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Cerebrospinal fluid (CSF) flow is crucial for brain homeostasis and its dysfunction is highly associated with neurodegenerative diseases. Restoring CSF circulation is proposed as a key strategy for the treatment of the diseases. Among the methods to improve CSF circulation, focused ultrasound (FUS) stimulation has emerged as a promising non-invasive brain stimulation technique, with effectiveness evidenced by ex vivo studies. However, due to technical disturbances in in vivo imaging combined with FUS, direct evidence of real-time in vivo CSF flow enhancement by FUS remains elusive. To investigate whether FUS administered through the skull base can enhance CSF influx in living animals with various real-time imaging techniques. We demonstrate a novel method of applying FUS through the skull base, facilitating cortical CSF influx, evidenced by diverse in vivo imaging techniques. Acoustic simulation confirmed effective sonication of our approach through the skull base. After injecting fluorescent CSF tracers into cisterna magna, FUS was administered at the midline of the jaw through the skull base for 30 min, during which imaging was performed concurrently. Enhanced CSF influx was observed in macroscopic imaging, demonstrated by the influx area and intensity of the fluorescent dyes after FUS. In two-photon imaging, increased fluorescence was observed in the perivascular space (PVS) after stimulation. Moreover, particle tracking of microspheres showed more microspheres entering the imaging field, with increased mean speed after FUS. Our findings provide direct real-time in vivo imaging evidence that FUS promotes CSF influx and flow in the PVS. [Display omitted] • Applying low-intensity FUS through the skull base enhanced cortical CSF influx. • In vivo imaging techniques evidenced real-time CSF dynamics facilitated by FUS. • FUS accelerated CSF dynamics exhibited by microsphere flow in the PVS. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) flow is crucial for brain homeostasis and its dysfunction is highly associated with neurodegenerative diseases. Restoring CSF circulation is proposed as a key strategy for the treatment of the diseases. Among the methods to improve CSF circulation, focused ultrasound (FUS) stimulation has emerged as a promising non-invasive brain stimulation technique, with effectiveness evidenced by ex vivo studies. However, due to technical disturbances in in vivo imaging combined with FUS, direct evidence of real-time in vivo CSF flow enhancement by FUS remains elusive. Objective: To investigate whether FUS administered through the skull base can enhance CSF influx in living animals with various real-time imaging techniques. Methods: We demonstrate a novel method of applying FUS through the skull base, facilitating cortical CSF influx, evidenced by diverse in vivo imaging techniques. Acoustic simulation confirmed effective sonication of our approach through the skull base. After injecting fluorescent CSF tracers into cisterna magna, FUS was administered at the midline of the jaw through the skull base for 30 min, during which imaging was performed concurrently. Results: Enhanced CSF influx was observed in macroscopic imaging, demonstrated by the influx area and intensity of the fluorescent dyes after FUS. In two-photon imaging, increased fluorescence was observed in the perivascular space (PVS) after stimulation. Moreover, particle tracking of microspheres showed more microspheres entering the imaging field, with increased mean speed after FUS. Conclusion: Our findings provide direct real-time in vivo imaging evidence that FUS promotes CSF influx and flow in the PVS.

