UNASSIGNED: Transcranial focused ultrasound (tFUS) is an emerging neuromodulation approach that has been demonstrated in animals but is difficult to translate to humans because of acoustic attenuation and scattering in the skull. Optimal dose delivery requires subject-specific skull porosity estimates which has traditionally been done using CT. We propose a deep learning (DL) estimation of skull porosity from T1-weighted MRI images which removes the need for radiation-inducing CT scans.
UNASSIGNED: We evaluate the impact of different DL approaches, including network architecture, input size and dimensionality, multichannel inputs, data augmentation, and loss functions. We also propose back-propagation in the mask (BIM), a method whereby only voxels inside the skull mask contribute to training. We evaluate the robustness of the best model to input image noise and MRI acquisition parameters and propagate porosity estimation errors in thousands of beam propagation scenarios.
UNASSIGNED: Our best performing model is a cGAN with a ResNet-9 generator with 3D 64×64×64 inputs trained with L1 and L2 losses. The model achieved a mean absolute error of 6.9% in the test set, compared to 9.5% with the pseudo-CT of Izquierdo et al. (38% improvement) and 9.4% with the generic pixel-to-pixel image translation cGAN pix2pix (36% improvement). Acoustic dose distributions in the thalamus were more accurate with our approach than with the pseudo-CT approach of both Burgos et al. and Izquierdo et al, resulting in near-optimal treatment planning and dose estimation at all frequencies compared to CT (reference).
UNASSIGNED: Our DL approach porosity estimates with ~7% error, is robust to input image noise and MRI acquisition parameters (sequence, coils, field strength) and yields near-optimal treatment planning and dose estimates for both central (thalamus) and lateral brain targets (amygdala) in the 200-1000 kHz frequency range.

Transcranial focused ultrasound enables precise and non-invasive manipulations of deep brain circuits in humans, promising to provide safe and effective treatments of various neurological and mental health conditions. Ultrasound focused to deep brain targets can be used to modulate neural activity directly or localize the release of psychoactive drugs. However, these applications have been impeded by a key barrier-the human skull, which attenuates ultrasound strongly and unpredictably. To address this issue, we have developed an ultrasound-based approach that directly measures and compensates for the ultrasound attenuation by the skull. No additional skull imaging, simulations, assumptions, or free parameters are necessary; the method measures the attenuation directly by emitting a pulse of ultrasound from an array on one side of the head and measuring with an array on the opposite side. Here, we apply this emerging method to two primary future uses-neuromodulation and local drug release. Specifically, we show that the correction enables effective stimulation of peripheral nerves and effective release of propofol from nanoparticle carriers through an ex vivo human skull. Neither application was effective without the correction. Moreover, the effects show the expected dose-response relationship and targeting specificity. This article highlights the need for precise control of ultrasound intensity within the skull and provides a direct and practical approach for addressing this lingering barrier.

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.

UNASSIGNED: Transcranial focused ultrasound (TFUS) is an emerging neuromodulation tool for temporarily altering brain activity and probing network functioning. The effects of TFUS on the default mode network (DMN) are unknown.
UNASSIGNED: The study examined the effects of transcranial focused ultrasound (TFUS) on the functional connectivity of the default mode network (DMN), specifically by targeting the posterior cingulate cortex (PCC). Additionally, we investigated the subjective effects of TFUS on mood, mindfulness, and self-related processing.
UNASSIGNED: The study employed a randomized, single-blind design involving 30 healthy subjects. Participants were randomly assigned to either the active TFUS group or the sham TFUS group. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were conducted before and after the TFUS application. To measure subjective effects, the Toronto Mindfulness Scale, the Visual Analog Mood Scale, and the Amsterdam Resting State Questionnaire were administered at baseline and 30 min after sonication. The Self Scale and an unstructured interview were also administered 30 min after sonication.
UNASSIGNED: The active TFUS group exhibited significant reductions in functional connectivity along the midline of the DMN, while the sham TFUS group showed no changes. The active TFUS group demonstrated increased state mindfulness, reduced Global Vigor, and temporary alterations in the sense of ego, sense of time, and recollection of memories. The sham TFUS group showed an increase in state mindfulness, too, with no other subjective effects.
UNASSIGNED: TFUS targeted at the PCC can alter DMN connectivity and cause changes in subjective experience. These findings support the potential of TFUS to serve both as a research tool and as a potential therapeutic intervention.

