin concentration (*P < 0.05); (4) an enhancement of Pearson correlation coefficient between the relative power of γ frequency band (30-80 Hz), hγ frequency band (80-150 Hz) and total hemoglobin concentration following transcranial ultrasound stimulation (*P < 0.05); and (5) strongest cross-correlation observed at negative delay for θ frequency band, and positive delay for α, ß, γ, hγ frequency bands. Collectively, these results demonstrate that cortical neurovascular coupling evoked by transcranial ultrasound stimulation exhibits selectivity concerning neuronal types and local field potential frequency bands.

High-throughput ultrasound neuromodulation in awake and freely behaving rats.

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.