Abstract Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and destruction of the cerebrovascular system is a major factor in the cascade of secondary injuries caused by TBI. Laser speckle imaging (LSCI)has high sensitivity in detecting cerebral blood flow. LSCI can visually show that transcranial focused ultrasound stimulation (tFUS) treatment stimulates angiogenesis and increases blood flow. To study the effect of tFUS on promoting angiogenesis in Controlled Cortical impact (CCI) model. tFUS was administered daily for 10 min and for 14 consecutive days after TBI. Cerebral blood flow was measured by LSCI at 1, 3, 7 and 14 days after trauma. Functional outcomes were assessed using LSCI and neurological severity score (NSS). After the last test, Nissl staining and vascular endothelial growth factor (VEGF) were used to assess neuropathology. TBI can cause the destruction of cerebrovascular system. Blood flow was significantly increased in TBI treated with tFUS. LSCI, behavioral and histological findings suggest that tFUS treatment can promote angiogenesis after TBI.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and destruction of the cerebrovascular system is a major factor in the cascade of secondary injuries caused by TBI. Laser speckle imaging (LSCI)has high sensitivity in detecting cerebral blood flow. LSCI can visually show that transcranial focused ultrasound stimulation (tFUS) treatment stimulates angiogenesis and increases blood flow. To study the effect of tFUS on promoting angiogenesis in Controlled Cortical impact (CCI) model. tFUS was administered daily for 10 min and for 14 consecutive days after TBI. Cerebral blood flow was measured by LSCI at 1, 3, 7 and 14 days after trauma. Functional outcomes were assessed using LSCI and neurological severity score (NSS). After the last test, Nissl staining and vascular endothelial growth factor (VEGF) were used to assess neuropathology. TBI can cause the destruction of cerebrovascular system. Blood flow was significantly increased in TBI treated with tFUS. LSCI, behavioral and histological findings suggest that tFUS treatment can promote angiogenesis after TBI. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound stimulation is a promising brain stimulation technique for its noninvasiveness and higher spatial resolutions and is used for various neuromodulation applications. As the skull is the primary barrier to delivering ultrasound to the deep brain region, it induces unpredictable ultrasound exposure. The objective of the study is to design customised transducers and assess the effects of the skull on ultrasound wave propagation. Computational skull models were constructed using computerised tomography scans. A full-wave finite-difference time-domain simulation platform, Sim4Life, was then used to design and simulate ultrasound wave propagation. In addition, the impacts of the skull were assessed through sensitivity analysis in the intracranial intensity, pressure, full width at half maximum, and energy deposition. Compared to the intracranial intensity distribution when the transducer is placed over the top area of the skull, the peak intensity increased by 23.4% for transmission through the temporal window. The temporal window, the thinnest part of the skull, provides a site for intracranial peak intensity and optimal focal spot area using focused ultrasound. The numerical investigation in this study provided a guideline for targeting and dosing, accounting for and lessening variability in studies addressing transcranial focused ultrasound applications. [ABSTRACT FROM AUTHOR]

Characterized by high morbidity, mortality, and disability, stroke usually causes symptoms of cerebral hypoxia due to a sudden blockage or rupture of brain vessels, and it seriously threatens human life and health. Rehabilitation is the essential treatment for post-stroke patients suffering from functional impairments, through which hemiparesis, aphasia, dysphagia, unilateral neglect, depression, and cognitive dysfunction can be restored to various degrees. Noninvasive brain stimulation (NIBS) is a popular neuromodulatory technology of rehabilitation focusing on the local cerebral cortex, which can improve clinical functions by regulating the excitability of corresponding neurons. Increasing evidence has been obtained from the clinical application of NIBS, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, without a standardized protocol, existing studies on NIBS show a wide variation in terms of stimulation site, frequency, intensity, dosage, and other parameters. Its application for neurorehabilitation in post-stroke patients is still limited. With advances in neuronavigation technologies, functional near-infrared spectroscopy, and functional MRI, specific brain regions can be precisely located for stimulation. On the basis of our further understanding on neural circuits, neuromodulation in post-stroke rehabilitation has also evolved from single-target stimulation to co-stimulation of two or more targets, even circuits and the network. The present study aims to review the findings of current research, discuss future directions of NIBS application, and finally promote the use of NIBS in post-stroke rehabilitation. [ABSTRACT FROM AUTHOR]

Transcranial focused Ultrasound Stimulation (TUS) at low intensities is emerging as a novel non-invasive brain stimulation method with higher spatial resolution than established transcranial stimulation methods and the ability to selectively stimulate also deep brain areas. Accurate control of the focus position and strength of the TUS acoustic waves is important to enable a beneficial use of the high spatial resolution and to ensure safety. As the human skull causes strong attenuation and distortion of the waves, simulations of the transmitted waves are needed to accurately determine the TUS dose distribution inside the cranial cavity. The simulations require information of the skull morphology and its acoustic properties. Ideally, they are informed by computed tomography (CT) images of the individual head. However, suited individual imaging data is often not readily available. For this reason, we here introduce and validate a head template that can be used to estimate the average effects of the skull on the TUS acoustic wave in the population.The template was created from CT images of the heads of 29 individuals of different ages (between 20–50 years), gender and ethnicity using an iterative non-linear co-registration procedure. For validation, we compared acoustic and thermal simulations based on the template to the average of the simulation results of all 29 individual datasets. Acoustic simulations were performed for a model of a focused transducer driven at 500 kHz, placed at 24 standardized positions by means of the EEG 10–10 system. Additional simulations at 250 kHz and 750 kHz at 16 of the positions were used for further confirmation. The amount of ultrasound-induced heating at 500 kHz was estimated for the same 16 transducer positions. Our results show that the template represents the median of the acoustic pressure and temperature maps from the individuals reasonably well in most cases. This underpins the usefulness of the template for the planning and optimization of TUS interventions in studies of healthy young adults. Our results further indicate that the amount of variability between the individual simulation results depends on the position. Specifically, the simulated ultrasound-induced heating inside the skull exhibited strong interindividual variability for three posterior positions close to the midline, caused by a high variability of the local skull shape and composition. This should be taken into account when interpreting simulation results based on the template.