Transcranial focused ultrasound stimulation (tFUS) has emerged as a promising neuromodulation technique that delivers acoustic energy with high spatial resolution for inducing long-term potentiation (LTP)- or depression (LTD)-like plasticity. The variability in the primary effects of tFUS-induced plasticity could be due to different stimulation patterns, such as intermittent versus continuous, and is an aspect that requires further detailed exploration. In this study, we developed a platform to evaluate the neuromodulatory effects of intermittent and continuous tFUS on motor cortical plasticity before and after tFUS application. Three groups of rats were exposed to either intermittent, continuous, or sham tFUS. We analyzed the neuromodulatory effects on motor cortical excitability by examining changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We also investigated the effects of different stimulation patterns on excitatory and inhibitory neural biomarkers, examining c-Fos and glutamic acid decarboxylase (GAD-65) expression using immunohistochemistry staining. Additionally, we evaluated the safety of tFUS by analyzing glial fibrillary acidic protein (GFAP) expression. The current results indicated that intermittent tFUS produced a facilitation effect on motor excitability, while continuous tFUS significantly inhibited motor excitability. Furthermore, neither tFUS approach caused injury to the stimulation sites in rats. Immunohistochemistry staining revealed increased c-Fos and decreased GAD-65 expression following intermittent tFUS. Conversely, continuous tFUS downregulated c-Fos and upregulated GAD-65 expression. In conclusion, our findings demonstrate that both intermittent and continuous tFUS effectively modulate cortical excitability. The neuromodulatory effects may result from the activation or deactivation of cortical neurons following tFUS intervention. These effects are considered safe and well-tolerated, highlighting the potential for using different patterns of tFUS in future clinical neuromodulatory applications.

Chronic pain, a complex and debilitating condition, poses a significant challenge to both patients and healthcare providers worldwide. Conventional pharmacological interventions often prove inadequate in delivering satisfactory relief while carrying the risks of addiction and adverse reactions. In recent years, electric neuromodulation emerged as a promising alternative in chronic pain management. This method entails the precise administration of electrical stimulation to specific nerves or regions within the central nervous system to regulate pain signals. Through mechanisms that include the alteration of neural activity and the release of endogenous pain-relieving substances, electric neuromodulation can effectively alleviate pain and improve patients\' quality of life. Several modalities of electric neuromodulation, with a different grade of invasiveness, provide tailored strategies to tackle various forms and origins of chronic pain. Through an exploration of the anatomical and physiological pathways of chronic pain, encompassing neurotransmitter involvement, this narrative review offers insights into electrical therapies\' mechanisms of action, clinical utility, and future perspectives in chronic pain management.

Optical tracking is a real-time transducer positioning method for transcranial focused ultrasound (tFUS) procedures, but the predicted focus from optical tracking typically does not incorporate subject-specific skull information. Acoustic simulations can estimate the pressure field when propagating through the cranium but rely on accurately replicating the positioning of the transducer and skull in a simulated space. Here, we develop and characterize the accuracy of a workflow that creates simulation grids based on optical tracking information in a neuronavigated phantom with and without transmission through an ex vivo skull cap. The software pipeline could replicate the geometry of the tFUS procedure within the limits of the optical tracking system (transcranial target registration error (TRE): 3.9 ± 0.7 mm). The simulated focus and the free-field focus predicted by optical tracking had low Euclidean distance errors of 0.5±0.1 and 1.2±0.4 mm for phantom and skull cap, respectively, and some skull-specific effects were captured by the simulation. However, the TRE of simulation informed by optical tracking was 4.6±0.2, which is as large or greater than the focal spot size used by many tFUS systems. By updating the position of the transducer using the original TRE offset, we reduced the simulated TRE to 1.1 ± 0.4 mm. Our study describes a software pipeline for treatment planning, evaluates its accuracy, and demonstrates an approach using MR-acoustic radiation force imaging as a method to improve dosimetry. Overall, our software pipeline helps estimate acoustic exposure, and our study highlights the need for image feedback to increase the accuracy of tFUS dosimetry.