Background: Owing to its high spatial resolution and penetration depth, transcranial focused ultrasound stimulation (tFUS) is one of the most promising approaches to non-invasive neuromodulation. Identifying the impact of endogenous neural activity on neuromodulation outcome is critical to harnessing the potential of tFUS. Objective: Here we sought to identify the relationship between pre-stimulation neural activity and the neuronal response to tFUS. Methods: We applied 3 min of continuous-wave tFUS to the hippocampal region of the rat while recording local field potentials (LFP) and multi-unit activity (MUA) from the target. We also tested the application of tFUS but with an air gap separating the transducer and the skull, as well as active stimulation of the contralateral olfactory bulb. Results: We observed a modest but significant increase in firing rate during hippocampal tFUS, but not during stimulation of the olfactory bulb or when an air gap was present. Importantly, the observed firing rate increase was significantly modulated by the power of baseline oscillations in the LFP, with low levels of delta (1–3 Hz) and high levels of theta (4–10 Hz) and gamma (30–250 Hz) power producing significantly larger firing rate increases. Firing rate increases were also amplified by a factor of 7× when stimulation was applied during periods of frequent sharp-wave ripple (SWR) activity. Conclusion: Our findings suggest that baseline brain rhythms may effectively “gate” the response to tFUS.

The lack of sensory feedback represents one of the main drawbacks of commercial upper limb prosthesis. Transcranial Focused Ultrasound Stimulation (tFUS) seems to be a valid non-invasive technique for restoring sensory feedback allowing to deliver acoustic energy to cortical sensory areas with high spatial resolution and depth penetration. This paper aims at studying in simulation the use of tFUS on cortical sensory areas to evaluate its effects in terms of latency ad firing rate of the cells response, for understanding if these parameters influence the safety and the efficacy of the stimulation. In this paper, in order to study the propagation of the ultrasound wave from the transducer to the cortical cells, a multiscale approach was implemented by building a macroscopic model, which estimates the pressure profile in a simplified 2D human head geometry, and coupling it with the SONIC microscale model, that describes the electrical behaviour of a cortical neuron. The influence of the stimulation parameters and of the skull thickness on the latency and the firing rate are evaluated and the obtained behaviour is linked to the sensory response obtained on human subjects. Results have shown that slight changes in the transducer position should not affect the efficacy of the stimulation; however, high skull thickness leads to lower cells activation. These results will be useful for evaluating safety and effectiveness of tFUS for sensory feedback in closed-loop prosthetic systems.

Objective: Transcranial focused ultrasound (TUS) can suppress human motor cortical excitability. However, it is unclear whether the TUS may interact with transcranial magnetic stimulation (TMS) when they co-delivered in multiple trials., Methods: Nineteen subjects received three different TUS-TMS co-stimulation protocols to the motor cortex including concurrent stimulation (TUS-TMS-C), separated stimulation (TUS-TMS-S), and TMS only. In each condition, two runs of 30 stimulation trials were conducted with a five-minute rest between runs. Motor-evoked potentials (MEP) were recorded during stimulation and at 0, 10, 20, and 30 min after stimulation. The MEP amplitudes after intervention were normalized to the mean pre-intervention MEP amplitude and expressed as MEP ratios. An additional test with TUS alone was applied to all participants to assess whether TUS itself can elicit after-effects., Results: There were no significant after-effects of all three interventions on MEP ratios. However, 11 subjects who showed online inhibition (OI + ) during the TUS-TMS-C protocol, defined as having MEP ratio less than 1 during TUS-TMS-C, showed significant MEP suppression at 10, 20 and 30 min after TUS-TMS-C. In 8 subjects did not show online inhibition (OI-), defined as having MEP ratios greater than 1 during TUS-TMS-C, showed no significant inhibitory after-effects. OI + and OI- status did not change in a follow-up repeat TUS-TMS-C test. TUS alone did not generate inhibitory after-effects in either OI + or OI- participants., Conclusions: Our results showed that co-delivery of TUS and TMS can elicit inhibitory after-effect in subjects who showed online inhibition, suggesting that TUS and TMS may interact with each other to produce plasticity effects., Significance: TUS and TMS may interact with each other to modulate cortical excitability., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Characterized by high morbidity, mortality, and disability, stroke usually causes symptoms of cerebral hypoxia due to a sudden blockage or rupture of brain vessels, and it seriously threatens human life and health. Rehabilitation is the essential treatment for post-stroke patients suffering from functional impairments, through which hemiparesis, aphasia, dysphagia, unilateral neglect, depression, and cognitive dysfunction can be restored to various degrees. Noninvasive brain stimulation (NIBS) is a popular neuromodulatory technology of rehabilitation focusing on the local cerebral cortex, which can improve clinical functions by regulating the excitability of corresponding neurons. Increasing evidence has been obtained from the clinical application of NIBS, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, without a standardized protocol, existing studies on NIBS show a wide variation in terms of stimulation site, frequency, intensity, dosage, and other parameters. Its application for neurorehabilitation in post-stroke patients is still limited. With advances in neuronavigation technologies, functional near-infrared spectroscopy, and functional MRI, specific brain regions can be precisely located for stimulation. On the basis of our further understanding on neural circuits, neuromodulation in post-stroke rehabilitation has also evolved from single-target stimulation to co-stimulation of two or more targets, even circuits and the network. The present study aims to review the findings of current research, discuss future directions of NIBS application, and finally promote the use of NIBS in post-stroke rehabilitation.

Compared with the conventional method of transcranial focused ultrasound stimulation using a single transducer or a focused beam, the compression and tensile forces are generated from the high-pressure gradient of a standing wave that can generate increased stimulation. We experimentally verified a neuromodulation system using patterned interference radiation force (PIRF) and propose a method for obtaining the magnitude of the radiation force, which is considered the main factor influencing ultrasound neuromodulation. The radiation forces generated using a single focused transducer and a standing wave created via two focused transducers were compared using simulations. Radiation force was calculated based on the relationship between the acoustic pressure, radiation force and time-averaged second-order pressure obtained using an acoustic streaming simulation. The presence of the radiation force was verified by measuring the time-averaged second-order pressure generated due to the radiation force, by using a glass tube. [ABSTRACT FROM AUTHOR]

Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons. Currently, several different techniques have been developed - or are currently being investigated – to treat a wide variety of neurological and neuropsychiatric disorders. Recently, in vivo and in vitro studies have revealed that neuromodulation can also induce myelination, meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy. These findings come on the heels of a paradigm shift in the view of myelin's role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation. In the present review, we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activity-dependent myelination. We also highlight several considerations for neuromodulatory techniques, including the need for further research into spatiotemporal precision, dosage, and the safety and efficacy of transcranial focused ultrasound stimulation, an emerging neuromodulation technology. As the field of neuromodulation continues to evolve, it could potentially bring forth methods for the treatment of demyelinating diseases, and as such, further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.

Owing to its high spatial resolution and penetration depth, transcranial focused ultrasound stimulation (tFUS) is one of the most promising approaches to non-invasive neuromodulation. Identifying the impact of endogenous neural activity on neuromodulation outcome is critical to harnessing the potential of tFUS. Here we sought to identify the relationship between pre-stimulation neural activity and the neuronal response to tFUS. We applied 3 min of continuous-wave tFUS to the hippocampal region of the rat while recording local field potentials (LFP) and multi-unit activity (MUA) from the target. We also tested the application of tFUS but with an air gap separating the transducer and the skull, as well as active stimulation of the contralateral olfactory bulb. We observed a modest but significant increase in firing rate during hippocampal tFUS, but not during stimulation of the olfactory bulb or when an air gap was present. Importantly, the observed firing rate increase was significantly modulated by the power of baseline oscillations in the LFP, with low levels of delta (1–3 Hz) and high levels of theta (4–10 Hz) and gamma (30–250 Hz) power producing significantly larger firing rate increases. Firing rate increases were also amplified by a factor of 7× when stimulation was applied during periods of frequent sharp-wave ripple (SWR) activity. Our findings suggest that baseline brain rhythms may effectively "gate" the response to tFUS. • We stimulated the hippocampus with focused ultrasound while capturing the LFP and MUA from the targeted area. • We hypothesized that the neuronal response to stimulation would be influenced by pre-stimulation neural activity. • The effect on spiking was larger during periods of low delta (1–3 Hz), high theta (4–10 Hz), and high gamma (30–250 Hz) power. • The firing rate increase produced by tFUS was 7X stronger when applied during periods of frequent sharp-wave ripples (SWR). [ABSTRACT FROM AUTHOR]