Repetitive stimulation procedures are used in neuromodulation techniques to induce persistent excitatory or inhibitory brain activity. The directivity of modulation is empirically regulated by modifying the stimulation length, interval, and strength. However, bidirectional neuronal modulations using ultrasound stimulations are rarely reported. This study presents bidirectional control of epileptiform activities with repetitive transcranial-focused ultrasound stimulations in a rat model of drug-induced acute epilepsy. It is found that repeated transmission of elongated (40 s), ultra-low pressure (0.25 MPa) ultrasound can fully suppress epileptic activities in electro-encephalography and cerebral blood volume measurements, while the change in bursting intervals from 40 to 20 s worsens epileptic activities even with the same burst length. Furthermore, the suppression induced by 40 s long bursts is transformed to excitatory states by a subsequent transmission. Bidirectional modulation of epileptic seizures with repeated ultrasound stimulation is achieved by regulating the changes in glutamate and γ-Aminobutyric acid levels, as confirmed by measurements of expressed c-Fos and GAD65 and multitemporal analysis of neurotransmitters in the interstitial fluid obtained via microdialysis.

Non-invasive ultrasound neuromodulation (USNM) is a powerful tool to explore neural circuits and treat neurological disorders. Due to the heterogeneity of the skull and regional variations in modulation and treatment objectives, it is necessary to develop an efficient and spatially controllable neuromodulation approach. Recently, transcranial focused ultrasound (tFUS) combined with external biomicro/nanomaterials for brain stimulation has garnered significant attention. This study focused on tFUS combined with perfluoropentane (PFP) nanodroplets (NDs) to improve the efficacy and spatial controllability of USNM. The developed two-stage variable pulse tFUS sequence that include the acoustic droplet vaporization (ADV) pulse for vaporizing PFP NDs into microbubbles (MBs) and the USNM sequence for inducing mechanical oscillations of the formed MBs to enhance neuronal activity. Further, adjusting the acoustic pressure of the ADV pulse generated the controllable vaporization regions, thereby achieving spatially controllable neuromodulation. The results showed that the mean densities of c-fos+ cells expression in the group of PFP NDs with ADV (109 ± 19 cells/mm2) were significantly higher compared to the group without ADV (37.34 ± 8.24 cells/mm2). The acoustic pressure of the ADV pulse with 1.98 MPa and 2.81 MPa in vitro generated the vaporization regions of 0.146 ± 0.032 cm2 and 0.349 ± 0.056 cm2, respectively. Under the same stimulation conditions, a larger vaporization region was also obtained with higher acoustic pressure in vivo, inducing a broader region of neuronal activation. Therefore, this study will serve as a valuable reference for developing the efficient and spatially controllable tFUS neuromodulation strategy.

UNASSIGNED: Transcranial focused ultrasound therapy (tcFUS) offers precise thermal ablation for treating Parkinson\'s disease and essential tremor. However, the manual fine-tuning of fiber tracking and segmentation required for accurate treatment planning is time-consuming and demands expert knowledge of complex neuroimaging tools. This raises the question of whether a fully automated pipeline is feasible or if manual intervention remains necessary.
UNASSIGNED: We investigate the dependence on fiber tractography algorithms, segmentation approaches, and degrees of automation, specifically for essential tremor therapy planning. For that purpose, we compare an automatic pipeline with a manual approach that requires the manual definition of the target point and is based on FMRIB software library (FSL) and other open-source tools.
UNASSIGNED: Our findings demonstrate the high feasibility of automatic fiber tracking and the automated determination of standard treatment coordinates. Employing an automatic fiber tracking approach and deep learning (DL)-supported standard coordinate calculation, we achieve anatomically meaningful results comparable to a manually performed FSL-based pipeline. Individual cases may still exhibit variations, often stemming from differences in region of interest (ROI) segmentation. Notably, the DL-based approach outperforms registration-based methods in producing accurate segmentations. Precise ROI segmentation proves crucial, surpassing the importance of fine-tuning parameters or selecting algorithms. Correct thalamus and red nucleus segmentation play vital roles in ensuring accurate pathway computation.
UNASSIGNED: This study highlights the potential for automation in fiber tracking algorithms for tcFUS therapy, but acknowledges the ongoing need for expert verification and integration of anatomical expertise in treatment planning.