Low-intensity transcranial focused ultrasound stimulation (tFUS), as a noninvasive neuromodulation modality, has shown to be effective in animals and even humans with improved millimeter-scale spatial resolution compared to its noninvasive counterparts. But conventional tFUS systems are built with bulky single-element ultrasound (US) transducers that must be mechanically moved to change the stimulation target. To achieve large-scale ultrasound neuromodulation (USN) within a given tissue volume, a US transducer array should electronically be driven in a beamforming fashion (known as US phased array) to steer focused ultrasound beams towards different neural targets. This paper presents the theory and design methodology of US phased arrays for USN at a large scale. For a given tissue volume and sonication frequency (f), the optimal geometry of a US phased array is found with an iterative design procedure that maximizes a figure of merit (FoM) and minimizes side/grating lobes (avoiding off-target stimulation). The proposed FoM provides a balance between the power efficiency and spatial resolution of a US array in USN. A design example of a US phased array has been presented for USN in a rat's brain with an optimized linear US array. In measurements, the fabricated US phased array with 16 elements (16.7×7.7×2 mm3), driven by 150 V (peak-peak) pulses at f = 833.3 kHz, could generate a focused US beam with a lateral resolution of 1.6 mm and pressure output of 1.15 MPa at a focal distance of 12 mm. The capability of the US phased array in beam steering and focusing from -60o to 60o angles was also verified in measurements. [ABSTRACT FROM AUTHOR]

In order to improve the spatial resolution of transcranial focused ultrasound stimulation (tFUS), we have recently proposed microscopic ultrasound stimulation (μUS). In μUS, either an electronically phased array of ultrasound transducers or several millimeter-sized focused transducers are placed on the brain surface or sub-millimeter-sized transducers are implanted inside the brain tissue to steer and deliver a focused ultrasound pressure directly to the neural target. A key element in both tFUS and μUS is the ultrasound transducer that converts electrical power to acoustic pressure. The literature lacks a comprehensive study (in a quantitative manner) of the transducer characteristics, such as dimension, focusing, acoustic matching, backing material, and sonication frequency (fp), in the μUS. This paper studies the impact of these design parameters on the acoustic beam profile of millimeter-sized transducers with the emphasis on the stimulation spatial resolution and energy efficiency, which is defined as the μUS figure-of-merit (FoM). For this purpose, disc-shaped focused and unfocused piezoelectric (PZT-5A) transducers with different dimension (diameter, thickness), backing material (PCB, air) and acoustic matching in the frequency range of 2.2–9.56 MHz were fabricated. Our experimental studies with both water and sheep brain phantom medium demonstrate that acoustically matched focused transducers with high quality factor are desirable for μUS, as they provide fine spatial resolution and high acoustic intensities with low input electrical power levels (i.e., high FoM). [ABSTRACT FROM AUTHOR]

Transcranial focused Ultrasound Stimulation (TUS) at low intensities is emerging as a novel non-invasive brain stimulation method with higher spatial resolution than established transcranial stimulation methods and the ability to selectively stimulate also deep brain areas. Accurate control of the focus position and strength of the TUS acoustic waves is important to enable a beneficial use of the high spatial resolution and to ensure safety. As the human skull causes strong attenuation and distortion of the waves, simulations of the transmitted waves are needed to accurately determine the TUS dose distribution inside the cranial cavity. The simulations require information of the skull morphology and its acoustic properties. Ideally, they are informed by computed tomography (CT) images of the individual head. However, suited individual imaging data is often not readily available. For this reason, we here introduce and validate a head template that can be used to estimate the average effects of the skull on the TUS acoustic wave in the population. The template was created from CT images of the heads of 29 individuals of different ages (between 20-50 years), gender and ethnicity using an iterative non-linear co-registration procedure. For validation, we compared acoustic and thermal simulations based on the template to the average of the simulation results of all 29 individual datasets. Acoustic simulations were performed for a model of a focused transducer driven at 500 kHz, placed at 24 standardized positions by means of the EEG 10-10 system. Additional simulations at 250 kHz and 750 kHz at 16 of the positions were used for further confirmation. The amount of ultrasound-induced heating at 500 kHz was estimated for the same 16 transducer positions. Our results show that the template represents the median of the acoustic pressure and temperature maps from the individuals reasonably well in most cases. This underpins the usefulness of the template for the planning and optimization of TUS interventions in studies of healthy young adults. Our results further indicate that the amount of variability between the individual simulation results depends on the position. Specifically, the simulated ultrasound-induced heating inside the skull exhibited strong interindividual variability for three posterior positions close to the midline, caused by a high variability of the local skull shape and composition. This should be taken into account when interpreting simulation results based on the template., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

The lack of sensory feedback represents one of the main drawbacks of commercial upper limb prosthesis. Transcranial Focused Ultrasound Stimulation (tFUS) seems to be a valid non-invasive technique for restoring sensory feedback allowing to deliver acoustic energy to cortical sensory areas with high spatial resolution and depth penetration. This paper aims at studying in simulation the use of tFUS on cortical sensory areas to evaluate its effects in terms of latency ad firing rate of the cells response, for understanding if these parameters influence the safety and the efficacy of the stimulation. In this paper, in order to study the propagation of the ultrasound wave from the transducer to the cortical cells, a multiscale approach was implemented by building a macroscopic model, which estimates the pressure profile in a simplified 2D human head geometry, and coupling it with the SONIC microscale model, that describes the electrical behaviour of a cortical neuron. The influence of the stimulation parameters and of the skull thickness on the latency and the firing rate are evaluated and the obtained behaviour is linked to the sensory response obtained on human subjects. Results have shown that slight changes in the transducer position should not affect the efficacy of the stimulation; however, high skull thickness leads to lower cells activation. These results will be useful for evaluating safety and effectiveness of tFUS for sensory feedback in closed-loop prosthetic systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scarpelli, Stefano, Cordella and Zollo.)

Objective . Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation (NIBS) technique. TUS can reach deeper areas and target smaller regions in the brain than other NIBS techniques, but its application in humans is hampered by the lack of a straightforward and reliable procedure to predict the induced ultrasound exposure. Here, we examined how skull modeling affects computer simulations of TUS. Approach . We characterized the ultrasonic beam after transmission through a sheep skull with a hydrophone and performed computed tomography (CT) image-based simulations of the experimental setup. To study the skull model's impact, we varied: CT acquisition parameters (tube voltage, dose, filter sharpness), image interpolation, segmentation parameters, acoustic property maps (speed-of-sound, density, attenuation), and transducer-position mismatches. We compared the impact of modeling parameter changes on model predictions and on measurement agreement. Spatial-peak intensity and location, total power, and the Gamma metric (a measure for distribution differences) were used as quantitative criteria. Modeling-based sensitivity analysis was also performed for two human head models. Main results . Sheep skull attenuation assignment and transducer positioning had the most important impact on spatial peak intensity (overestimation up to 300%, respectively 30%), followed by filter sharpness and tube voltage (up to 20%), requiring calibration of the mapping functions. Positioning and skull-heterogeneity-structure strongly affected the intensity distribution (gamma tolerances exceeded in>80%, respectively>150%, of the focus-volume in water), necessitating image-based personalized modeling. Simulation results in human models consistently demonstrate a high sensitivity to the skull-heterogeneity model, attenuation tuning, and transducer shifts, the magnitude of which depends on the underlying skull structure complexity. Significance . Our study reveals the importance of properly modeling the skull-heterogeneity and its structure and of accurately reproducing the transducer position. The results raise red flags when translating modeling approaches among clinical sites without proper standardization and/or recalibration of the imaging and modeling parameters., (© 2021 IOP Publishing Ltd.)

Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons. Currently, several different techniques have been developed - or are currently being investigated - to treat a wide variety of neurological and neuropsychiatric disorders. Recently, in vivo and in vitro studies have revealed that neuromodulation can also induce myelination, meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy. These findings come on the heels of a paradigm shift in the view of myelin's role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation. In the present review, we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activity-dependent myelination. We also highlight several considerations for neuromodulatory techniques, including the need for further research into spatiotemporal precision, dosage, and the safety and efficacy of transcranial focused ultrasound stimulation, an emerging neuromodulation technology. As the field of neuromodulation continues to evolve, it could potentially bring forth methods for the treatment of demyelinating diseases, and as such, further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted., Competing Interests: None